CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

212608Orig1s000

MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA/BLA Multi-disciplinary Review and Evaluation NDA 212608 AYVAKIT (avapritinib)

NDA/BLA Multi-Disciplinary Review and Evaluation Application Type New Drug Application (NDA)/New Molecular Entity (NME) Application Number(s) 212608 Priority or Standard Priority Submit Date(s) June 14, 2019 Received Date(s) June 14, 2019 PDUFA Goal Date February 14, 2020 Division/Office DO3/OOD Established/Proper Name Avapritinib (Proposed) Trade Name AYVAKIT Pharmacologic Class Kinase inhibitor Code name BLU-285 Applicant Blueprint Medicines Corporation Dosage form 100 mg, 200 mg, and 300 mg tablets Applicant proposed Dosing 300 mg orally once daily Regimen Applicant Proposed For the treatment of adult patients with unresectable or Indication(s)/Population(s) metastatic gastrointestinal stromal tumor (GIST) who have a platelet-derived growth factor receptor alpha (PDGFA) exon 18 mutation, regardless of prior therapy Applicant Proposed SNOMED CT Indication Gastrointestinal Stromal Tumor Disease Term for each Proposed Indication Recommendation on Approval Regulatory Action Recommended For the treatment of adults with unresectable or metastatic Indication(s)/Population(s) GIST harboring a platelet-derived growth factor receptor alpha (if applicable) (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations Recommended SNOMED CT Indication Disease Gastrointestinal Stromal Tumor Term for each Indication (if applicable) Recommended Dosing 300 mg orally once daily Regimen

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Reference ID: 4543562 NDA/BLA Multi-disciplinary Review and Evaluation NDA 212608 AYVAKIT (avapritinib)

Table of Contents Table of Tables ...... 5 Table of Figures ...... 8 Reviewers of Multi-Disciplinary Review and Evaluation ...... 9 Glossary ...... 10 1 Executive Summary ...... 11 Product Introduction ...... 11 Conclusions on the Substantial Evidence of Effectiveness ...... 12 Benefit-Risk Assessment ...... 13 Patient Experience Data ...... 17 2 Therapeutic Context ...... 18 Analysis of Condition ...... Error! Bookmark not defined. Analysis of Current Treatment Options ...... 18 3 Regulatory Background ...... 19 U.S. Regulatory Actions and Marketing History ...... 19 Summary of Presubmission/Submission Regulatory Activity ...... 19 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ...... 22 Office of Scientific Investigations (OSI) ...... 22 Product Quality ...... 22 Clinical Microbiology ...... 23 Devices and Companion Diagnostic Issues ...... 23 5 Nonclinical Pharmacology/Toxicology...... 25 Executive Summary ...... 25 Referenced NDAs, BLAs, DMFs ...... 28 Pharmacology ...... 28 ADME/PK ...... 35 Toxicology ...... 39 General Toxicology ...... 39 Genetic Toxicology ...... 46 Carcinogenicity ...... 48 Reproductive and Developmental Toxicology ...... 48 Other Toxicology Studies ...... 51 6 Clinical Pharmacology ...... 53 Executive Summary ...... 53 2 Version date: April 2, 2018

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Summary of Clinical Pharmacology Assessment ...... 54 Pharmacology and Clinical Pharmacokinetics ...... 54 General Dosing and Therapeutic Individualization ...... 55 Comprehensive Clinical Pharmacology Review ...... 56 General Pharmacology and Pharmacokinetic Characteristics ...... 56 Clinical Pharmacology Questions ...... 58 7 Sources of Clinical Data and Review Strategy ...... 64 Table of Clinical Studies ...... 64 Review Strategy ...... 66 8 Statistical and Clinical and Evaluation ...... 67 Review of Relevant Individual Trials Used to Support Efficacy ...... 67 BLU-285-1101 (NAVIGATOR) ...... 67 Study Results ...... 74 8.1.3 Integrated Review of Effectiveness ...... 87 8.1.4 Integrated Assessment of Effectiveness ...... 91 8.2 Review of Safety ...... Error! Bookmark not defined. 8.2.1 Safety Review Approach ...... 92 8.2.2 Review of the Safety Database ...... 92 8.2.3 Adequacy of Applicant’s Clinical Safety Assessments ...... 96 8.2.4 Safety Results ...... 96 8.2.5 Analysis of Submission-Specific Safety Issues ...... 126 8.2.6 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ...... 126 8.2.7 Safety Analyses by Demographic Subgroups ...... 126 8.2.10 Safety in the Postmarket Setting ...... 127 8.2.11 Integrated Assessment of Safety ...... 128 8.3 Statistical Issues ...... 130 8.4 Conclusions and Recommendations ...... 130 9 Advisory Committee Meeting and Other External Consultations ...... 133 10 Pediatrics ...... 134 11 Labeling Recommendations ...... 135 11.2 Prescription Drug Labeling ...... 135 12 Risk Evaluation and Mitigation Strategies (REMS) ...... 137 13 Postmarketing Requirements and Commitment ...... 138 14 Division Director (DHOT) ...... Error! Bookmark not defined. 15 Division Director (OCP) ...... Error! Bookmark not defined. 3 Version date: April 2, 2018

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16 Division Director (OB) Comments ...... Error! Bookmark not defined. 17 Division Director (Clinical) Comments ...... 140 18 Office Director (or designated signatory authority) Comments ...... 141 19 Appendices ...... 142 19.2 References ...... Error! Bookmark not defined. 19.3 Financial Disclosure ...... 144 19.4 Nonclinical Pharmacology/Toxicology...... Error! Bookmark not defined. 19.5 OCP Appendices (Technical documents supporting OCP recommendations) ...... 145 19.5.1 ...... 145 19.5.2 ...... 146 19.5.3 Population PK and/or PD Analyses ...... 157 19.5.4 Exposure-Response Analyses ...... 164 19.5.5 ...... 168 19.6 Additional Clinical Outcome Assessment Analyses ...... Error! Bookmark not defined.

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Table of Tables

Table 1. Agents Approved for the Treatment of GIST ...... 19 Table 2: In Vitro Inhibitory Activity of Avapritinib Against a Panel of GIST Relevant Mutants .... 29 Table 3: In Vitro Inhibition of non-D842V PDGFRα Mutations ...... 29 Table 4: Phototoxicity in Mouse Fibroblasts ...... 51 Table 5: General Pharmacology and Pharmacokinetics ...... 56 Table 6: Best overall response for patients with PDGFRα exon 18 non-D842V mutations in Study BLU-285-1101 (N=6)...... 60 Table 7. Dose Modification for Trial BLU-285-1101 ...... 71 Table 8. Expected Confidence Intervals for Group 2, N=31 ...... 72 Table 9. Confidence Intervals for Group 3, N=50 ...... 73 Table 10. Confidence Intervals for Group 1, N=100 ...... 73 Table 11. Protocol Violations ...... 76 Table 12. Treatment Discontinuation, BLU-285-1101 ...... 77 Table 13. Study Discontinuation, BLU-285-1101 ...... 78 Table 14. Demographic Factors, GIST with a PDGFRα Exon 18 Mutation ...... 79 Table 15. Baseline Disease Characteristics, GIST with a PDGFRα Exon 18 Mutation ...... 80 Table 16. Prior Therapy, GIST with a PDGFRα Exon 18 mutation ...... 81 Table 17. Demographic Factors, GIST with a PDGFRα D842V Mutation ...... 82 Table 18. Baseline Disease Characteristics, GIST with a PDGFRA D842V Mutation ...... 83 Table 19. Prior Therapy, GIST with a PDGFRα D842V Mutation ...... 84 Table 20. ORR and DOR Results for Patients with GIST Harboring a PDGFRα Exon 18 Mutation 85 Table 21. Subgroup Analyses by Age, Gender, and Race ...... 86 Table 22. Subgroup Analyses by Baseline Disease Characteristics ...... 87 Table 23. Demographics for Patients from Trial BLU-285-1002 ...... 90 Table 24. ORR for Patients with GIST who Harbor a D842V mutation from Study BLU-285-1002 ...... 90 Table 25. Safety Populations...... 93 Table 26. Duration of Exposure to Avapritinib in the Safety Population ...... 93 Table 27. Planned Total Daily Dose of Avapritinib in The Safety Population ...... 94 Table 28. Demographics of the Safety Populations ...... 95 Table 29. Primary Reason for All Deaths ...... 97 Table 30. Deaths Occurring within 30 Days of the Last Dose of Avapritinib ...... 98 Table 31. Serious Adverse Events by System Organ Class ...... 102 Table 32: Serious Adverse Events by Preferred Term ...... 103 Table 33. Treatment Interruptions, reductions or withdrawals ...... 104 Table 34. TEAEs Leading to Dose Interruption ...... 104 Table 35. TEAEs Leading to Dose Reductions ...... 105 Table 36. TEAEs Leading to Dose Discontinuations ...... 106 Table 37. Intracranial Bleeding ...... 107 Table 38. Preferred terms included in CNS Effects ...... 108 Table 39. CNS Effects ...... 110 5 Version date: April 2, 2018

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Table 40. Cognitive Impairment ...... 111 Table 41. Cognitive Impairment by Age Group ...... 111 Table 42. Speech Effects ...... 113 Table 43. Mood Effects ...... 113 Table 44. Sleep Effects ...... 114 Table 45. Hallucinations ...... 114 Table 46. Preferred terms included in KIT Class Effects ...... 115 Table 47. KIT Associate Adverse Events ...... 117 Table 48. Edema ...... 117 Table 49. Myelosuppression ...... 118 Table 50. Rash ...... 119 Table 51. Skin Pigment Changes ...... 120 Table 52. Cardiac Disorders ...... 121 Table 53. Thyroid disorders ...... 121 Table 54. Common Treatment Emergent Adverse Events ...... 122 Table 55. Laboratory Abnormalities Occurring in >10% of Patients ...... 124 Table 56. Vital Sign Abnormalities ...... 125 Table 57. Point Estimates and the 90% CIs ...... 125 Table 58. TEAES with a Difference of Incidence Among Racial groups ...... 127 Table 68. Clinical PK Studies in NDA 212608 Submission ...... 146 Table 69. Summary and Statistical Comparison of Avapritinib Pharmacokinetic Parameters After Administration of Avapritinib 200 mg as 1 × 200 mg Tablet or 2 × 100 mg Capsules Under Fasted Conditions (Study BLU-285-0101) ...... 148 Table 70. Summary of Avapritinib PK on Cycle 1 Day 1 Following Avapritinib Single-dose (Upper Table) and on Cycle 1 Day 15 Following Repeat-dose (Lower Table) in Patients with GIST (Study BLU-285-1101) ...... 151 Table 71. Summary of BLU111207 PK on Cycle 1 Day 1 Following Avapritinib Single-dose (Upper Table) and on Cycle 1 Day 15 Following Repeat-dose (Lower Table) in Patients with GIST (Study BLU-285-1101) ...... 152 Table 72. Summary of BLU111208 PK on Cycle 1 Day 1 Following Avapritinib Single-dose (Upper Table) and on Cycle 1 Day 15 Following Repeat-dose (Lower Table) in Patients with GIST (Study BLU-285-1101) ...... 153 Table 73: Parameter Estimates of the Final PopPK Model ...... 160 Table 74: Primary Analysis: Summary of Best Response by Central Radiology per mRECIST 1.1 (Safety Population: PDGFRA Exon 18 Patients) ...... 165 Table 75: Baseline Covariates across 4 Exposure Quartiles in the Exposure-Efficacy Analyses...... Error! Bookmark not defined. Table 76: Baseline Covariates across 4 Exposure Quartiles in the Exposure-Safety Analyses. .. 167 Table 77. Comparison of PBPK predicted and observed PK parameters for avapritinib ...... 173 Table 78. PBPK predicted and observed Cmax and AUC values of avapritinib in absence and presence of itraconazole ...... 176 Table 79. PBPK predicted and observed Cmax and AUC values of avapritinib in absence and presence of rifampin ...... 177

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Table 80. PBPK predicted Cmax and AUC ratios for avapritinib following single-dose and at steady-state in the presence of CYP3A4 inhibitors using healthy population model ...... 178 Table 81. Comparison of population model predictions for Cmax and AUC ratios for avapritinib steady-state in the presence of CYP3A4 modulators ...... 179

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Table of Figures

Figure 1: Activity of Avapritinib on KIT Exon 17 Mutants in HMC1.2 and P815 Cells ...... 30 Figure 2: Activity of Avapritinib on Mutant PDGFRα D842V in CHO-K1 Cells ...... 31 Figure 3: Anti-tumor Activity and Body Weight Changes Following Avapritinib in a Mouse P815 Mastocytoma Tumor Model ...... 32 Figure 4: Anti-tumor Activity of Avapritinib in an Imatinib-resistant Patient-derived Xenograft Model of Human GIST ...... 33 Figure 5: Anti-tumor Activity and Inhibition of Mutant KIT in a Patient-derived Xenograft Model of Human GIST ...... 33 Figure 6: Distribution of KIT mutated exons and responses - 4L+ population in Study BLU-285- 1101 (N=110)...... Error! Bookmark not defined. Figure 7. Study Scheme BLU-285-1101 ...... 67 Figure 8: Effect of Formulation (Capsule versus 100 mg Tablet) on Avapritinib Dose-normalized Cmax and AUC (Study BLU-285-1101) ...... 149 Figure 9: Mean (+Standard Deviation) Plasma Concentration-Time Profiles of Avapritinib in Patients with GIST (Study BLU-285-1101) ...... 154 Figure 10: Mean (+ Standard Deviation) Plasma Concentration-Time Profiles of BLU111207 and BLU111208 in Patients with GIST (Study BLU-285-1101) ...... 155 Figure 11: Power Analysis of Avapritinib Systemic Exposure vs Dose Following Administration of Avapritinib in Patients With GIST (Study BLU-285-1101) ...... 156 Figure 12: Schematic of the Base Population PK Model...... 157 Figure 13: Goodness of Fit Plots of the Final Model ...... 158 Figure 14: Visual Predictive Checks of Avapritinib Concentration-Time Data Stratified by Population...... 159 Figure 15: Covariate Effects on avapritinib Exposuer (AUC0-35 days or Cmax) ...... 161 Figure 16: Comparison of post-hoc CL across hepatic function...... 162 Figure 17: Comparison of post-hoc CL across renal function...... 163 Figure 18: Observed Avapritinib Concentration-Time Profile across PPI Usage...... 164 Figure 19: Boxplot of Best Overall Response vs Cave_ss...... 166 Figure 20: Relationship between avapritinib Exposure and ORR in Patients with 4L+ GIST Tumor...... Error! Bookmark not defined. Figure 21: Relationship between Avapritinib Exposure and Grade 3/4 AE and Cognitive Effects...... 167 Figure 22. PBPK predicted and observed PK profiles of avapritinib ...... 172 Figure 23. PBPK predicted and observed PK profiles of avapritinib following multiple dosing . 175 Figure 24. PBPK predicted hepatic CYP3A4 values following multiple dosing of avapritinib ..... 175 Figure 25. PBPK predicted and observed PK profile of avapritinib in absence and presence of itraconazole...... 176

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Reviewers of Multi-Disciplinary Review and Evaluation

Regulatory Project Manager Idara Udoh Nonclinical Reviewer Alexander Putman Nonclinical Team Leader Whitney Helms Office of Clinical Pharmacology Reviewer(s) Wentao Fu, Youwei Bi, Manuela Grimstein Office of Clinical Pharmacology Team Leader(s) Jeanne Fourie Zirkelbach, Jiang Liu, Xinyuan Zhang Clinical Reviewer Christy Osgood Clinical Team Leader Ashley Ward Safety Analyst (if applicable) Yutao Gong Statistical Reviewer Pourab Roy Statistical Team Leader Pallavi Mishra-Kalyani Associate Director of Labeling Stacy Shord Cross-Disciplinary Team Leader Ashley Ward Division Director (DHOT) John Leighton Division Director (OCP) Atiqur Rahman Division Director (OB) Rajeshwari Sridhara Division Director (DO3) Steven Lemery Office Director (or designated signatory authority) Marc Theoret

Additional Reviewers of Application OPQ Xing Wang, Anamitro Banerjee, Raymond Frankewich, Suong Tran, Parnali Chatterjee, Banu Zolnik, James Laurenson, Shamika Brooks Microbiology Diane Goll, Rakhi Shah OPDP Robert Nguyen, Susannah O’Donnell OSI Yang-Min Ning, Aisha Johnson, Kassa Ayalew OSE/DEPI Richard Swain OSE/DMEPA Janine Stewart, Chi-Ming Tu OSE/DRISK Elizabeth Everhart, Till Olikal Other Rosane Charlab Orbach, Oluseyi Adeniyi OPQ=Office of Pharmaceutical Quality OPDP=Office of Prescription Drug Promotion OSI=Office of Scientific Investigations OSE= Office of Surveillance and Epidemiology DEPI= Division of Epidemiology DMEPA=Division of Medication Error Prevention and Analysis DRISK=Division of Risk Management

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Glossary

ADME absorption, distribution, metabolism, excretion BLA biologics license application CDER Center for Drug Evaluation and Research CDRH Center for Devices and Radiological Health CFR Code of Federal Regulations CMC chemistry, manufacturing, and controls CRF case report form DHOT Division of Hematology Oncology Toxicology ECG electrocardiogram eCTD electronic common technical document FDA Food and Drug Administration GCP good clinical practice IND Investigational New Drug ISE integrated summary of effectiveness ISS integrated summary of safety ITT intent to treat MedDRA Medical Dictionary for Regulatory Activities NCI-CTCAE National Cancer Institute-Common Terminology Criteria for Adverse Event NDA new drug application NME new molecular entity OPQ Office of Pharmaceutical Quality OSE Office of Surveillance and Epidemiology OSI Office of Scientific Investigation PD pharmacodynamics PI prescribing information PK pharmacokinetics PMC postmarketing commitment PMR postmarketing requirement PREA Pediatric Research Equity Act PRO patient reported outcome REMS risk evaluation and mitigation strategy SAE serious adverse event SAP statistical analysis plan TEAE treatment emergent adverse event

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1 Executive Summary

Product Introduction

On June 14, 2019, in accordance with Section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act and Title 21 of the Code of Federal Regulations (CFR) Part 314, Blueprint Medicines Corporation (hereafter the Applicant) submitted New Drug Application (NDA) 212608 seeking regular approval of avapritinib for the following proposed indication:

the treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumors (GIST) who have a platelet-derived growth factor receptor alpha (PDGFRα) exon 18 mutation, (b) (4) PDGFRα D842V mutation, regardless of prior therapy.

Avapritinib, a new molecular entity, is a kinase inhibitor with the chemical name (S)-1-(4- fluorophenyl)-1-(2-(4-(6-(1-methyl-1Hpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin- yl)pyrimidin-5-yl)ethan-1-amine. The molecular formula is C26H27FN10, and the molecular weight is 498.57 g/mol. Avapritinib has the following chemical structure:

Avapritinib tablets are for oral use. Tablets will be marketed in three strengths that contain 100 mg, 200 mg, or 300 mg of avapritinib per tablet. The tablets contain the following inactive ingredients in the tablet core: copovidone, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated; the film coat contains polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The blue printing ink contains ammonium hydroxide, black iron oxide, esterified shellac, FD&C blue 1, isopropyl alcohol, n-butyl alcohol, propylene glycol, and titanium dioxide.

The proposed dosing schedule is 300 mg administered orally once daily until disease progression or unacceptable toxicity.

On September 19, 2019, during the review of the NDA, FDA issued a “Proprietary Name Request – Conditionally Acceptable” letter, stating that the Applicant’s proposal for the 11 Version date: April 2, 2018

Reference ID: 4543562 NDA/BLA Multi-disciplinary Review and Evaluation NDA 212608 AYVAKIT (avapritinib)

proprietary name, AYVAKIT, was found to be conditionally acceptable.

Conclusions on the Substantial Evidence of Effectiveness

The primary review team has concluded, and I concur, that the information submitted by the Applicant has provided substantial evidence for the effectiveness of avapritinib for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRα) exon 18 mutation, including PDGFRα D842V mutations. The review team recommends, and I concur, that the indication be granted under the regular approval pathway.

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Benefit-Risk Assessment

Benefit-Risk Summary and Assessment Avapritinib is a small molecule that inhibits multiple receptor tyrosine kinases, including KIT and PDGFRα. Approximately 10% of patients with GIST harbor mutations in PDGFRα that are central to disease biology, predominantly D842V. The Applicant’s proposed indication assessed in this review is for the treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumors (GIST) who have a platelet- (b) (4) derived growth factor receptor alpha (PDGFRα) exon 18 mutation, PDGFRα D842V mutation, regardless of prior therapy. The benefit-risk assessment supports regular approval in this indication, although the wording will be changed slightly to be consistent with FDA labeling standards.

This conclusion is based on the results of a single open-label, single arm study of avapritinib in patients with GIST (the NAVIGATOR trial). Patients received avapritinib 300 mg or 400 mg orally once daily until disease progression or unacceptable toxicity. The trial initially enrolled patients at a starting dose of 400 mg, which was later reduced to 300 mg due to toxicity. The recommended dose for marketing was determined to be 300 mg once daily. As there was no apparent difference in overall response rate (ORR) between patients who received 300 mg daily compared to those who received 400 mg daily, these patients were pooled for the efficacy evaluation. The major efficacy outcome measure was ORR based on disease assessment by independent radiological review using modified RECIST v1.1 criteria, in which lymph nodes and bone lesions were not target lesions and progressively growing new tumor nodules within a pre-existing tumor mass was progression. An additional efficacy outcome measure was duration of response (DOR).

Patients with unresectable or metastatic GIST harboring a PDGFRα exon 18 mutation were identified by local or central assessment using a PCR- or NGS-based assay. The assessment of efficacy was based on a total of 43 patients, including 38 patients with PDGFRα D842V mutations. The median duration of follow up for patients with PDGFRα exon 18 mutations was 10.6 months (range: 0.3 to 24.9 months). The ORR was 84% (95% CI: 69, 93) in patients with PDGFRα exon 18 mutations, and 89% (95% CI: 75, 97) in the subset with PDGFRα D842V mutations. Most responses were partial responses. Median duration of response was not reached; 61% of the responding patients with an exon 18 mutation had a response lasting 6 months or longer, similar in the subset with D842V mutations.

Tyrosine kinase inhibitors targeting KIT and PDGFR have been used successfully to treat patients with GIST, as evidenced by the previous approvals of imatinib, sunitinib, and regorafenib in the 1st, 2nd, and 3rd line setting, respectively. However, GIST with PDGFRα D842V mutations represents a relatively rare tumor for which there are no effective therapies, as the mutation confers resistance to all three available therapies. The high response rate observed in this population on the NAVIGATOR trial is evidence of the ability of avapritinib to effectively inhibit PDGFRα with D842V mutations. Other PDGFRα mutations in exon 18 that are not D842V substitutions also occur in GIST, albeit even more rarely. In the 5 patients with non-D842V exon 18 mutations treated on the study, avapritinib yielded an ORR of 40%. After analyzing all available clinical and 13 Version date: April 2, 2018

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nonclinical data regarding the activity of avapritinib and of available therapies in patients with non-D842V exon 18 mutations, and considering disease biology, the review team has recommended that the indication be granted to patients with any PDGFRα exon 18 mutation, in line with the recommendations in FDA’s guidance document entitled, “Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease”, and I concur. Given what is known about the central importance of the mechanism of action in GIST biology, the unmet need and rarity of the patient population, and the high response rate observed, I also agree with the review team that the data generated by the Applicant support Regular Approval in this indication.

The safety of avapritinib has been characterized in > 300 patients. The most common adverse reactions (incidence ≥ 20%) are edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation, abdominal pain, constipation, rash and dizziness. Facial edema is also frequently noted. Most of these adverse reactions are not serious or severe. Avapritinib appears to carry a risk of CNS effects, which occurred in 58% of patients who received avapritinib across the development program. The most frequent CNS effects were related to cognitive impairment, which occurred in 41% of patients, although only 3.6% of patients experienced Grade ≥ 3 cognitive impairment. Avapritinib also appears to carry a risk of intracranial hemorrhage, which occurred in 1% of patients with GIST and 3% of patients with any malignancy across the development program. These risks are acceptable for a patient population that has a serious and life-threatening disease, and for whom currently available therapies are ineffective. However, the Applicant will be issued post-marketing requirements to further describe the incidence, risk factors for, and effectiveness of management guidelines for these toxicities to further inform patients, practitioners, and product labeling.

Dimension Evidence and Uncertainties Conclusions and Reasons • Annual incidence of GIST in the U.S. is 4000-6000 cases per year. GIST is a serious disease that is frequently • Overall 5-year survival rate for GIST is 76%; drops to 48% for patients fatal. with unresectable or metastatic GIST. Analysis of • Approximately 80% of GISTs have a mutation in KIT; approximately Mutually exclusive mutations in KIT and Condition 10% have a mutation in PDGFRα (mutually exclusive). PDGFRα are central to GIST pathogenesis. • PDGFRα alterations in GIST cluster in Exon 18, majority (~75%) are D842V point mutations. • Imatinib is approved for unresectable or metastatic KIT-mutated GIST There are no FDA-approved therapies for Current and as adjuvant treatment following resection of KIT-mutated GIST PDGFRα-mutated GIST. Treatment • Sunitinib is approved for GIST after disease progression on or Options intolerance to imatinib This population has an unmet medical need. 14 Version date: April 2, 2018

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Dimension Evidence and Uncertainties Conclusions and Reasons • Regorafenib is approved for locally advanced, unresectable, or metastatic GIST after previous treatment with imatinib and sunitinib • Literature reports suggest that patients with a D842V mutation in PDGFRα are intrinsically resistant to imatinib, sunitinib, and regorafenib. • The ORR of avapritinib in 43 patients with GIST harboring a PDGFRα Avapritinib yielded durable responses in 84% exon 18 mutation (38 of which were a D842V mutation) was 84% of patients with PDGFRα exon 18 mutated (95% CI: 69, 93). This included 3 complete and 33 partial responses. GIST. Given the rarity of this patient Median duration of response was not reached (range 1.9+ months to population, the magnitude of the effect size, 20.3+ months). 61% of responders had a response that lasted ≥ 6 and the lack of effective therapies for this Benefit months. patient population, the FDA considers this effect to be well-characterized. • A randomized study of avapritinib versus regorafenib in patients with GIST previously treated with imatinib and 1 or 2 other tyrosine kinase inhibitors is ongoing, with a primary endpoint of PFS. • The most common adverse reactions (incidence ≥ 20%) are edema, The overall short-term safety profile of nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased avapritinib is acceptable for the treatment of a appetite, diarrhea, hair color changes, increased lacrimation, serious and life-threatening condition such as abdominal pain, constipation, rash and dizziness. GIST. Further information about the incidence, • Avapritinib appears to carry a risk of CNS effects, which occurred in and risk factors for CNS effects and intracranial 58% of patients who received avapritinib across the development hemorrhage are needed from randomized Risk and Risk program. The most frequent CNS effects were related to cognitive studies that can help distinguish events related Management impairment, which occurred in 41% of patients, although only 3.6% of to avapritinib from background and further patients experienced Grade ≥ 3 cognitive impairment. inform product labeling. • Avapritinib appears to carry a risk of intracranial hemorrhage, which occurred in 1% of patients with GIST and 3% of patients with any A patient medication guide will be provided to malignancy across the development program. inform and educate patients of the risks of CNS effects and intracranial hemorrhage and when to seek immediate medical attention. Labeling 15 Version date: April 2, 2018

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Dimension Evidence and Uncertainties Conclusions and Reasons should include warnings for CNS effects and intracranial hemorrhage, and instructions for monitoring and dose modifications for toxicities.

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Patient Experience Data

Patient Experience Data Relevant to this Application (check all that apply) □ The patient experience data that were submitted as part of the Section of review where application include: discussed, if applicable [e.g., Section 6.1 Study endpoints] □ Clinical outcome assessment (COA) data, such as □ Patient reported outcome (PRO) □ Observer reported outcome (ObsRO) □ Clinician reported outcome (ClinRO) □ Performance outcome (PerfO) □ Qualitative studies (e.g., individual patient/caregiver interviews, focus group interviews, expert interviews, Delphi Panel, etc.) □ Patient-focused drug development or other stakeholder meeting summary reports □ Observational survey studies designed to capture patient experience data Natural history studies □ □ Patient preference studies (e.g., submitted studies or scientific publications) □ Other: (Please specify): □ Patient experience data that were not submitted in the application, but were considered in this review: □ Input informed from participation in meetings with patient stakeholders □ Patient-focused drug development or other stakeholder meeting summary reports □ Observational survey studies designed to capture patient experience data □ Other: (Please specify): X Patient experience data was not submitted as part of this application.

X Cross Discipline Team Leader (Ashley Ward, M.D., this section was finalized Dec 24, 2019)

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2 Therapeutic Context

Analysis of Condition

Gastrointestinal stromal tumors (GIST) are the most common nonepithelial neoplasms affecting the gastrointestinal tract and are most commonly located in the stomach and proximal small intestine (Riettinen M, 2001). The annual incidence of GIST in the United States is between 4,000 to 6,000 cases per year. The overall 5-year survival rate for GIST is 76%; however, patients with unresectable or metastatic GIST have a 48% 5-year survival (Ma G, 2015). Approximately 90% of GISTs have a mutation in either v-KIT Hardy-Zuckerman 4 Feline Sarcoma Viral Oncogene Homolog (KIT) or the related protein platelet-derived growth factor alpha (PDGFRα). Mutations in KIT lead to constitutive activation. The majority of KIT mutations are found in exon 11; however, mutations in exons 9, 13, or 17 have also been described (CioffiA, 2015). For tumors that do not have a KIT mutation, the most common mutation described is a PDGFRα D842V mutation. Up to ten percent of GISTs are driven by PDGFRα D482V mutations.

Analysis of Current Treatment Options

Surgical resection followed by adjuvant treatment with the tyrosine kinase inhibitor (TKI), imatinib for 36 months is the primary therapy for patients with high-risk localized GIST. For patients with unresectable or metastatic GIST, initial therapy is with KIT-directed TKIs including imatinib, sunitinib, and regorafenib. Treatment with first-line therapy, imatinib, is associated with sustained responses in 50% of patients with metastatic disease.

There are no therapies specifically approved for GIST harboring a PDGFRα D842V mutation. Retrospective analyses suggest that PDGFRα D842V mutation-positive GIST responds poorly to imatinib, regorafenib, and sunitinib. Two retrospective analyses genotyped 3,975 patients with GIST and identified 60 patients with PDGFRα mutations. Of these 60 patients, 32 tumors harbored a PDGFRα D842V mutation and the remainder had a mutation in PDGFRα exons 4, 12, or 18. Of these 32 patients, zero [95% confidence interval (CI): 0, 11%] had a response to imatinib according to Response Evaluation Criteria in Solid Tumors (RECIST). When imatinib, sunitinib, and other TKIs were used in second-line treatment of patients with GIST tumors that harbor a PDGFRα D842V mutation, the median PFS was only 2.1 months (Cassier PA, 2012). Additionally, in a study conducted by Yoo et. al., 18 patients with PDGFRα-mutant GIST were treated with imatinib; 9 of these patients had a PDGFRα D842V mutation and 5 of the patients with PDGFRα D842V mutations were evaluable for response. None of the 5 patients responded to imatinib as first-line treatment or to sunitinib as second-line treatment per RECIST (Yoo C, 2015).

Table 1 displays the currently approved therapies for unresectable or metastatic GIST.

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Table 1. Agents Approved for the Treatment of GIST

Endpoint Used to Agent Indication Treatment Effect Establish Efficacy Unresectable and/or OS 400 mg vs 800 mg 49.0 vs 48.7 months metastatic GIST that is Kit P=0.98 Imatiniba (CD117) positive PFS 400mg vs 800 mg 18.9 vs 23.2 months ORR 400 mg vs 800 mg 51.4% vs 53.9%

RFS 12 months of 58% vs 75% HR (95%CI): 0.46 (0.32, 0.65) Adjuvant treatment of therapy versus RFS 36

patients following months treatment Imatinib resection of Kit (CD117) OS 12 months of Median OS NR in either group positive GIST therapy versus OS 36 13% deaths vs 6% deaths months treatment HR (95% CI): 0.45 (0.22, 0.89)

GIST after disease PFS versus placebo HR(95%CI): 0.33 (0.24,0.47) Sunitinib progression on or intolerance to imatinib ORR versus placebo 6.8% (95% CI 3.7,11.1) vs. 0

Locally advanced, OS versus placebo NR vs NR unresectable, or HR (95%CI): 0.77 (0.42, 1.41) Regorafenib metastatic GIST who have 4.8 vs 0.9 months been previously treated PFS versus placebo with imatinib and sunitinib HR (95% CI): 0.27 (0.19, 0.39)

Sources: Summarized from the USPI for imatinib; sunitinib; and regorafenib Abbreviations: OS, Overall Survival; PFS, Progression Free Survival; ORR, Objective Response Rate; NR, not reached; CI, confidence interval; RFS, recurrence-free survival; TTP, Time to Tumor Progression a. initially received accelerated approval based on ORR, conversion to full approval based on PFS and OS b. Based on retrospective analysis of 3975 patients with GIST, which identified 60 patients with PDGFRα mutations. Of these 60 patients, 37 tumors harbored a PDGFRα D842V mutation c. Based on patients treated second line with sunitinib

3 Regulatory Background

U.S. Regulatory Actions and Marketing History

Avapritinib is not currently marketed in the United States

Summary of Presubmission/Submission Regulatory Activity

• On June 9, 2015, IND 125379 was submitted to the Division of Oncology Products 2 (DOP2) containing Protocol BLU-285-1101, a dose-finding study in patients with GIST and other relapsed and refractory solid tumors. The IND was allowed to proceed on July 9, 2015.

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• On January 6, 2016, avapritinib was granted orphan drug designation for the treatment of GIST. • On October 4, 2016, BLU-285 was granted Fast Track designation (FTD) for the following indications: o Treatment of patients with unresectable or metastatic GIST that progressed following treatment with imatinib and a second tyrosine kinase inhibitor to demonstrate a statistically robust and clinically meaningful improvement in progression-free survival (PFS) compared with available therapy o Treatment of patients with unresectable or metastatic GIST harboring a PDGFRα D842V mutation regardless of prior therapy to demonstrate a statistically robust and clinically meaningful improvement in PFS compared with available therapy. • On April 19, 2017, a Type B End-of-Phase 1 (EOP1) meeting was held to discuss the clinical development program for avapritinib for the treatment of patients with GIST harboring a PDGFRα D842V mutation, regardless of prior therapy. The following key points were made: o Patients with unresectable GIST harboring a PDGFRα D842V mutation regardless of prior therapy represent a severe and life-threatening condition with an unmet medical need. o Overall response rate (ORR) and DOR data from 50 patients with unresectable or metastatic GIST harboring the PDGFRα D842V mutation in a single-arm trial may be sufficient to provide substantial evidence of effectiveness in support of a request for accelerated approval. The magnitude of the ORR as well as the DOR in these 50 patients will be important in determining whether the data is sufficient to support an NDA submission. o Whether the development program for avapritinib for the treatment of patients with unresectable or metastatic GIST harboring the PDGFRα D842V will support accelerated or regular approval will be determined once more data is available. Factors influencing these decisions are as follows: • Whether the results of the retrospective natural history study, BLU-285-1002, being conducted by Blueprint are consistent with the results from published studies showing that patients with PDGFRα D842V mutation positive GIST have very low response rates to FDA approved therapies for GIST. • Whether the ORR in patients with GIST with PDGFRα D842V has a lower limit of the 95% confidence interval that excludes the observed response rate with available therapies and is clinically meaningful with a sufficient duration of follow-up (all patients followed for ≥ 6 months since onset of response). • On June 1, 2017, BLU-285 was granted breakthrough designation for the following indication: o Treatment of patients with unresectable or metastatic GIST harboring the PDGFRα D842V mutation. (b) (4) •

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o An initial NDA submission for patients with unresectable or metastatic GIST harboring a PDFGRα D842V mutation regardless of prior therapy may be appropriate following completion of Study BLU-285-1101 and the natural history study. It was noted that there were only three patients with PDGFRα non-D842V mutations enrolled in the clinical trial which may not provide sufficient information for approval in the entire PDGFRα exon 18 population. o Blueprint stated that enrollment of patients with D842V mutations was slower than anticipated and wondered if an NDA submitted with a smaller data set would be acceptable. FDA expressed concern that a smaller data set may not contain sufficient information regarding the safety and efficacy of avapritinib in the proposed indication to support a regulatory decision. Blueprint and FDA discussed alternatives to increase enrollment, including just in time enrollment of patients or expanded access. FDA stated that for patients enrolled under expanded access programs, Blueprint could collect images to confirm ORR and DOR. (b) (4) o

• On August 3, 2018, Blueprint submitted a Type C meeting request to continue discussions regarding the avapritinib clinical development and registration program. FDA issued final written responses on September 17, 2018, which included the following comments: o The proposed NDA includes an indication of GIST harboring PDGFRα exon 18 mutations. There are only four patients with PDGFRα non-D842V mutations which may not provide sufficient information for approval in the entire PDGFRα exon 18 population. (b) (4) o

• On February 6, 2019, a Type B pre-NDA meeting was held. The following key agreements were made: (b) (4) o

o FDA agreed with the proposed data cut-off date of November 16, 2018, for the initial NDA filing. o FDA agreed that the results of BLU-285-1101 support the filing of an NDA for avapritinib in patients with unresectable or metastatic GIST harboring PDGFRA exon (b) (4) 18 mutation, including PDGFRA D842V mutation regardless of prior therapy. FDA noted the limited number of patients who harbor non-PDGFRα D842V mutations (n=5); whether the data from these few

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patients would support an indication that includes all PDGFRα exon 18 mutations will be determined during review of the submission. • On June 14, 2019 the NDA was submitted, using a data cut of November 16, 2018. The Applicant requested priority review, which was granted by the FDA on August 1, 2019.

4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety

Office of Scientific Investigations (OSI)

Clinical data from an ongoing, open-label study (BLU-285-1101) were submitted to the Agency in support of this NDA for avapritinib for the above proposed indications. Three clinical investigators, Dr. Robin Jones (Site 1101), Dr. Margaret Von Mehren (Site 2001), and Dr. Michael Heinrich (Site 2003), the study sponsor, and the contract research organization (CRO) which performed independent review of tumor assessment scans, were selected for clinical inspections.

The inspections verified the Applicant’s submitted clinical data with source records at the clinical investigator and CRO sites. There were no objectionable observations identified in the sponsor inspection. Based on the results of these inspections, the data derived from these clinical investigator sites and the CRO appear to be acceptable and supportive of this NDA for avapritinib.

Product Quality

Avapritinib drug substance is a white to off-white to yellow crystalline solid. The proposed (b) (4) manufacturing process . Avapritinib has one chiral center. (b) (4) Avapritinib is manufactured

Avapritinib drug substance is controlled using a specification that contains tests for Identity by IR spectrum, Assay and impurities using HPLC, (b) (4) (b) (4) undesired , residual solvents, , solid state form using (b) (b) (4) (b) (4) XRPD, and particle size distribution (D10: NLT (4) μm; D50: μm; D90: NMT μm). (b) (4) Avapritinib drug substance is packaged in . The retest period for avapritinib (b) (b) (4) drug substance is (4) months, stored at . The drug substance information in the NDA has been reviewed and found adequate.

Avapritinib drug product is an immediate release tablet for oral administration. The tablets are (b) (4) available in 100 mg, 200 mg, and 300 mg strengths. All tablet strengths are proportional in active and inactive ingredients. The 22 Version date: April 2, 2018

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(b) (4) proposed tablet has a high drug load ) and contains common excipients for sold oral (b) (4) (b) (4) dosage form: microcrystalline cellulose , copovidone , croscarmellose sodium (b) (4) (b) (4) (b) (4) , magnesium stearate and . The drug product specification includes appearance, identity, assay, content uniformity, degradation products, (b) (4) dissolution and . There are no specified degradants. The applicant conducted a risk analysis for elemental impurities as per ICH Q3D and concluded the potential risk of elemental impurities in avapritinib tablets is low and no additional controls are required. Analytical methods are adequately validated. Avapritinib tablets (30 counts) are packaged in (b) (4) (b) (4) 60 cc HDPE bottles with foil induction seal liner and 0.5 g desiccant canister. Based on 18 months stability data and Biopharm recommendation, an 18- month shelf-life is granted for the 100 mg and 200 mg strengths. A 12-month shelf-life is granted for the 300 mg strength. The NDA is recommended for APPROVAL from the drug product perspective.

Clinical Microbiology

(b) (4) Solid oral dosage form. Process is No micro testing in drug product release specs. Micro test results provided for all batch analyses and was found to be adequate.

Devices and Companion Diagnostic Issues

(b) (4)

(b) (4)

Because these mutations are rare (and occur in a rare tumor type) and there is lack of available therapies for this patient population, the PDGFRα exon 18 application may be approved with a PMC to complete the development of the CDx for the D842V somatic mutation (see section 13 for details). This approach is consistent with FDA actions taken in other applications (e.g., refer to publicly available approval letters with PMCs for crizotinib [ROS1 indication], entrectinib, larotrectinib, and pembrolizumab [MSI-H indication]).

An in vitro companion diagnostic test also will not be available to test for non-D842V exon 18 mutations at the time of approval. Development of a test in this setting will be challenging given that it is expected that only 30 to 60 patients or less a year will be identified as having a non-D842V exon 18 mutation. The remaining exon 18 mutations are a diverse subset of mutations including substitutions, in-frame deletions, and deletions/insertions of various lengths. Given the diversity and rarity of these mutations it will be difficult to obtain enough and appropriate samples to develop a clinically validated assay for non-D842V exon 18 mutations.

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Appears this way on original

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5 Nonclinical Pharmacology/Toxicology

Executive Summary

Avapritinib is a tyrosine kinase inhibitor that targets PDGFRα, PDGFRα D842 mutants, and other exon 18 mutants, as well as KIT and multiple KIT exon 11, 11/17, and 17 mutants; the established pharmacological class is kinase inhibitor. Certain mutations in PDGFRα and KIT can result in the autophosphorylation and constitutive activation of these receptors which can support cell proliferation in GIST. Specifically, avapritinib inhibited the kinase activity of wild- type PDGFRα (IC50 value of 1.4 nM) and PDGFRα D842 mutants (Y, I, and V with IC50 values of 0.12, 0.13, and 0.24 nM, respectively). Avapritinib also demonstrated activity against multiple KIT exon 11, 11/17, and 17 mutants with IC50 values ≤ 25 nM. Although inhibition of wild-type KIT occurred at an approximate 3-fold higher concentration (IC50 value of 73 nM) compared to the KIT mutants, in a separate kinome screen, avapritinib bound to wild-type KIT, wild-type PDGFRα, PDGFRβ, and colony stimulating factor 1 receptor (CSF1R) with Kds ≤ 17 nM. In in vitro cellular assays, avapritinib inhibited the autophosphorylation of KIT D816V and PDGFRα D842V mutants associated with resistance to FDA-approved approved kinase inhibitors, with IC50s of 4 nM and 30 nM, respectively. The M499 metabolite of avapritinib also inhibited KIT D816V phosphorylation with an IC50 approximately 15 nM, suggesting that it is an active metabolite; however, the predicted free Cmax of the more active M499 enantiomer is less than 2 nM, suggesting this metabolite may not contribute significantly to the activity of avapritinib despite having similar activity to the parent based on available data. Avapritinib also exhibited anti- tumor activity in a mouse mastocytoma tumor model with an activating KIT exon 17 mutation and in an imatinib-resistant patient-derived xenograft model of human GIST with activating KIT exon 11/exon17 mutations.

The Applicant conducted stand-alone GLP-compliant safety pharmacology studies in rats and dogs to assess the effect of avapritinib on the central nervous system, pulmonary function, and the cardiovascular system. In a modified Irwin test, rats administered 45 mg/kg/day of oral avapritinib for 15 consecutive days showed an increased sensitivity to stimuli and tremors. To further investigate these adverse findings, Blueprint conducted a non-GLP compliant electroencephalographic (EEG) assessment in rats administered up to 50 mg/kg/day of oral avapritinib for 9 consecutive days. At the highest dose tested, one rat had a seizure on Day 8 while another rat had adverse EEG findings that typically precede seizure activity. The mean exposure levels (AUC) in these animals were approximately half of those observed clinically at the 300 mg daily dose (15400 ng.h/mL). Consistent with these findings, seizures or tremors occurred in general toxicology studies in dogs in both 4- and 13-week studies as well as in a small number of patients with GIST. While avapritinib demonstrated little potential for off- target pharmacological activity against a panel of receptors, transporters, ion channels, and enzymes at clinically relevant concentrations, avapritinib inhibited the type 2 sodium channel with an IC50 of 0.3 μM. Allelic variations in the type 2 sodium channel have been associated with seizure disorders (Heron et al., 2002; Sugaware et al., 2001; Schwarz et al., 2019). Although the IC50 for type 2 sodium channel inhibition is higher than the predicted free Cmax of 20 nM in

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humans at the 300 mg daily dose, exposures in animal safety studies were higher than the clinical exposure suggesting that inhibition of this pathway may contribute to seizures in animals. In addition, avapritinib was able to cross the blood brain barrier (approximately 50% of plasma concentrations following a single dose) and some tissue accumulation after repeated dose administration is possible. A contributing role for avapritinib-mediated inhibition of the type 2 sodium channel in clinical neurological symptoms cannot be excluded.

There were no avapritinib-related adverse effects on pulmonary function or the cardiovascular system at single doses up to 45 mg/kg. Avapritinib blocked hERG channel potential with an IC50 of 2.4 μM; however, this IC50 is 1.5 times the free Cmax in humans at the 300 mg dose. Consistent with these findings, avapritinib did not have effects on QT prolongation clinically or in in vivo nonclinical studies.

The Applicant evaluated the toxicity of avapritinib in GLP-compliant repeated-dose toxicity studies in rats and dogs. Rats received up to 30 mg/kg/day of oral avapritinib, once per day, for 3 months, resulting in mean exposure levels (AUC) up to 6 times the AUC of 15400 ng.h/mL in humans at the 300 mg daily dose. At doses ≥ 20 mg/kg/day avapritinib resulted in the death of five male animals. Although the Applicant did not determine a clear cause of death, toxicity consisted of decreased cellularity in the bone marrow and thymus, anemia, thrombocytosis, adrenal hypertrophy, thickness of the zone of hypertrophic cartilage, inflammation of the heart and lungs, nephropathy, and liver toxicity. Anemia occurs clinically as well. Female reproductive organ toxicity also occurred and consisted of cystic degeneration of corpora lutea at doses ≥ 5 mg/kg/day (a dose resulting in exposures approximately 1.3 times the human exposure based on AUC at the 300 mg daily dose). This adverse female reproductive organ finding was included in Section 13.1 of the label and advice that avapritinib may impair female fertility was included in Section 8.3 of the label. Although tremors did not occur in the 3-month toxicity study in rats, tremors did occur in rats administered oral avapritinib at doses ≥ 100 mg/kg/day (a dose resulting in exposures based on AUC approximately 8 times those in humans at the 300 mg daily dose) after 4 days of dosing in a 28-day toxicity study.

Dogs received up to 30 mg/kg/day of oral avapritinib, once per day, for 3 months, resulting in mean exposure levels (AUC) up to 1.5 times those in humans at the 300 mg dose. Death occurred in nearly all high-dose dogs due to multifocal hemorrhage in the spinal cord and brain. Edema in the choroid plexus also occurred. Intracranial hemorrhage occurs clinically as well. Though the clinical findings are included in the Warnings and Precautions section of the label, due to the severity and low exposure multiples in dogs compared to humans, these nonclinical findings were also included in Section 13.2 of the label. Dogs also displayed tremors that may be related to the type 2 sodium channel off-target pharmacological activity, as described above, or PDGFRα inhibition given that PDGFRα knockout mice have defective oligodendrocyte development and severe hypomyelination in various regions of the brain, and tremors (Fruttiger et al., 1999). Although tremors did not occur clinically, given the other CNS-related adverse events in humans (seizures and cognitive effects), the occurrence of tremors in animals was included in Section 13.2 of the label. Additional toxicities in dogs consisted of decreased cellularity in the bone marrow, thymus, and lymph nodes, anemia, thrombocytosis,

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angiectasis/hemorrhage of adrenal glands, gastrointestinal infiltration/atrophy, and liver toxicity. Male reproductive organ toxicity also occurred and consisted of hypo-spermatogenesis at doses ≥ 7.5 mg/kg/day (approximately 0.4 times the human exposure based on AUC at the 300 mg daily dose). This adverse male reproductive organ finding was included in Section 13.1 of the label and advice that avapritinib may impair male fertility was included in Section 8.3 of the label.

While in vitro assays suggested similar metabolism between rats, dogs, and humans, there was a single metabolite, M690, identified at high levels in humans that was not present at significant levels in rats or dogs. Though the toxicity of this metabolite was not assessed in animal studies, the toxicity profile in humans vs. animals is similar, suggesting that M690 is not contributing unique toxicity to the avapritinib profile. Based on a single dose in vivo pharmacokinetic study in rats, the pharmacologically active metabolite M499 has appropriate toxicological coverage to assess its safety.

In humans, avapritinib can cause adverse cognitive effects including memory impairment, cognitive disorder, confusional state, and encephalopathy at the recommended 300 mg dose. To investigate these adverse cognitive effects, the Applicant assessed the ability of avapritinib to affect short-term learning using an operant reversal test, spatial memory using a spontaneous alternation maze, and fear conditioning using a contextual fear conditional task in rats administered 30 mg/kg/day (approximately 3 times the human exposure based on AUC at the 300 mg daily dose) of oral avapritinib for up to 16 days. In contrast to the positive controls, avapritinib did not affect learning, memory, or fear conditioning. Other than the type 2 sodium channel discussed above, avapritinib did not inhibit any other tested CNS-related receptors at clinically relevant concentrations, making inhibition of these receptors unlikely to be contributing to the clinical effects. Based on recent literature, in addition to seizure disorders, allelic variants in the type 2 sodium channel have also been associated with cognitive impairment (Schwarz et al., 2019). Although the etiology of the adverse cognitive effects in humans is not clear, as discussed above, avapritinib-induced inhibition of both PDGFRα and the type 2 sodium channel may be involved.

The Applicant did not conduct studies investigating the carcinogenic potential of avapritinib as such studies are not needed to support a marketing application for patients with advanced cancer. Avapritinib was not mutagenic in a bacterial reverse mutation (Ames) assay. Avapritinib was clastogenic in the in vitro chromosome aberration test in human peripheral blood lymphocytes at concentrations ≥ 5 μg/mL (22-hour incubation); these aberrations appeared structural rather than numerical. Avapritinib was, however, not clastogenic in the in vivo rat bone marrow micronucleus test at doses up to 150 mg/kg. Based on the weight of evidence, avapritinib was not considered genotoxic.

Dedicated fertility and pre- and post-natal development studies were neither conducted nor necessary to support the development of avapritinib in patients with advanced cancer. PDGFRα is critically important during embryogenesis including the development of the central nervous system, neural crest, and a variety of mesenchymal cell types. KIT is critically important in the

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migration of embryonic stem cells and the development of pigment-forming cells, germ cells, red blood cells, and mast cells. To address the potential for avapritinib-mediated reproductive activity, the Applicant conducted an embryo-fetal development studies with avapritinib in rats. Daily oral administration of avapritinib to pregnant rats resulted in decreased fetal body weights, post-implantation loss, and increases in visceral (hydrocephaly, septal defect, and stenosis of the pulmonary trunk) and skeletal (sternum) malformations at doses ≥ 10 mg/kg/day (a dose resulting in exposures approximately 2.7 times the exposure based on AUC at the 300 mg human dose). Based on these adverse findings, the team recommends a warning for embryo-fetal toxicity in Section 5 of the label. Because of the potential for embryo-fetal toxicity, a recommendation for females and males of reproductive potential to use contraception during treatment with avapritinib and, based on a half-life of 57 hours with an additional month due to the positive in vitro chromosome aberration assay finding, 6 weeks after the final dose is included in Section 8.3 of the label. Lactating women are advised not to breastfeed during treatment with avapritinib and, based on a half-life of 57 hours, 2 weeks after the final dose.

Based on the results from in vitro and in vivo phototoxicity studies, avapritinib has a slight potential for phototoxicity. This potentially adverse finding was included in Section 13.2 of the label.

There are no outstanding issues from a nonclinical perspective that would prevent the approval of avapritinib for the treatment of patients with unresectable or metastatic GIST who have a PDGFRA exon 18 mutation; therefore, the nonclinical team recommends approval.

Referenced NDAs, BLAs, DMFs

None

Pharmacology

Primary pharmacology

A. In Vitro Studies

Avapritinib demonstrated in vitro inhibitory activity against human KIT and PDGFRα mutant kinases (Study BPM-0001 and BPM-0006). Elucidation of the crystal structure of avapritinib in complex with the KIT protein showed that avapritinib is an ATP competitive inhibitor that binds to the active conformation of the KIT kinase (data not shown). Avapritinib demonstrated in vitro inhibitory activity against KIT exon 17 mutant enzymes including KIT D816V (IC50= 0.27 nM) and PDGFRα exon 18 mutants including D842V (IC50= 0.24 nM). As shown in Table 1, further examination in additional studies demonstrated that avapritinib inhibits the in vitro activity of a variety of KIT and PDGFRα mutants (Study BPM-0050, BPM-0016, BPM-0006). Furthermore, in response to several information requests, the Applicant submitted additional in

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vitro data regarding the ability of avapritinib to inhibit other PDGFRα mutations to support the inclusion of exon 18 mutations other than D842V in the indication statement. Investigators transfected CHO cells with a series of PDGRα mutations previously identified in patients with GIST and cultured these cells with avapritinib or imatinib at a range of concentrations for 90 minutes before lysing cells and immunoprecipitating PDGFRα. Investigators ran these samples on a Western blot and stained for phosphorylated PDGFRα to determine the IC50s for inhibition of PDGFRA autophosphorylation. As shown in Table 2, avapritinib inhibited the phosphorylation of multiple PDGFRα mutations in exon 18 with similar IC50s to D842V but had no activity against the D842V in combination with a T674I mutation.

Table 2: In Vitro Inhibitory Activity of Avapritinib Against a Panel of GIST Relevant Mutants

(Applicant Table reproduced from Study BPM-0050, BPM-0016, and BPM-0006)

Table 3: In Vitro Inhibition of non-D842V PDGFRα Mutations

(Applicant Table reproduced from 11/17/19 Submission)

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The Applicant assessed the selectivity of avapritinib across a panel of over 450 human kinases using a KINOMEscan binding assay (Study BPM-0002). In addition to the KIT D816V (Kd of 0.3 nM) and D816H (Kd of 0.4 nM) mutants, avapritinib bound with Kds ≤ 50 nM to wild-type KIT (Kd of 17 nM), wild-type PDGFRα (Kd of 1 nM), PDGFRβ (Kd of 1 nM), colony stimulating factor 1 receptor (CSF1R; Kd of 6 nM), and Fms-like tyrosine kinase 3 (FLT3; Kd of 31 nM).

Avapritinib inhibited the cellular kinase activity of mutant KIT in cancer cells lines harboring activating KIT exon 17 mutations (Study BPM-0003, BPM-0004). The first cell line utilized was HMC1.2, a human mast cell leukemia cell line which harbors an activated KIT exon 11/exon 17 (V560G/D816V) mutant kinase. Following a 90-minute incubation with increasing concentrations of avapritinib, investigators measured the autophosphorylation or phosphorylation of mutant KIT D816V in HMC1.2 cells using an AlphaLISA assay or western blot analysis, respectively. Based on the results from the AlphaLISA assay, avapritinib inhibited the autophosphorylation of mutant KIT in HMC1.2 cells with an IC50 of 4 nM. Based on western blot analysis, avapritinib (BLU-285) dose-dependently inhibited the phosphorylation of mutant KIT D816V and downstream signaling through the Akt pathway in HMC1.2 cells (Figure 1 - left panel). Avapritinib also inhibited the cellular proliferation of HMC 1.2 cells with an IC50 of 125 nM after a 3-day incubation (data not shown). Utilizing the same methodology described above, the Applicant also examined the ability of avapritinib to inhibit the cellular kinase activity of mutant KIT in P815 cells, a mouse mastocytoma cell line harboring a KIT exon 17 mutation (mouse KIT D814Y) homologous to the human activating KIT D816Y mutation (Demehri et al., 2006). Avapritinib inhibited the autophosphorylation of mouse mutant KIT K814Y (human KIT D816Y mutation) in P815 cells with an IC50 of 22 nM. As shown in Figure 1 (right panel), avapritinib (BLU-285) dose-dependently inhibited the phosphorylation of mouse mutant KIT K814Y (human KIT D816Y mutation) and downstream signaling through the Akt pathway in P815 cells. Avapritinib also inhibited the cellular proliferation of P815 cells with an IC50 of 202 nM (data not shown).

Figure 1: Activity of Avapritinib on KIT Exon 17 Mutants in HMC1.2 and P815 Cells

(Applicant Figure reproduced from Study BPM-0003 and BPM-0004)

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One of the primary human metabolites of avapritinib (M499, refer to Metabolism in Section 5.4) also inhibited the cellular kinase activity of mutant KIT in cancer cell lines harboring activating KIT exon 17 mutations (Study BPM-00051). Following a 90-minute incubation with increasing concentrations of avapritinib human metabolites, investigators measured the autophosphorylation of mutant KIT D816V in HMC1.2 cells using an AlphaLISA assay. The M499 metabolite inhibited the autophosphorylation of mutant KIT D816V in HMC1.2 cells with an IC50 of 15 nM, which is approximately 4-fold less-potent than avapritinib (IC50 of 4 nM). Further analysis of M499 showed that it is a mix of two enantiomers with the M499-R (08) enantiomer showing increased activity compared to the M499-S (07) enantiomer (IC50s of 12.4 and 41.8, respectively); these compounds were ≥ 99.4% protein bound (Study 1907121). Based on the enantiomers predicted free Cmax of ≤ 3 nM at the 300 mg avapritinib dose, they are unlikely to contribute significantly to the activity of avapritinib.

Consistent with the selectivity observed in the biochemical binding assays, avapritinib inhibited wild-type KIT autophosphorylation activity in the M-07e human megakaryoblastic leukemia cell line less potently (IC50 = 192 nM) than autophosphorylation in KIT exon 17 mutant cell lines HMC1.2 (IC50 = 4 nM) and P815 (IC50 = 22 nM), as described above (Study BPM-0005).

Avapritinib inhibited the cellular kinase activity of mutant PDGFRα in an engineered cell line expressing the PDGFRα D842V mutant protein (Study BPM-0006). The Applicant exposed transfected CHO-K1 cells that express the human PDGFRα D842V mutant protein to increasing concentrations of avapritinib for 90 minutes and measured the inhibition of autophosphorylation using ELISA or western blot analysis. Based on the results using ELISA, avapritinib inhibited the autophosphorylation of mutant PDGFRα D842V in CHO-K1 cells with an IC50 of 30 nM. Based on western blot analysis, avapritinib (BLU-285) dose-dependently inhibited the autophosphorylation of mutant PDGFRα D842V in CHO-K1 cells (Figure 2), while imatinib, an FDA-approved tyrosine kinase inhibitor indicated for the treatment patients with GIST, was inactive against mutant PDGFRα D842V at concentrations up to 1000 nM.

Figure 2: Activity of Avapritinib on Mutant PDGFRα D842V in CHO-K1 Cells

BLU112718 is an unknown molecule under development by the Applicant and will not be discussed further. Imatinib is an FDA-approved tyrosine-kinase inhibitor indicated for the treatment of patients with GIST. Crenolanib is a PDGFRα D842V mutant inhibitor (Heinrich et al., 2012) and was included as a positive control. (Applicant Figure reproduced from Study BPM-0006)

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B. In Vivo Studies

To assess the in vivo anti-tumor activity of avapritinib, the Applicant utilized a mouse P815 mastocytoma tumor model in which tumor growth was driven by an activating KIT exon 17 mutation (Study BMC-20140304A). Female BALB/c nude mice (10/group) were subcutaneously implanted with 1x106 mouse P815 mastocytoma tumor cells harboring a KIT exon 17 mutation (mouse KIT D814Y) homologous to the human activating KIT D816Y mutation (Demehri et al., 2006). Once the mean tumor mass reached 70 mm3 (Day 5), mice received oral avapritinib, once per day, for 10 days. As shown in Figure 3 (left panel), daily oral administration of avapritinib resulted in dose-dependent inhibition of tumor growth. At doses of ≥ 10 mg/kg/day, avapritinib caused complete tumor growth inhibition and regression. All doses of avapritinib were well tolerated with no impact on animal body weight (Figure 3, right panel). In contrast, oral administration of the non-selective kinase inhibitor dasatinib (25 mg/kg, BID) resulted in marginal tumor growth inhibition and significant body weight loss throughout the course of the study.

Figure 3: Anti-tumor Activity and Body Weight Changes Following Avapritinib in a Mouse P815 Mastocytoma Tumor Model

(Applicant Figure reproduced from Study BMC-20140304A)

Avapritinib also demonstrated anti-tumor activity in an imatinib-resistant, patient-derived xenograft model of human GIST in which tumor growth was driven by an activating KIT exon 11/exon 17 double mutant (delW557K558/Y823D; Study BPM-0015). In this model, the KIT exon 17 mutant was an alternate amino acid substitution at residue 823 (Y823D) that is also observed in imatinib-relapsed/refractory KIT-driven GIST (Garner et al., 2014). Once the tumors reached approximately 167 mm3 in size, non-SCID mice (11/group) received 3, 10, or 30 mg/kg of oral avapritinib, once per day, for 28 days. Two FDA-approved tyrosine kinase inhibitors indicated for the treatment of patients with GIST, imatinib (50 mg/kg, BID) and regorafenib (30 mg/kg/day), were included as comparators. As shown in Figure 4, daily administration of avapritinib resulted in dose-responsive inhibition of tumor growth. As expected, imatinib was inactive in this tumor model while regorafenib produced moderate tumor growth inhibition.

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Figure 4: Anti-tumor Activity of Avapritinib in an Imatinib-resistant Patient-derived Xenograft Model of Human GIST

(Applicant Figure reproduced from Study BPM-0015)

Utilizing the same imatinib-resistant patient-derived xenograft model of human GIST described above, the Applicant conducted a separate in vivo study to assess the anti-tumor activity of avapritinib at higher doses with a pharmacodynamic assessment included (Study BPM-0010 and BPM-0011). Once the tumors reached approximately 185 mm3 in size, NOD-SCID mice (12/group) received 30 or 100 mg/kg of oral avapritinib, once per day, for 27 days. Tumors were collected from 3 mice/group on Day 8 to measure inhibition of mutant KIT autophosphorylation and the phosphorylation of other downstream signaling proteins via western blot analysis. As shown in Figure 5 (left panel), daily administration of both doses of avapritinib resulted in significant tumor growth inhibition that was sustainable for at least 4 weeks after the last dose of avapritinib. As shown in Figure 5 (right panel), avapritinib dose-dependently inhibited the autophosphorylation of mutant KIT and the phosphorylation of downstream signaling proteins (Erk and Akt) in these mice.

Figure 5: Anti-tumor Activity and Inhibition of Mutant KIT in a Patient-derived Xenograft Model of Human GIST

(Applicant Figure reproduced from Study BPM-0010 and BPM-0011)

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Secondary Pharmacology The Applicant evaluated the off-target pharmacological activity of avapritinib against a panel receptors, transporters, and enzymes (Study 100013720; 100014090). At a concentration of 10 μM, avapritinib demonstrated greater than 50% inhibition on the following targets: 5- hydroxytryptamine transporter, adenosine A2A receptor, gamma aminobutyric acid-gated chloride channel, dopamine transporter, histamine H2 receptor, kappa opioid receptor, muscarinic acetylcholine M2 and M3 receptors, norepinephrine transporter, mu opioid receptor, and the type 2 sodium channel. In subsequent studies, avapritinib had IC50 values of 0.3, 2.2, 2.9, and 5.8 μM against the type 2 sodium channel, norepinephrine transporter, histamine H2 receptor, and muscarinic acetylcholine M2 receptor, respectively.

The Applicant also examined off target pharmacological activity of avapritinib against a panel of ion channels and receptors expressed in human embryonic kidney (HEK293) or Chinese hamster ovary (CHO) cells (Study 171127.CMV). At the highest concentration of 10 μM, avapritinib inhibited GABAA α1/β2/γ2 (30%) and GABAA α2/β2/γ2 (32%) receptors, and the following ion channels: hNav1.1 (Tonic – 21% and Phasic – 26%), hCav2.1 (23%), hCav3.2 (29%).

Given the high level of avapritinib protein binding in human plasma and an estimated unbound Cmax of 12 ng/mL (0.02 μM) for avapritinib in humans at the 300 mg daily dose, none of these secondary targets are likely to be pharmacologically relevant.

Safety Pharmacology The Applicant conducted stand-alone GLP-compliant safety pharmacology studies in rats and dogs to assess the effect of avapritinib on the central nervous system, respiratory function, and the cardiovascular system.

To evaluate the effect of avapritinib on the central nervous system, the Applicant evaluated female Sprague Dawley rats (6/dose group) administered 0, 15, 30, or 45 mg/kg of oral (b) (4) avapritinib for 15 consecutive days in a modified Irwin test (Study -124502). On Days 7-10, treatment with 30 mg/kg of avapritinib increased corneal and pinna reflex in 1/6 animals. On Days 11-14, treatment with 45 mg/kg of avapritinib induced an increased touch response, increased corneal and pinna reflex, head flicking, exophthalmos, increased startle response, aggressiveness, vocalization, increased pain response, and/or tremors in up to 2/6 animals. These findings showed an increase in sensitivity to stimuli and are potentially underlying indicators of pre-convulsive activity.

In consideration of the pre-convulsive activity findings in the modified Irwin test, and the (b) (4) tremors and clonic convulsions in the 28-day repeated-dose toxicity study in rats (Study - 124507; refer to additional studies in the general toxicology section), the Applicant conducted a non-GLP compliant electroencephalographic (EEG) assessment in female Sprague Dawley rats (8/dose group) administered 15, 30, or 50 mg/kg/day of oral avapritinib for 9 consecutive days (b) (4) (Study -124530). EEG data were recorded for at least 5 minutes in the unanesthetized state at approximately 2, 4, and 6 hours post-dosing on days 0 and 8. One 50 mg/kg/day animal was found dead on Day 8 with dark red discoloration of the lungs and oviducts, red fluid-filled cysts

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in the ovaries, and red matting on the nasal and buccal at necropsy. Another 50 mg/kg/day animal had a seizure on Day 8 which lasted for approximately 5 minutes and correlated to an avapritinib plasma concentration of 6,710 ng/mL (13 uM; ~156 nM free drug based on 98.8% protein binding). The seizure was characterized by repeated bursts of extremely high amplitude EEG, occurring in 4-5 second intervals, and preceded by escalating sharp waves and myoclonic movements. A third 50 mg/kg/day animal showed high amplitude bursts of organized sharp waves accompanied with asymmetric facial grimaces, twitching of the face and eyes, and strong myoclonic movements on Day 8. This animal had an avapritinib plasma concentration of 8,880 ng/mL (18 uM).

To evaluate the effect of avapritinib on the cardiovascular system and respiratory parameters, the Applicant administered single 0, 15, 20, or 45 mg/kg doses of avapritinib to telemetered male Beagle dogs (4/dose group) using a Latin square crossover design with approximately 7 (b) (4) days between doses (Study -124501). Cardiovascular and respiratory data were obtained from each animal for approximately 24 hours post-dose. There were no avapritinib-related effects on cardiovascular parameters (heart rate, mean arterial blood pressure, and systolic, diastolic, and pulse pressure), body temperature, ECG waveform morphology, duration of PR, QRS, RR, QT, and QTcV intervals, respiratory parameters (respiratory frequency, tidal volume, and minute volume), or the clinical condition of the animals.

To further evaluate the potential effects of avapritinib on the cardiovascular system, the Applicant assessed the ability of avapritinib to inhibit the human ether-à-go-go related gene (hERG) potassium channel stably expressed in HEK293 cells (human embryonic kidney cell type; Study 140717.XSM). Avapritinib blocked hERG channel potential with an IC50 of 2.4 μM; however, this IC50 is approximately 1.5-fold higher than the Cmax in humans at the 300 mg dose (813 ng/mL; 1.6 μM) and is therefore unlikely to cause QT prolongation.

ADME/PK

Type of study Major findings Absorption Pharmacokinetics of BLU112317-1 after Male Sprague Dawley rats received a single 1 mg/kg Intravenous and Oral Administrations to intravenous dose of avapritinib. Male SD rats; Study No. (b) (4)-P13-8343R07 Cmax (ng/mL): Not available AUC (ng.h/mL): 1997 T1/2 (hours): 8

Male Sprague Dawley rats received a single 2.5 mg/kg oral dose of avapritinib. Cmax (ng/mL): 432 AUC (ng.h/mL): 4207 T1/2 (hours): 6 Bioavailability: 78%

A Pharmacokinetic Study of X720776 Male Sprague Dawley rats received a single oral dose of 10, Following Single Oral Gavage 30, 100, or 300 mg/kg of avapritinib. Exposure levels were

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Type of study Major findings Administration to Male Sprague Dawley dose proportional from 10 to 30 mg/kg, and less than dose Rats; Study No. BMC-20140123B-RPK proportional from 30 to 100 mg/kg and 100 to 300 mg/kg. Cmax (ng/mL): 2143 (LD); 5483 (MLD); 9183 (MHD); 13800 (HD) AUC (ng.h/mL): 19333 (LD); 57167 (MLD); 142500 (MHD); 179333 (HD) T1/2 (hours): 6-18 Bioavailability: Not available

Pharmacokinetics of BLU112317-2 after Male Beagle dogs received a single 0.5 mg/kg intravenous Intravenous and Oral Administrations to dose of avapritinib. (b) (4) Male Beagle dogs; Study No. P14- Cmax (ng/mL): Not available 8449D02 AUC (ng.h/mL): 494 T1/2 (hours): 11

Male Beagle dogs received a single 1 mg/kg oral dose of avapritinib. Cmax (ng/mL): 56 AUC (ng.h/mL): 765 T1/2 (hours): 11 Bioavailability: 77%

Plasma Pharmacokinetic Study of X720776 Male Beagle dogs received a single oral dose of 25 or 50 Following Single Oral (PO) Administration mg/kg/day of avapritinib. Exposure levels were less than to Non-Naïve Male Beagle Dogs; Study No. dose proportional. BMC-20140310 Cmax (ng/mL): 1262 (LD); 1513 (HD) AUC (ng.h/mL): 21567 (LD); 27033 (HD) T1/2 (hours): 10 Bioavailability: Not available Distribution Evaluation of Protein Binding of X720776 The Applicant assessed the in vitro protein binding of in Human, Monkey, Dog, Rat, and Mouse avapritinib in rat, mouse, dog, monkey, and human plasma Plasma Using Equilibrium Dialysis; Study at concentrations of 0.1, 1, and 10 μM. Avapritinib No. (b) (4) P14-9193 demonstrated high protein binding (>98.5%) in the plasma of all species tested.

A Pharmacokinetic, Mass Balance, and Male Sprague-Dawley rats received a single 30 mg/kg oral Tissue Distribution Study of [14C]-Kiev dose of radiolabeled (14C) avapritinib. following Oral (Gavage) or Intravenous • Measurable levels of avapritinib were present in the (Bolus) Administration to Rats; Study No. blood from 0.25 to 72 hours post-dose. 124696 • Cmax in plasma was 6990 ng/mL at 8 hours post- dose. • Avapritinib tissue concentrations were highest in the lung and adrenal gland, and lowest in the uveal tract and adipose tissue. • With exception to the adrenal, harderian, pituitary, and thyroid glands, tissues were devoid of avapritinib by 168 hours post-dose.

Male pigmented Long Evans rats received a single 30 mg/kg oral dose of radiolabeled (14C) avapritinib.

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Type of study Major findings • Cmax in plasma was 5470 ng/mL at 8 hours post- dose. • Avapritinib tissue concentrations were highest in the uveal tract, pigmented skin, and adipose tissue. • With exception to the uveal tract and eye lens, tissues were devoid of avapritinib by 168 hours post-dose. • Avapritinib was still present in the uveal tract at 504 hours post-dose.

Determination of Avapritinib Male Sprague Dawley rats with surgically implemented Concentrations in ISF, Plasma, CSF and microdialysis probes in the prefrontal cortex and Brain Tissue, as Well as Neurotransmitter hippocampus received a single 30 mg/kg oral dose of Levels following a Single Oral avapritinib. Plasma, brain interstitial fluid (ISF), Administration to Sprague Dawley Rats; cerebrospinal fluid (CSF), and brain tissue were collected up Study No. 1666 to 24 hours post-dose. • Cmax in plasma was 2140 ng/mL at 3 hours post- dose; Cmax in ISF was 73 ng/mL at 6.5 hours post- dose; Cmax in CSF was 1.24 ng/mL (sample taken at 24 hours post-dose); Cmax in brain tissue was 1030 ng/mg (~50% plasma concentration; sample taken at 24 hours post-dose) • Avapritinib did not significantly alter neurotransmitter levels (dopamine, serotonin, glutamate, norepinephrine, gamma-aminobenzoic acid, glycine, and acetylcholine) in ISF.

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Type of study Major findings Metabolism In Vitro Metabolism of [3H]-BLU-285 in the [3H] avapritinib was relatively stable in the presence of Presence of Cryopreserved Hepatocytes human liver microsomes or hepatocytes with unchanged and Liver Microsomes from Sprague- avapritinib accounting for > 90% of total radioactivity. The Dawley Rats, Beagle Dogs and Humans; primary metabolic pathways for [3H] avapritinib after Study No. BLU-R4174 incubation with human liver microsomes or hepatocytes were N-demethylation (M484) and oxidation of the primary amine to a tertiary alcohol (M499). These metabolites were also present in rat and dog liver microsomes (see table below) and hepatocytes. An oxidized N-demethylated metabolite (M485), and hydroxylation/oxidation metabolites (M514a/b) also occurred in rats and/or dog liver extracts.

Metabolites of Avapritinib in Liver Microsomes

Based on a separate pharmacokinetic study in humans, the Metabolite Profiles of [14C]-BLU-285 in major human metabolic pathways of avapritinib were Plasma, Urine, Bile, and Feces of Rats hydroxy glucuronidation (M690) and oxidative deamination Following a Single IV and Oral Dose of (M499). In these animal studies, male Sprague-Dawley rats [14C]-BLU-285; Study No. BLU-R7153, and received a single 30 mg/kg oral dose of radiolabeled (14C) Metabolite Profiles of BLU-285 in Plasma avapritinib and male Beagle dogs received a single 400 mg of Beagle Dogs Following a Single Oral oral dose of avapritinib. The major circulating metabolites Dose of 400 mg BLU-285; Study No. BLU- are shown in the following table, compared to levels in R8415 human plasma.

Metabolites of Avapritinib in Rat, Dog, and Human Plasma

ND: Not Detected

Bile duct-cannulated male Sprague-Dawley rats received a single 5 mg/kg intravenous dose of radiolabeled (14C) avapritinib. The level of avapritinib metabolites in bile were 4.8% for M499 and 5.7% for M690. Excretion A Pharmacokinetic, Mass Balance, and In intact male Sprague Dawley rats, excretion following a Tissue Distribution Study of [14C]-Kiev single oral dose of radiolabeled (14C) avapritinib was through following Oral (Gavage) or Intravenous feces (91%) and urine (7%). (Bolus) Administration to Rats; Study No. 124696 In bile duct-cannulated male Sprague Dawley rats, excretion following a single intravenous dose of (14C) avapritinib was through bile (54%), feces (32%), and urine (6%). TK data from general toxicology studies Refer to Section 5.5.1 TK data from reproductive toxicology studies Refer to Section 5.5.4

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LD: low dose; MLD: mid-low dose; MHD: mid-high dose; HD: high dose.

Toxicology

General Toxicology

Study Title / Number: A 3-Month (Once Daily) Oral (Gavage) Toxicity and (b) (4) Toxicokinetic Study of BLU-285 in Sprague Dawley Rats / -124522

Key Study Findings: • One MD male and four HD males were found dead between Days 31 and 68. The causes of death are unknown. • Decreased cellularity occurred in the bone marrow and thymus and likely resulted in increased splenic hematopoiesis. • Additional toxicity consisted of anemia, elevated platelet levels, adrenal hypertrophy, increased thickness of the zone of hypertrophic cartilage, inflammation of the heart and lungs, nephropathy, and liver toxicity (alterations in clinical chemistry parameters without a histopathological correlate). • Female reproductive organ toxicity consisted of cystic degeneration of the corpora lutea in the ovaries.

(b) (4) Conducting laboratory and location: GLP compliance: Yes

Methods Dose and frequency of dosing: 0, 10/5, 20/15, or 30/25 mg/kg/day in males and females, respectively Daily for 3 months Route of administration: Oral gavage Formulation/Vehicle: 0.5% carboxymethylcellulose-sodium [w/v] and 1% Tween® 80 [v/v] in deionized water [pH 2-3] Species/Strain: Rat / Sprague-Dawley (Crl:CD®[SD]) Number/Sex/Group: 10 Age: Approximately 8 weeks Satellite groups/ unique design: For toxicokinetics - 3 animals/sex for control and 9 animals/sex for avapritinib dose groups / No unique study design Dose justification: Based on results from a previously conducted 28- day repeated-dose toxicity study in rats; doses up to 30/20 mg/kg/day in males and females, respectively, did not result in moribundity or mortality (refer to additional studies). Deviations from study protocol affecting interpretation of results: No

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Observations and Results: Parameters Major findings Mortality Four HD males were found dead between Days 31 and 68. Histopathology findings in these animals included decreased cellularity of hematopoietic cells and hemorrhage in the bone marrow, increased thickness of the zone of hypertrophic cartilage in the femur, increased extramedullary hematopoiesis in the spleen, decreased cortical lymphoid cellularity in the thymus, adrenal cortical hypertrophy, nephropathy, inflammation in the urinary bladder, inflammation of the epicardial surface of the heart, and congestion of the lungs. Since the magnitude of these histopathology findings was similar to those animals which survived to the scheduled necropsy, the cause of death is unknown.

One MD toxicokinetic male was found dead on Day 61. The Applicant did not perform a microscopic examination of tissues from this animal. The cause of death is unknown.

One LD male was found dead on Day 68. Histopathology findings included congestion of the liver, lungs, and adrenal cortex, increased extramedullary hematopoiesis in the spleen, and thymic hemorrhage. The cause of death for this animal is unclear; however, the incompletely collapsed lungs with mild congestion is likely caused by gavage error. Clinical Signs A dose-responsive increase in the incidence of red material around the nose (≥ Day 11) and eyes (≥ Day 25) occurred in males. Body Weights At study week 13, mean body weights were 11, 17, and 17% higher than the control group in the 10, 20, and 30 mg/kg/day males, respectively, and 9, 12, and 10% higher than the control group in the 5, 15, and 25 mg/kg/day females, respectively. Ophthalmoscopy Unremarkable Hematology Percent Differences in Mean Values vs. Concurrent Controls

Clinical Chemistry Percent Differences in Mean Values vs. Concurrent Controls

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Urinalysis A generally dose-responsive increase in leukocytes was present in urine. An increase in urine pH also occurred (up to a pH value of 7.9, compared to ~6.6 in control animals). Gross Pathology Adverse gross pathology findings only occurred in females. Percent Differences in Mean Values vs. Concurrent Controls (relative to body weight).

Organ Weights Percent Differences in Mean Values vs. Concurrent Controls (relative to body weight)

NA denotes not applicable

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Histopathology Adequate battery: Yes

*Severity of findings was generally dose-dependent Grades 1, 2, 3, 4, 5 refer to minimal, mild, moderate, marked, and severe, respectively NA denotes not applicable Reversibility Not assessed Toxicokinetics Dose proportionality: Generally dose proportional, except males on Day 90 were less than dose proportional. Accumulation: Yes Sex differences: Exposure levels were higher in females.

LD: low dose; MD: mid dose; HD: high dose.

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Study Title / Number: A 3-Month (Once Daily) Oral (Gavage) Toxicity and Toxicokinetic Study (b) (4) of Avapritinib in Beagle Dogs / -124523

Key Study Findings: • 7/8 HD animals were found dead on Days 20-47 due to multifocal hemorrhage in the spinal cord and brain. Tremors also occurred in these animals. • Decreased cellularity occurred in the bone marrow, thymus, and lymph nodes and likely resulted in increased splenic hematopoiesis. • Additional toxicity consisted of choroid plexus edema, anemia, elevated platelet levels, angiectasis/hemorrhage of adrenal glands, gastrointestinal infiltration/atrophy, and liver toxicity (elevated aspartate aminotransferase without a histopathological correlate). • Male reproductive organ toxicity consisted of a dose-responsive increase in severity of hypospermatogenesis in the testes.

(b) (4) Conducting laboratory and location: GLP compliance: Yes

Methods Dose and frequency of dosing: 0, 7.5, 15, or 30 mg/kg/day Daily for 3 months Route of administration: Oral gavage Formulation/Vehicle: 0.5% carboxymethylcellulose-sodium [w/v] and 1% Tween® 80 [v/v] in deionized water [pH 2-3] Species/Strain: Dog / Beagle Number/Sex/Group: 4 Age: 6-7 months Satellite groups/ unique design: None / No Dose justification: Based on results from a previously conducted 4- week repeated-dose toxicity study in dogs; doses up to 15 mg/kg/day did not result in moribundity or mortality (refer to additional studies). Deviations from study protocol affecting interpretation of results: No

Observations and Results: Parameters Major findings Mortality One LD male was found dead on Day 80. The cause of death was gavage error based on adverse clinical signs and histopathological findings.

Three HD males and 4 HD females were found dead on Days 20-47. Multifocal hemorrhage in the spinal cord (minimal) and brain (mild-moderate) occurred in all these animals and was the cause of death. Adverse clinical signs in these animals included partial eye closure (3 animals), clear ocular discharge (6 animals), pale extremities (5 animals), and tremors (5 animals). The single remaining HD male was electively euthanized on Day 49.

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Clinical Signs In the LD and MD animals, adverse clinical signs included clear ocular discharge and pale nose, gums, and extremities. Adverse clinical signs in HD animals were previously described in the Mortality section. Body Weights Unremarkable Ophthalmoscopy Unremarkable Electrocardiography Unremarkable Hematology Percent Differences in Mean Values vs. Concurrent Controls

*collected at time of early sacrifice Clinical Chemistry Percent Differences in Mean Values vs. Concurrent Controls

*collected at time of early sacrifice Urinalysis Unremarkable Gross Pathology Small spleen and thymus consistent with organ weight findings below. Organ Weights A dose-responsive decrease in spleen (≤ 67%), thymus (≤ 75%), and testes (≤ 28%), weight occurred. Histopathology In addition to the following findings, hypospermatogenesis occurred in all males with a Adequate battery: Yes dose-responsive increase in severity (≤ moderate).

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*Severity of findings was generally dose-dependent **Intestinal tract includes the duodenum, jejunum, ileum, cecum, colon, and rectum; highest severity score presented. Grades 1, 2, 3, 4, 5 refer to minimal, mild, moderate, marked, and severe, respectively Reversibility Not assessed Toxicokinetics Dose proportionality: Generally dose proportional. Accumulation: No significant accumulation was noted. Sex differences: No significant differences were noted.

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*N=1-2 on Day 41 since 30 mg/kg/day animals were sacrificed prior to Day 90 LD: low dose; MD: mid dose; HD: high dose.

General toxicology; additional studies

The Applicant conducted a GLP-compliant repeated-dose toxicology study in Sprague-Dawley rats (15/sex/group) administered avapritinib daily at doses up to 150 mg/kg/day for 28 days, (b) (4) with a 14-day recovery period (Study -124507). Due to mortality and signs of excessive toxicity, the Applicant lowered the dosage level of all avapritinib treated groups, resulting in dose levels of 10, 30, or 100 mg/kg/day in males and 5, 20, or 75 mg/kg/day in females. Adverse clinical signs contributing to moribundity included tremors, clonic convulsions, cool and pale extremities, and salivation. The Applicant added a supplemental toxicology group to assess whether any test article-related effects were a result of a cumulative effect of the previous dosage levels. In this supplemental group, males and females tolerated 30 and 20 mg/kg/day, respectively, for 27 consecutive days. Adverse findings were generally consistent with results (b) (4) from the 3-month repeated-dose toxicology study in rats ( -124522) and consisted of hematopoietic toxicity, elevated platelets, adrenal hypertrophy, liver toxicity, and irreversible degeneration of the male (testes with reduced sperm in the epididymis) and female (ovaries) reproductive organs.

The Applicant conducted a GLP-compliant repeated-dose toxicology study in Beagle dogs (5/sex/group) administered avapritinib daily at doses up to 60 mg/kg/day for 28 days, with a (b) (4) 14-day recovery period (Study -124508). Due to mortality and signs of excessive toxicity, the Applicant lowered the dosage level of all avapritinib treated groups, resulting in dose levels of 7.5 or 15 mg/kg/day. Adverse findings were generally consistent with results from the 3-month (b) (4) repeated-dose toxicology study in dogs (-124523) and consisted of brain hemorrhage, hematopoietic toxicity, elevated platelets, liver toxicity, gastrointestinal inflammation, and irreversible hypospermia.

Genetic Toxicology

In Vitro Reverse Mutation Assay in Bacterial Cells (Ames) Study Title / Number: Salmonella-E. coli Mammalian Microsome Reverse Mutation Assay / (b) (4) -124504 Key Study Findings: • Avapritinib was not genotoxic in the presence or absence of S9 activation.

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• Cytotoxicity occurred ≥ 100 μg/plate in TA1537 - S9, ≥ 250 μg/plate in TA100 and TA1535 +/- S9, TA1537 + S9, TA98 - S9, and ≥ 500 μg/plate in TA98 + S9. • Standard positive controls confirm the sensitivity and validity of the assay.

GLP compliance: Yes Test system: Salmonella strains TA1535, TA1537, TA98, TA100; Escherichia coli strain WP2uvrA; ≤ 500 μg/plate of avapritinib for Salmonella strains; ≤ 5000 μg/plate of avapritinib; +/- S9 Study is valid: Yes

In Vitro Assays in Mammalian Cells Study Title / Number: In Vitro Chromosome Aberration Test in Cultured Human Peripheral (b) (4) Blood Lymphocytes / -124505

Key Study Findings: • Statistically significant increase in % aberrant cells at 20 μg/mL in the 3-hour treatments with and without metabolic activation. • Additionally, there was an increase in % aberrant cells at 5.00 μg/mL in the 22-hour treatment without metabolic activation. Although this increase was not statistically significant when compared to the vehicle control, it was outside of the historical control range for the vehicle control. • Positive controls caused substantial increases in the proportion of structural chromosomal aberrations confirming the sensitivity and validity of the study.

GLP compliance: Yes Test system: human peripheral blood lymphocytes; ≤ 20 μg/mL of avapritinib in the 3-hour test and ≤ 5 μg/mL in the 22-hour test; +/- S9 in the 3-hour test; - S9 in the 22-hour test Study is valid: Yes

In Vitro Chromosome Aberration Test

**p ≤0.01, significantly different from control based on Fishers Exact Test (b) (Applicant Figure reproduced from Study (4) -124505)

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In Vivo Clastogenicity Assay in Rodent (Micronucleus Assay) Study Title / Number: An In Vivo Bone Marrow Micronucleus Assay with Avapritinib in (b) (4) Sprague Dawley Rats / -124506

Key Study Findings: • Oral administration of avapritinib up to 150 mg/kg/day for 3 days did not induce micronuclei in polychromatic erythrocytes of the bone marrow of rats. • Positive control material induced a significant increase in the frequency of micronucleated polychromatic erythrocytes confirming the sensitivity and validity of the study.

GLP compliance: Yes Test system: Sprague Dawley rat, bone marrow micronuclei; 30/10, 75/20, and 150/50 mg/kg/day of oral avapritinib once per day for 3 consecutive days in males/females, respectively. Positive control: 60 mg/kg cyclophosphamide Study is valid: Yes

Carcinogenicity

Not conducted per ICH S9.

Reproductive and Developmental Toxicology

Based on its mechanism of action, avapritinib can cause fetal harm or developmental anomalies. KIT is critically important in the migration of embryonic stem cells and the (b) (4) development of pigment-forming cells, germ cells, red blood cells, and mast cells ( ). While KIT deficient mice are viable, they are sterile due to germ cell deficiency.

PDGFRα is critically important during embryogenesis including the development of the central nervous system, neural crest, and a variety of mesenchymal cell types (Hoch and Soriano, 2003). PDGFRα deficient mice exhibit incomplete cephalic closure, increased apoptosis of neural crest cells, impaired myotome and testis formation, abnormal mucosal linings, thoracic (b) (4) skeletal defects, and midgestational lethality ( ). In addition, PDGFRα deficient male mice develop a progressive reduction of testicular size, Leydig cells loss, and spermatogenic arrest (Gnessi et al., 2000).

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Embryo-Fetal Development Study Title / Number: An Oral (Gavage) Enhanced Dose Range-Finding Study of the Effects of Avapritinib on Embryo-Fetal Development with Toxicokinetic in Sprague Dawley Rats / 124704

Key Study Findings: • Maternal toxicity was limited to a 15 and 20% decrease in mean body weight in 20 and 30 mg/kg dose group animals. • A dose-responsive increase in post-implantation (up to 99%) loss occurred. • Fetal toxicity consisted of a dose-responsive decrease (up to 39%) in mean body weight, anasarca at doses ≥ 20 mg/kg, visceral abnormalities (hydrocephaly, septal defect, and stenosis of the pulmonary trunk) at doses ≥ 10 mg/kg, and skeletal abnormalities of the sternum at doses ≥ 20 mg/kg.

Conducting laboratory and location: (b) (4)

GLP compliance: Yes

Methods Dose and frequency of dosing: 0, 5, 10, 20, and 30 mg/kg/day Daily from Days 6 to 17 post coitum Route of administration: Oral gavage Formulation/Vehicle: 0.5% carboxymethylcellulose-sodium [w/v] and 1% Tween® 80 [v/v] in deionized water [pH 2-3] Species/Strain: Rat / Sprague-Dawley (Crl:CD®[SD]) Number/Sex/Group: 10/group Satellite groups: For toxicokinetics - 8/group Study design: Time-mated rats were treated once daily via oral gavage from Days 6 to 17 post coitum. Cesarean section occurred on Day 21. Dose justification: Based on results from a previously conducted 4- week repeated-dose toxicity study in rats; ≥ 30 mg/kg/day resulted in moribundity and morbidity after > 23 days of daily dosing (refer to general toxicology; additional studies). Deviation from study protocol affecting interpretation of results: No

Observations and Results: Parameters Major findings Mortality None Clinical Signs Unremarkable

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Body Weights On Day 21, a 15 and 20% decrease in maternal mean body weight occurred in 20 and 30 mg/kg animals, respectively. Cesarean Cesarean section data: As detailed in the following table, a dose-responsive Section increase in post-implantation loss occurred.

Fetal body weight: A 17, 29, and 39% decrease in mean fetal body weight occurred at doses of 10, 20, and 30 mg/kg, respectively. Offspring Fetal external exam: Fetal anasarca occurred in 3 late resorptions in 2 litters Necropsy from the 20 mg/kg group and 2 late resorptions in 1 litter in the 30 mg/kg group.

Fetal visceral exam:

Fetal skeletal exam:

Toxicokinetics Dose proportionality: Generally dose proportional Maternal exposure on Day 17:

LD: low dose; MLD: mid-low dose; MHD: mid-high dose HD: high dose.

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Other Toxicology Studies

In humans, avapritinib can cause adverse cognitive effects including memory impairment, cognitive disorder, confusional state, and encephalopathy at the recommended 300 mg dose. To investigate these adverse cognitive effects, the Applicant conducted an operant reversal test in male Winster (Han) rats (7-8/group) administered 30 mg/kg/day of oral avapritinib for 12 days (Study 18.0009). As comparators, the Applicant used a vehicle control, the anxiolytic drug, diazepam (8 mg/kg PO), and the antiepileptic drug, phenytoin (25 mg/kg IP). The anti- cholinergic drug, scopolamine (0.5 mg/kg SC), was the positive control. Based on the results, avapritinib did not affect learning performance whereas diazepam, phenytoin, and scopolamine disrupted learning performances.

To further examine adverse effects on memory behavior, the Applicant assessed the ability of avapritinib to affect behavior in a spontaneous alternation maze and a contextual fear conditional task (Study 1671). Male Sprague Dawley rats (10/group) were administered 30 mg/kg/day of oral avapritinib for up to 16 days, compared to vehicle control and the anti- cholinergic drug, scopolamine (1 mg/kg, IP). In contrast to scopolamine which impaired working memory in both tests, avapritinib did not have any adverse effect on memory behavior under the conditions tested.

To evaluate the phototoxic potential of avapritinib in vitro, the Applicant conducted a GLP- complaint neutral red uptake phototoxicity study in BALB/c 3T3 mouse fibroblasts (Study 20137416). Phototoxicity was measured using the relative reduction in viability of BALB/c 3T3 mouse fibroblasts exposed to the test article (~90 minutes) plus ultraviolet radiation (5 J/cm2 of UVA and 22 mJ/cm2 of UVB). Promethazine was the positive control. As shown in Table 4, avapritinib minimally exceeded the effect threshold of the mean photo effect (MPE) in the presence of ultraviolet radiation in one of the two assessments (Assay 2), and therefore demonstrated a slight phototoxic potential.

Table 4: Phototoxicity in Mouse Fibroblasts

(Applicant Table reproduced from Study 20137416)

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The Applicant also conducted an in vivo GLP-complaint phototoxicity study in female Long- Evans pigmented rats (5/dose group) administered 0, 5, 15, or 30 mg/kg/day of oral avapritinib for 3 consecutive days (Study 20142828), followed by a single exposure to ultraviolet radiation (10 J/cm2 of UVA and ~142 mJ/cm2 of UVB) approximately 4 hours-post the last dose. An additional group of 5 rats were administered 30 mg/kg/day of avapritinib without ultraviolet radiation exposure. One 30 mg/kg/day rat exposed to ultraviolet radiation showed grade 1 erythema indicative of a mild phototoxic response. No other adverse findings indicative of phototoxicity occurred including ophthalmologic or histopathologic findings.

Alexander H. Putman Whitney S. Helms Alexander H. Putman, PhD Whitney S. Helms, PhD Primary Reviewer Team Leader

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6 Clinical Pharmacology

Executive Summary

The proposed avapritinib dosing regimen is 300 mg orally once daily on an empty stomach at least one hour before and two hours after a meal. The primary evidence of efficacy and safety is provided by a Phase 1, open-label study BLU-285-1101 in adult patients with unresectable or metastatic GIST • harboring a PDGFRα exon 18 mutation including PDGFRα D842V mutations regardless of prior therapy. Additional safety data are from a Phase 3 study in patients with advanced GIST (Study BLU-285- 1303) and a Phase 1 study in patients with advanced systemic mastocytosis (AdvSM) (Study BLU-285-2101).

The clinical pharmacology review focused on evaluating how the underlying KIT or PDGFRA mutation influence response to avapritinib, the acceptability of avapritinib dosing recommendations for drug-drug interactions (DDIs) and for patients with hepatic or renal impairment.

Recommendations

The Office of Clinical Pharmacology has reviewed the information contained in NDA 212608. This NDA is approvable from a clinical pharmacology perspective. The key review issues with specific recommendations/comments are summarized below:

Review Issue Recommendations and Comments Pivotal and Supportive The primary evidence of effectiveness comes from a single evidence of effectiveness arm, dose finding and expansion cohort Study BLU-285-1101. General dosing instructions The proposed avapritinib dosing regimen of 300 mg orally once daily on an empty stomach is effective and appears to have a manageable safety profile. Dosing in patient subgroups • Avoid coadministration of avapritinib with strong or (intrinsic and extrinsic factors) moderate CYP3A inhibitors. If coadministration of avapritinib with a moderate CYP3A inhibitor cannot be avoided, reduce the starting dose of avapritinib from 300 mg once daily to 100 mg once daily. • The pharmacokinetics (PK) of avapritinib in patients with severe hepatic impairment is unknown. See Post- Marketing Requirements and Commitments for PMR regarding severe hepatic impairment. Labeling Generally acceptable. The review team has specific content and formatting change recommendations.

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Bridge between the to-be- The proposed to-be-marketed formulation is 100 mg strength marketed and clinical trial tablets, 200 mg strength tablets and 300 mg strength tablets. formulations The 100 mg strength tablet was used in the registrational Study BLU-285-1101. A strength-based waiver was granted for the 200 mg strength tablets based on in vitro data.

Post-Marketing Requirements and Commitments

PMC or Key Issue(s) Key Considerations for PMR to Rationale Design Features be Addressed Avapritinib The effect of severe hepatic Complete a pharmacokinetic trial to dose in impairment on the determine an appropriate dose of avapritinib patients with exposure of avapritinib is to minimize toxicity in patients with severe severe hepatic unknown and dose hepatic impairment in accordance with the impairment. adjustment may be needed. FDA Guidance for Industry entitled “Pharmacokinetics in Patients with Impaired PMR Hepatic Function: Study Design, Data

Analysis, and Impact on Dosing and Labeling” found at https://www.fda.gov/downloads/Drugs/Guid anceComplianceRegulatoryInformation/Guid ances/UCM072123.pdf

Summary of Clinical Pharmacology Assessment

Pharmacology and Clinical Pharmacokinetics

Avapritinib exhibited dose-proportional increases in AUC and Cmax across the dose range of 30 mg to 400 mg following both single dose and repeated doses. At the recommended dosage of 300 mg once daily, the mean (CV%) steady state Cmax of avapritinib was 813 ng/mL (52%) and the mean steady state area under the concentration-time curve (AUC0-24h) was 15400 h•ng/mL (48%). The mean plasma elimination half-life (t1/2) is 32 to 57 hours. Following repeated 300 mg once daily administration, steady-state was achieved after 15 days and avapritinib accumulated with a geometric mean accumulation ratio of 3.1 to 4.6.

ADME Properties

Absorption: The median time to peak concentration (Tmax) ranged from 2.0 to 4.1 hours following single 30 mg to 400 mg doses of avapritinib. The Cmax of avapritinib was increased by 59% and the AUC0-INF was increased by 29% when avapritinib was taken with a high-calorie,

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high-fat meal (approximately 909 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to those in the fasted state. Distribution: The mean apparent volume of distribution of avapritinib is 1200 L. In vitro protein binding of avapritinib is 98.8%. The blood-to-plasma ratio is 0.95. Metabolism: Avapritinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9 in vitro. Following a single oral dose of approximately 310 mg of radiolabeled avapritinib to healthy subjects, unchanged avapritinib (49%) and its metabolites M690 (hydroxy glucuronide; 35%) and M499 (oxidative deamination; 14%) were the major circulating compounds. Following oral administration of avapritinib 300 mg once daily in patients, the steady state AUC of M499 is approximately 80% of the AUC of avapritinib. M499 is not likely to contribute to efficacy at the recommended dose of avapritinib.

Elimination: The mean t1/2 of avapritinib was 32 hours to 57 hours following single 30 mg to 400 mg doses of avapritinib. The steady state mean apparent oral clearance of avapritinib is 19.5 L/h. Excretion: Following a single oral dose of approximately 310 mg of radiolabeled avapritinib to healthy subjects, 70% of the radioactive dose was recovered in feces (11% unchanged) and 18% in urine (0.23% unchanged).

General Dosing and Therapeutic Individualization

General Dosing

The proposed avapritinib dosing regimen is 300 mg orally once daily on an empty stomach at least one hour before and two hours after a meal. The primary evidence of efficacy and safety was provided by an open-label study, BLU-285-1101, in adult patients with unresectable or metastatic GIST, including adult patients with unresectable or metastatic GIST harboring a PDGFRα exon 18 mutation (including PDGFRα D842V mutations) and in adult patients with unresectable or metastatic GIST treated with at least 3 prior lines of therapy. Additional safety data are from a Phase 3 study in patients with advanced GIST (Study BLU-285-1303) and a dose finding study in patients with AdvSM (Study BLU-285-2101). The proposed dosage is effective and has a manageable safety profile.

Therapeutic Individualization

No clinically significant differences in the PK of avapritinib were observed based on, sex, race, body weight, mild to moderate (renal impairment, or mild to moderate hepatic impairment. The effect of severe renal impairment, end-stage renal disease, or severe hepatic impairment on the pharmacokinetics of avapritinib is unknown.

From a mechanistic perspective, the proposed indication in PDGFRα exon 18 population is acceptable based on available clinical and nonclinical evidence.

Outstanding Issues

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We will issue one PMR to assess the effect of severe hepatic impairment on the PK of avapritinib. Refer to Post-Marketing Requirements and Commitments for details.

Comprehensive Clinical Pharmacology Review

General Pharmacology and Pharmacokinetic Characteristics

Table 5: General Pharmacology and Pharmacokinetics

Pharmacology

Mechanism of Avapritinib is a tyrosine kinase inhibitor that targets PDGFRα and PDGFRα D842 mutants

Action as well as multiple KIT exon 11, 11/17 and 17 mutants. Active Moieties Avapritinib is the major circulating moiety in human plasma. No major active metabolites are identified. The most common circulating metabolites is M499, which has two enantiomers: BLU111207 (35% of avapritinib AUC at steady state) and BLU111208 (42% of avapritinib AUC at steady state). Both enantiomers have lower fraction unbound values compared to that of avapritinib. BLU111207 is 10.5-fold less potent and BLU111208 is 3.1- fold less potent compared to avapritinib against KIT D816V in vitro. M499 is not likely to contribute to efficacy at the recommended dose of avapritinib.

QT Prolongation The ability of avapritinib to prolong the QT interval was assessed in in an open-label, single-arm study in patients with GIST. Avapritinib was administered to 27 patients at the recommended dosage of 300 mg or 400 mg once daily. No large mean increase in QTc (i.e. > 20 ms) was detected at the observed steady state geometric mean maximum concentration (Cmax) of 899 ng/mL. General Information Bioanalysis Avapritinib and its major metabolite in plasma were measured using validated LC/MS-MS methods. A summary of the method validation reports is included as an appendix (19.5).

Healthy In a population PK analysis of avapritinib, the covariate analysis identified GIST disease Volunteers vs. status (healthy subject or patient with GIST) as a significant covariate on the relative Patients bioavailability of avapritinib, where patients with GIST were expected to have approximately 15% reduced bioavailability compared to healthy subjects. The effect of GIST disease status on avapritinib PK is not considered to be clinically relevant.

Drug exposure at AUC and Cmax were determined in Study BLU-285-1101 in patients at 300 mg once daily. steady state Following one single dose on Cycle 1 Day 1(C1D1), the geometric mean (CV%) AUC0-24h was following the 4140 (47%)·ng•h/mL and Cmax was 264 (62%) ng/mL. Following multiple doses at steady therapeutic state on Cycle 1 Day 15 (C1D15), the geometric mean (CV%) AUC0-24h was 15,400 dosing regimen (48%)·ng•h/mL and Cmax was 813 (52%) ng/mL. See section 19.5 for details.

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Minimal Not available. The 300 mg QD is the lowest starting dose in the dose expansion part (Part effective dose or 2) of Study BLU-285-1101. Forty-three patients were initially treated at 400 mg QD in the exposure dose expansion part (Part 2) of the trial. However, based on a joint Investigator and Sponsor review of the available safety, PK, pharmacodynamics, and clinical activity data on 13 June 2017, a new starting dose of 300 mg QD was selected as the initiation dose of avapritinib for the remainder of the expansion part of the trial with the option for dose escalation to 400 mg QD after 2 consecutive treatment cycles. None of the exon 18 patients had dose escalations from 300 to 400 mg.

Maximal Avapritinib 400 mg once daily as a monotherapy. tolerated dose or Dose Avapritinib exhibited dose-proportional increases in AUC and Cmax across the studied dose Proportionality range of 30 mg to 400 mg following both a single dose and repeated doses. See section 19.5 for detail. Accumulation Following repeated 300 mg once daily administration, steady-state was achieved after 15 days and avapritinib accumulated with a geometric mean accumulation ratio of 3.1 to 4.6.

Variability In patients after 300 mg QD doses at steady state on C1D15, the geometric mean (CV%) AUC0-24h and Cmax were 15400 (48%) ng•h/mL and 813 (52%) ng/mL, respectively. Absorption

Oral Absolute oral bioavailability has not been determined

Bioequivalent The proposed to-be-marketed formulation is 100 mg strength tablets, 200 mg strength (BE) Tablets tablets and 300 mg strength tablets. The 100 mg strength tablet was used in the formulation registrational Study BLU-285-1101. A strength-based waiver was granted for the 200 mg and 300 mg strength tablets based on in vitro data. During the development of avapritinib, 200 mg and 400 mg tablets were administered in healthy volunteer studies. Bioequivalent No clinically relevant difference between 4 × 100 mg and 1 × 400 mg strength tablets (BE) Tablets 1 × under fasted conditions (N = 62). 400 mg /4 × 100 Cmax AUClast AUC00-INF mg Strength GMR (90% CI) 1.05 (0.933, 1.19) 0.970 (0.900, 1.05) 0.969 (0.898, 1.05) Bioequivalent No clinically relevant difference between 1 × 200 mg tablets/2 × 100 mg capsules under (BE) evulation of fasted conditions (N = 30). 1 × 200 mg tablets/2 × 100 Cmax AUClast AUC00-INF mg capsules 0.898 (0.785, 1.03) 0.902 (0.808, 1.01) 0.942 (0.866, 1.02) formulation GMR (90% CI)

Oral Tmax The Tmax was between 2 and 4 hours. Food effect for Positive food effect 100 mg Tablets Cmax AUClast AUC00-INF Fasted/fed GMR (90% CI) 1.59 (1.38, 1.84) 1.27 (1.15, 1.40) 1.29 (1.14, 1.46)

Substrate Avapritinib is an inhibitor of P-glycoprotein (P-gp), BCRP, MATE1, MATE2-K, and BSEP, but transporter not an inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, OCT1, or OCT2. Avapritinib is not a systems [in vitro] substrate of P-gp or BCRP. The effect of M499 on transporter systems is unknown.

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Distribution Volume of Mean apparent volume of distribution at steady-state is 1200 L. Distribution Plasma Protein 98.8% Binding Blood to Plasma 0.95 Ratio Elimination Half -life The mean plasma elimination half-life of avapritinib was 32 hours to 57 hours.

Clearance The geometric mean apparent clearance (CL/F) at steady-state: 19.5 L/hr

Metabolism Primary Avapritinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9. metabolic pathway(s) Inhibitor/Inducer In vitro, avapritinib is a time-dependent inhibitor as well as an inducer of CYP3A. In vivo, avapritinib Cmax and AUC increased proportionally over the dose range of 30 mg to 400 mg after single dose or at steady state after once daily dose without time-dependent PK changes. The dose proportionality of avapritinib suggests that avapritinib is not a CYP3A modulator at the above dose range as avapritinib is also a sensitive CYP3A substrate. Avapritinib is an inhibitor of CYP2C9. Avapritinib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C19, or CYP2D6 at clinically relevant concentrations. Avapritinib is not an inducer of CYP1A2 or CYP2B6. M499 is an inhibitor of CYP3A, CYP2C8, or CYP2C9. M499 is not an inhibitor of CYP1A2, CYP2B6, CYP2C19, or CYP2D6 at clinically relevant concentrations. Excretion Primary Following a single oral dose of approximately 310 mg of radiolabeled avapritinib to healthy excretion subjects, 70% of the radioactive dose was recovered in feces (11% unchanged) and 18% in pathways urine (0.23% unchanged).

Clinical Pharmacology Questions

Does the clinical pharmacology program provide supportive evidence of effectiveness?

Yes. The primary evidence of effectiveness was obtained from Study BLU-285-1101. Study BLU- 285-1101 was initiated as a first-in-human (FIH) study of avapritinib but was expanded with registrational intent in advanced GIST based on initial efficacy observed in the dose escalation phase. Details regarding Study BLU-285-1101 are provided in Section 7.

Forty-three patients with unresectable or metastatic GIST who harbor PDGFRα exon 18 mutations (including PDGFRα D842V mutation), regardless of prior therapy (PDGFRα exon 18 population) received starting doses of 300 or 400 mg avapritinib. The ORR was 83.7% (95% CI: 69.3%, 93.2%), with 36 of the 43 patients achieving a best confirmed response of CR or PR. The

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ORR in the 300 mg starting dose group was slightly higher as compared to the ORR in the 400 mg group (87.5% vs 72.7%).

Is the proposed dosing regimen appropriate for the general patient population for which the indication is being sought?

The proposed dosage of 300 mg QD is effective and shows to have a manageable safety profile. Analysis of the overall safety data from 234 GIST patients with a starting dose of either 300/400 mg suggested better tolerability with avapritinib 300 mg QD relative to 400 mg QD. Specifically, there was a higher incidence of Grade 3+ AEs (82% vs 67%), AE leading to dose reduction (66% vs 41%), and AESIs of cognitive effects (48% vs 35%) in the 400 mg starting dose group compared to the 300 mg group.

Interpretation of the exposure-efficacy relationship in patients with PDGFRα Exon 18 mutations is challenging given the high response rate (ORR) and limited number of patients. Overall, there shows to be no trend for an exposure-ORR relationship in patients with PDGFRα exon 18 mutations.

Is an alternative dosing regimen or management strategy required for subpopulations based on intrinsic patient factors?

No. No clinically significant differences in the PK of avapritinib were observed based on age (18 to 90 years), sex, race (White, Black, or Asian), body weight (39.5 to 156.3 kg), mild to moderate (CLcr 30 to 89 mL/min estimated by Cockcroft-Gault) renal impairment, or mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 times ULN and any AST) to moderate (total bilirubin > 1.5 to 3 times ULN and any AST) hepatic impairment. The effect of severe renal impairment (CLcr 15 to 29 mL/min), end-stage renal disease (CLcr < 15 mL/min), or severe hepatic impairment (total bilirubin > 3 times ULN and any AST) on the pharmacokinetics of avapritinib is unknown.

A PMR is issued to assess the effect of severe hepatic impairment on avapritinib PK. The Applicant does not plan to perform a dedicated renal impairment study, as renal is a minor excretion pathway for avapritinib and severe renal impairment is not highly prevalent in the proposed patient population. The Applicant’s rationale is acceptable.

Effect of PDGFRα exon 18 and KIT variants on response:

Approximately 75% of GIST tumors are driven by oncogenic KIT or PDGFRA mutations. The remaining 15% appear to be characterized by alterations in other genes that include BRAF, NF1, or SDH (Nannini et al., 2017). Although the presence of KIT mutations was not used as a molecular selection criterion in Study BLU-285-1101, all enrolled patients had either PDGFRα or KIT mutations as determined by local or central testing.

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Over 50 PDGFRα exon 18 mutations have been reported in the literature. D842V is the most frequent (up to 75% of PDGFRα mutated tumors) and it is associated with resistance to tyrosine kinase inhibitors (TKIs) including imatinib, sunitinib, and regorafenib. Non-D842V exon 18 mutations are a diverse subset, which includes substitutions, in-frame deletions and deletions/insertions of various lengths with differential sensitivity to imatinib (Künstlinger et al., 2014; Lasota et al., 2004).

• PDGFRα Exon 18 mutation population in Study BLU-285-1101, 300/400 mg dose group (N=43):

D842V (N=38): The PDGFRα exon 18 population consisted of 43 patients (regardless of number of prior lines), and 38 had PDGFRα D842V mutations. Patients with PDGFRα D842V mutations were enrolled based on local or central mutation testing, the latter being an investigational use (b) (4) only assay, In addition, PDGFRα status was determined on study in plasma and tumor tissue (when available) for exploratory analyses using PCR-based or next generation sequencing (NGS)-based assays. The ORR was 83.7% in the whole exon 18 population and 89.5% among patients with D842V mutations.

Non-D842V (N=5): Five patients enrolled based on local testing had PDGFRα exon 18 mutations other than D842V (Table 6), of which 3 were confirmed by central testing using PCR-based or next generation sequencing (NGS)-based assays (tumor and/or plasma samples). In this subgroup of patients (N=5), the ORR was 40%. One additional patient receiving avapritinib 60 mg (not included in the efficacy population) also experienced a PR (Table 4). For additional details on responses and duration of responses, refer to Clinical Section 8.1.2.

Table 6: Best overall response for patients with PDGFRα exon 18 non-D842V mutations in Study BLU-285-1101 (N=6) PDGFRα Mutation Avapritinib Starting Best Overall Dose (mg) Response f p.D842Y a,d 300 SD p.D842_H845delinsV a 300 SD p.D842_H845del b,c,d,e 300 PR p.D842_H845del c 400 PD p.D842_H845del c,d 300 PR p.D842_I843delinsV a 60 PR Source: Reviewer-generated table based on pharmacogenomic findings (pf) tabulation dataset, Applicant response to an FDA Information Request dated November 05, 2019, and subject level response analysis (adresp) dataset. a-local testing only (tumor), b-central testing (tumor), c-central testing (plasma; sample collected from screening to cycle 1/day 1), d- 4L+ population, f-best overall confirmed response by central radiology per mRECIST 1.1 criteria, e- This patient had p.D846del based on local testing, later identified as p.D842_H845del based on central testing. At protein sequence level, p.D842_H845del and p.I843_D846del are equivalent mutations. PR=partial response, SD=stable disease, PD=progressive disease. PDGFRA reference sequences: NM_006206 (Coding DNA Sequence [CDS]) and NP_006197.1

The applicant also submitted cell line transfection assay results supporting the activity of avapritinib on various PDGFRα exon 18 mutations including substitutions, deletions and

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deletions/insertions (mostly in the D842-D846 region). Of note, based on these results, PDGFRα T674I in exon 15 appears to confer resistance to avapritinib. For details refer to Nonclinical Pharmacology/ Toxicology section 5.3.

Considering the responses with (resistant) D842V and a few other non-D842V genotypes, the non-clinical data supporting activity against exon 18 mutations, and the rarity of PDGFRα non- D842V mutations, the applicant’s proposed indication for exon 18 is acceptable provided the overall benefit-risk profile is acceptable. The representation of PDGFRα exon 18 mutations should clearly be specified in Section 14.

Are there clinically relevant food-drug or drug-drug interactions, and what is the appropriate management strategy?

Avapritinib is primarily metabolized by CYP3A4. CYP3A4 inhibitors or inducers have effects on avapritinib exposure. Avoid coadministration of avapritinib with strong or moderate CYP3A inhibitors. If coadministration of avapritinib with a moderate CYP3A inhibitor cannot be avoided, reduce the dose of avapritinib from 300 mg once daily to 100 mg once daily. Avoid coadministration of avapritinib with strong or moderate CYP3A inducers. In vitro, avapritinib is a time-dependent inhibitor as well as an inducer of CYP3A. Avapritinib is also an inhibitor of CYP2C9. The major metabolite M499 is an inhibitor of CYP3A, CYP2C8, or CYP2C9. In vitro, avapritinib is not a CYP3A modulator at 300 mg once daily.

The Cmax and AUC of avapritinib were increased when avapritinib was taken with a high-calorie, high-fat meal compared to the fasted state. Avapritinib is recommended to be administrated on an empty stomach, at least one hour before or two hours after a meal. The influence of Proton pump inhibitors (PPIs) on avapritinib bioavailability was not clinically significant based on a population PK analysis. Effect of CYP3A Inhibitors on Avapritinib Coadministration of avapritinib 200 mg single dose with itraconazole (a strong CYP3A inhibitor) 200 mg twice daily on Day 1 followed by 200 mg once daily for 13 days increased avapritinib Cmax by 1.4-fold and AUC0-INF by 4.2-fold in healthy subjects. Based on PBPK modeling, coadministration of avapritinib 300 mg once daily with itraconazole 200 mg once daily is predicted to increase avapritinib AUC by 7-fold at steady state. Coadministration of avapritinib 300 mg once daily with fluconazole 200 mg once daily (a moderate CYP3A inhibitor) is predicted to increase avapritinib AUC by 3.1-fold at steady state. Coadministration of avapritinib with cimetidine (a weak CYP3A inhibitor) is predicted to increase avapritinib AUC by 1.2-fold at steady state. Avoid coadministration of avapritinib with strong or moderate CYP3A inhibitors. If coadministration of avapritinib with a moderate CYP3A inhibitor cannot be avoided, reduce the dose of avapritinib from 300 mg orally once daily to 100 mg orally once daily. Effect of CYP3A inducers on Avapritinib

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Coadministration of avapritinib 400 mg single dose with rifampin (a strong CYP3A inducer) 600 mg once daily for 18 days decreased avapritinib Cmax by 74% and AUC0-INF by 92% in healthy subjects. Based on PBPK modeling, coadministration of avapritinib 300 mg once daily with efavirenz (a moderate CYP3A inducer) is predicted to decrease avapritinib Cmax by 55% and AUC by 62% at steady-state. Avoid coadministration of avapritinib with strong or moderate CYP3A inducers. Effect of Food on Avapritinib

The Cmax of avapritinib was increased by 59% and the AUC0-INF was increased by 29% when TRADENAME was taken with a high-calorie, high-fat meal (approximately 909 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to those in the fasted state. Avapritinib is recommended to be administrated on an empty stomach, at least one hour before or two hours after a meal. Effect of Avapritinib on CYP3A Substrate In vitro, avapritinib is a time-dependent inhibitor as well as an inducer of CYP3A and its major metabolite M499 is also an inhibitor of CYP3A. In vivo, avapritinib Cmax and AUC increased proportionally over the dose range of 30 mg to 400 mg after a single dose or at steady state after once daily dosing without time-dependent PK changes. The dose proportionality of avapritinib suggests that avapritinib is not a CYP3A modulator over the 30 to 400 mg dose range as avapritinib is also a sensitive CYP3A substrate however there is no time-dependent changes in its exposure. Effect of Avapritinib on CYP2C8 or CYP2C9 Substrate

Avapritinib is an inhibitor of CYP2C9 (R1 = 1.02) and M499 is an inhibitor of CYP2C8 (R1 = 1.23) or CYP2C9 (R1=1.16) using unbound Cmax at steady state and Ki values. None of the concomitant CYP2C8 or CYP2C9 substrates with avapritinib in studies BLU-285-1101, BLU-285-1303 and BLU- 285-2101 were sensitive substrates of CYP2C8 or CYP2C9. Effect of Acid-Reducing Agents on Avapritinib The aqueous solubility of avapritinib is pH-dependent, with higher pH resulting in lower solubility. The effect of concomitant PPI use on avapritinib PK was evaluated in the popPK model. During PK sample collection, 77 patients had 5 full days of PPI use, 7 patients had some PPI use in the prior 5 days and 259 patients never used PPIs in the prior 5 days. The effect of concomitant PPI use on relative bioavailability F1 is estimated to be 0.77. As there are 77 patients with 5 full days of PPI use in the analysis dataset, and the majority of PK samples (433 out of 718) were collected in the absorption phase within 4 hours of last dose, FDA agrees that this estimate should be relatively reliable and the effect of gastric acid reducing agents on the bioavailability of avapritinib is not clinically relevant.

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X X Youwei Bi Jiang Liu Pharmacometrics Primary Reviewer Pharmacometrics Team Leader X X Manuela Grimstein Xinyuan Zhang PBPK Primary Reviewer PBPK Team Leader X X Oluseyi Adeniyi Rosane Charlab Orbach Primary Reviewer Team Leader

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7 Sources of Clinical Data and Review Strategy

Table of Clinical Studies

No. of No. of patients Study Centers and Trial /NCT # Design Regimen/ schedule/ route Study Endpoints enrolled Population Countries Non-randomized Trial of Efficacy and Safety BLU-285-1101 Open-label, Part 1: Dose-escalation Part 1: Primary MTD and RP2D of Part 1: 46 Unresectable 17 centers/ (NAVIGATOR)/ single-arm, Part 2: MTD determined as 400 avapritinib, safety profile Part 2: 191 or metastatic 10 countries NCT02508532 dose- mg once daily, RP2D determined Part 2: ORR per mRECIST, DOR, safety GIST with or escalation, to be 300 mg once daily profile without a dose- D842V expansion mutation in PDFGRα BLU-285-1002 Multi-center, NA Primary: Assess best response, DOR, 22 Locally 3 centers/ 1 retrospective, and PFS advanced, country observational, Secondary: OS, spectrum of mutations metastatic or natural history in PDGFRα genet, time to recurrence or recurrent GIST PD following resection, sites of harboring recurrence and metastasis PDGFRα D842V mutations Randomized Trial to Support Safety BLU-285-1303 Open-label, Arm A: avapritinib 300 mg daily Primary: PFS per mRECIST 460 (planned) 3rd and 4th 92 centers/ (VOYAGER)/ randomized, Arm B regorafenib 160 mg daily Secondary: ORR m RECIST, OS, EORTC- line 17 countries NCT03465722 active control for 3 of every 4 weeks QLQ-C30, EORTC-QLQ-Q30, EORTC- unresectable QLQ-C30 GIST Non-randomized Trials to Support Safety BLU-285-2101 Open-label, Part 1: Dose-escalation Part 1: Primary MTD and RP2D of Part 1 32 Advanced 11 centers/ 2 (EXPLORER)/ single-arm, Part 2: 300 mg once daily and avapritinib, safety profile Part 2: ~55 systemic countries NCT02561988 dose 200 mg once daily Part 2: Dose finding, PK/PD and Quality (planned) mastocytosis escalation, of life dose expansion

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No. of No. of patients Study Centers and Trial /NCT # Design Regimen/ schedule/ route Study Endpoints enrolled Population Countries BLU-285-2203 Randomized Part 1: dose finding Part1: Part 1: ~ 40 Indolent and 25 centers/ 9 (PIONEER)/ placebo- Part 2 and 3: RP2D or placebo (planned) smoldering countries NCT03731260 controlled Part 2: ~72 systemic (planned) mastocytosis Part 3: patients from part 1 and 2

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Review Strategy

The key material used for the review of efficacy and safety included: • NDA 212608 • Relevant published literature (although reviewed for context, the literature was not necessary to take an action on this application)

Trial BLU-285-1101 was used for the primary analysis of efficacy and safety. The Applicant submitted a complete dataset for this study, using a data cut date of November 16, 2018. At the request of the FDA, the Applicant submitted a safety update using a data cut date of February 28, 2019. The initial dataset with the data cut date of November 16, 2018, was used for the basis of this review; however, the updated safety data was reviewed to ensure that any new safety signals would be identified.

To support the lack of activity of the approved TKIs in patients with GIST who harbor a PDGFRα D842V mutation, the Applicant submitted data from Study BLU-285-1002 a multi-center, retrospective, observational, natural history study of patients with locally advanced, metastatic or recurrent GIST harboring PDGFRAα D842V mutations.

The Applicant also submitted datasets from Studies BLU-285-2101 and BLU-285-1301. These studies were used to supplement the analysis of safety of avapritinib.

Summaries of data and statistical analyses by the reviewer were performed using JMP 12.0, SAS Version 9.4 (both SAS Institute, Inc., Cary, NC) and Excel 365 (Microsoft, Redmond, WA). MedDRA Adverse Events Diagnostic 1.5 (MAED) (FDA, Silver Spring, MD) was used to look for safety signals. Trial BLU-285-1101 was open-label and did not include a comparator arm, and therefore, the analyses of efficacy and safety are descriptive. Where possible, confidence intervals are provided to assist in the interpretation of the efficacy data. For additional statistical methodologies, see Section 8.1.1.

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8 Statistical and Clinical and Evaluation

Review of Relevant Individual Trials Used to Support Efficacy

BLU-285-1101 (NAVIGATOR)

Trial Design

Trial BLU-285-1101 is an ongoing, open-label, dose escalation, dose expansion trial of avapritinib in patients with unresectable or metastatic GIST.

Figure 6. Study Scheme BLU-285-1101

Dose escalation was conducted using a standard 3+3 design and is completed. The primary objectives of dose escalation were to assess safety and tolerability of avapritinib as monotherapy and to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of avapritinib. Dose expansion was conducted using a single-arm design, in 3 groups of patients with the following characteristics:

• Group 1: Patients with unresectable GIST who have progressed following treatment with imatinib and at least 1 of the following: sunitinib, regorafenib, sorafenib, dasatinib, pazopanib, or an experimental kinase-inhibitor therapy and who do not have a D842V mutation in PDGFRα

• Group 2: Patients with unresectable GIST harboring a D842V mutation in the PDGFRα gene

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experienced intolerance following treatment with imatinib (including in the adjuvant setting) and who have not received additional kinase-inhibitor therapy and do not have a known D842V mutation in PDGFRα

The primary objective of dose expansion is to: • Assess the overall response rate (ORR) by the Response Evaluation Criteria in Solid Tumors, version 1.1 modified for patients with GIST (mRECIST version 1.1) criteria in which lymph nodes and bone lesions were not target lesions and progressively growing new tumor nodules within a pre-existing tumor mass was counted as progression, in patients with GIST who: o harbor a D842V mutation in PDGFRα, o have progressed following treatment with imatinib and at least one other kinase inhibitor, and who are not known to have a D842V mutation in PDGFRα, o progressed on or experienced intolerance to imatinib, including in the adjuvant setting, and who have not received additional kinase-inhibitor therapy. The secondary objectives are to: • Characterize the pharmacokinetic (PK) profile of avapritinib, and correlate drug exposure with safety assessments, including changes in electrocardiogram (ECG) intervals, • Assess evidence of antineoplastic activity of avapritinib as measured by duration of response (DOR), progression free survival (PFS), and clinical benefit rate (CBR), • Assess antitumor activity as measured by Choi Criteria, to compare PFS on avapritinib with PFS on last prior anti-cancer therapy, to assess mutations in KIT, PDGFRα and other cancer-relevant genes in tumor tissue at baseline and at the end of treatment (EOT), • Determine the safety and tolerability of avapritinib.

Avapritinib was administered orally once daily on Days 1 to 28 of continuous 28-day cycles until disease progression, the development of unacceptable toxicity, or withdrawal of consent. Patients had their disease assessed by computed tomography (CT) or magnetic resonance imaging (MRI) after cycle 2 and every 2 cycles thereafter through Cycle 13. After 13 cycles were completed on trial, patients were assessed every 3 cycles.

Key Eligibility Criteria

• ≥ 18 years of age. • Eastern Cooperative Oncology Groups (ECOG) performance status (PS) of 0-2. • For Dose Escalation: Histologically- or cytologically-confirmed diagnosis of unresectable GIST or another advanced solid tumor. Patients with unresectable GIST must have disease that has progressed following imatinib and at least 1 of the following: sunitinib, regorafenib, sorafenib, dasatinib, pazopanib or an experimental kinase-inhibitor agent, or disease with a D842 mutation in the PDGFRα gene. Patients with an advanced solid tumor other than GIST must have relapsed or refractory disease without an available effective therapy. 68 Version date: April 2, 2018

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• For Dose Expansion: o Group 1: Patients must have a confirmed diagnosis of unresectable GIST that has progressed following imatinib and at least 1 of the following: sunitinib, regorafenib, sorafenib, dasatinib, pazopanib, or an experimental kinase-inhibitor agent and the patient does not have a D842V mutation in PDGFRα. o Group 2: Patients must have a confirmed diagnosis of unresectable GIST with a D842V mutation in the PDGFRα gene. The PDGFRα mutation will be identified by local or central assessment, either in an archival tissue sample or a new tumor biopsy obtained prior to treatment with avapritinib. o Group 3: Patients must have a confirmed diagnosis of unresectable GIST that has progressed and/or patients must have experienced intolerance to imatinib and not received additional kinase-inhibitor therapy. Patients must not have a known D842V mutation in PDGFRα. o Groups 1, 2, and 3: At least 1 measurable lesion defined by mRECIST version 1.1 for patients with GIST. o Groups 1 and 2: A tumor sample (archival tissue or a new tumor biopsy) has been submitted for mutational testing. o Group 3: Patients must not be known to be KIT wild type. • No prior anti-cancer drug less than 5 half-lives or 14 days (whichever is shorter) prior to the first dose of study drug. • No requirement for a concomitant medication that is a strong inhibitor or strong inducer of cytochrome P450 (CYP) 3A4. • No QT interval corrected using Fridericia’s formula (QTcF) > 450 milliseconds. • No history of a seizure disorder (e.g., epilepsy) or requirement for anti-seizure medication • No history of a cerebrovascular accident or transient ischemic attacks within 1 year prior to the first dose of study drug. • No known risk of intracranial bleeding, such as a brain aneurysm or history of subdural or subarachnoid bleeding. • No primary brain malignancy or metastases to the brain. • No clinically significant, uncontrolled, cardiovascular disease, including congestive heart failure Grades II, III or IV according to the New York Heart Association classification, myocardial infarction or unstable angina within the previous 6 months, or poorly controlled hypertension.

Dose Modification and Management Guidelines

Avapritinib was administered orally at a starting dose of 300 mg QD in continuous 28-day cycles. If the treating investigator considered it to be in the patient’s best medical interest, the dose could be increased to 400 mg QD under the following circumstances: • The patient has received two or more cycles of BLU-285 without any treatment-related AEs ≥ Grade 3 (unless the AE has resolved to Grade 1 or less), and without any cognitive,

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mood or intracranial bleeding AEs ≥ Grade 2 (regardless of resolution), and there is evidence of tumor increase. • The patient has received four or more cycles of BLU-285 without any treatment-related AEs ≥ Grade 3 (unless the AE has resolved to Grade 1 or less), and without any cognitive, mood or intracranial bleeding AEs ≥ Grade 2 (regardless of resolution), and the patient has not had a PR or CR.

Dose Reduction guidelines are presented in Table 7.

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Table 7. Dose Modification for Trial BLU-285-1101

(Source: Reproduced from Amendment 8 of Protocol BLU-285-1101 page 62)

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Statistical Analysis Plan

Efficacy Endpoints and Sample Size

Approximately 50 patients were planned for the dose determining population in dose escalation part of the study (Part 1). The primary endpoints of Part 1 include the MTD and RP2D of avapritinib and the overall safety profile of BLU-285, as assessed by the type, frequency, severity, timing, and relationship to study drug of any AEs, serious AEs (SAEs), and changes in vital signs, ECGs, and safety laboratory tests.

In the dose expansion phase of the study (Part 2), the primary efficacy endpoint is ORR, defined as the rate of confirmed CR or PR by mRECIST version 1.1 as assessed by central independent review in the response evaluable population, which includes all patients in the safety population who have at least 1 target lesion per mRECIST version 1.1, at baseline, have at least 1 post-baseline disease assessment by central radiology per mRECIST version 1.1, and have experienced no major protocol violations. Secondary endpoints of the study include duration of response (DOR), progression-free survival (PFS) by mRECIST version 1.1 as assessed by central independent review, and response rate by the Choi Criteria.

Reviewer’s comment: Time-to-event endpoints such as PFS are difficult to interpret in a non- randomized trial, and therefore are considered exploratory.

For patients with PDGFRα D842V mutation (Group 2), a sample size of 31 patients was planned to allow a test of the null hypothesis of ORR ≤ 10% versus an alternative hypothesis of ORR ≥ 35% using a Fisher’s exact test with 90% power at a two-sided 5% level of significance. An observed ORR of at least 26% in 31 patients in Group 2 will result in an exact binomial 95% CI with a lower bound that excludes 10%, as shown in Table 8.

Table 8. Expected Confidence Intervals for Group 2, N=31

Source: Reproduced from Table 13 on page 93 of Protocol Amendment 9 of BLU-285-1101, dated June 29, 2018

For patients with no PDGFRα D842V mutation in second line treatment (Group 3), a sample size of 50 patients was planned to allow for a test of the null hypothesis of ORR ≤ 10% versus an alternative hypothesis of ORR ≥ 25% using a Fisher’s exact test with 83% power at a two-sided 5% level of significance. An observed ORR of at least 20% in 50 patients in Group 3 will result in 72 Version date: April 2, 2018

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an exact binomial 95% CI with a lower bound that excludes 10%, as shown in Table 9.

Table 9. Confidence Intervals for Group 3, N=50

Source: Reproduced from Table 14 on page 93 of Protocol Amendment 9 of BLU-285-1101, dated June 29, 2018

Finally, for patients with no PDGFRα D842V mutation in 3+ line treatment (Group 1), a sample size of 100 patients was planned to allow for a test of the null hypothesis of ORR ≤ 5% versus an alternative hypothesis of ORR ≥ 15% using Fisher’s exact test with 90% power at a two-sided 5% level of significance. An observed ORR of at least 11% in 100 patients in Group 1 will result in an exact binomial 95% CI with a lower bound that excludes 5%, as shown in Table 10.

Table 10. Confidence Intervals for Group 1, N=100

Source: Reproduced from Table 15 on page 94 of Protocol Amendment 9 of BLU-285-1101, dated June 29, 2018

Protocol Amendments

The original protocol was dated May 28, 2015, and the first patient was enrolled on the study on October 12, 2015. Enrollment was completed in November of 2018, with N=237 enrolled. The study is ongoing. The study was revised a total of 8 times between activation and the data cut off date of November 16, 2018. Key protocol revisions are summarized as follows: • Amendment 6 (dated February 14, 2016) added a new primary study objective to

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determine the ORR in both patients with GIST that has progressed following treatment with imatinib and at least another kinase-inhibitor agent, and who are not known to have a D842V mutation in PDGFRα, and in patients with GIST who have progressed or who experienced intolerance to imatinib, including in the adjuvant setting, and who have not received additional kinase-inhibitor therapy and do not have a known D842V mutation in PDGRα. The study sample sizes for dose escalation and dose expansion were increased. The dose escalation population was increased from 25 to 50 accommodate the increased numbers recruited in escalation due to cohort enrichment. The dose expansion population was increased to evaluate the new primary objective, of ORR in both of the expansion groups. (b) (4) •

Study Results

Compliance with Good Clinical Practices

The Applicant stated in the NDA clinical study report for the BLU-285-1101 trial that the study was conducted in accordance with: 1. Consensus ethics principles derived from international ethics guidelines, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 2. The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines [E6] 3. Applicable laws and regulations 4. The protocol 5. Food and Drug Administration (FDA) GCP guidelines, FDA Financial Disclosure regulations

Financial Disclosure

A summary of financial disclosures for Trial BLU-285-1101 is provided in the appendix (Section 19.3). The Applicant submitted financial disclosure information from 100% of investigators; however, two sub-investigators had missing financial disclosure forms. Two principal (b) (6) investigators (sites ) had financial disclosures. Both disclosures were for grants in excess of $25,000 from the study sponsor to the investigator to fund ongoing research. Sites

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(b) (6) (b) (6) enrolled a total of patients, respectively. Neither site reported a site- specific response rate that was higher than the rates reported for the study population as a whole. Additionally, neither of these sites had lower rates of adverse events of serious adverse events compared to the study population as a whole. The Applicant took the following steps to minimize bias of the clinical study results: • Central review of imaging for primary endpoint • 100% source verification of all data points • Review of safety data (AE and SE rates to detect potential bias) It does not appear that enrollment of patients by these investigators biased the outcome of the study in favor of avapritinib.

Data Quality and Integrity

The Applicant submitted this NDA, including the data files, to the FDA CDER Electronic Document Room (EDR). The data in this submission are in Electronic Common Technical Document (eCTD) format, in accordance with FDA guidance on electronic submission. Definition files for the data sets were included. The clinical study reports and data sets are located at the following location: Application 212608 - Sequence 0001 - 0001 (1) 06/14/2019 ORIG-1 /Multiple Categories/Subcategories.

All major efficacy and safety analyses conducted by the applicant were reproduced or audited. Upon further clarification from the Applicant via responses to the FDA’s information requests during the course of the review, the reviewers were able to: • Reproduce the Applicant’s analysis and analysis results, and • Conduct FDA’s primary efficacy and safety analyses.

The integrity of the submission was supported by tracing the data in the ADAM datasets from a randomly selected subset of patients to the STDM data sets and then to the original data source (case report forms). The data provided by the Applicant in the ADAM datasets was traceable to the original data source in all cases; no anomalies were identified.

Protocol Violations/Deviations

The Applicant classified protocol violations as major or minor. A total of 470 protocol violations were reported for the 153 patients in the efficacy analysis for Trial BLU-285-1101. Table 11 lists the number of protocol violations by broad criterion. The most common deviations were assessment not performed per protocol; most of these were missing or late assessments.

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Table 11. Protocol Violations

Minor Major Total Patients with deviation 119/154 15/154 (10%) 120/154 (78%) (77%) Number of deviations 445/470 (9%) 19/470 (4.0%) 470/470 (100%) Deviations by Criterion Assessment no performed per protocol 232 (49%) 1 (0.2%) 233 (50%) Failure to Adhere to visit schedule 86 (18%) 2 (0.4%) 88 (19%) Laboratory Specimens not collected 60 (13%) 0 60 (13%) Investigational product noncomplience 33 (7%) 9 (1.9%) 42 (9%) Informed conset issue 26 (6%) 2 (0.4%) 28 (6%) Un-required assessmentor procedure performed 6 (1.3%) 0 6 (1.3%) Prohibited medication use 1 (0.2%) 1 (0.02%) 2 (0.4%) Prohibited device or procedure 1 (0.2%) 0 1 (0.2%) Serious adverse event report delay 0 2 (0.4%) 2 (0.4%) Source: Reviewer generated table – summarizing deviation analysis data (ADDV, November 16, 2018 data cut-off date, submitted by Applicant)

The Applicant identified 95% of the deviations as minor and 4% as major. The Applicant did not provide a classification for six of the events. Most of the major deviations were investigational product noncompliance including forgetting to take the investigational product, taking the wrong dose, or not withholding a dose when instructed by the investigator.

Recommended Dose

The Applicant requested an approval for 300 mg once daily for patients with GIST harboring a PDGFRα exon 18 mutations. Trial BLU-285-1101 initially determined 400 mg once daily to be the maximum tolerated dose of avapritinib and the dose expansion portion of the trial initially enrolled patients at a starting dose of 400 mg. Due to a high rate of central nervous system adverse events (see Section 8.2.4 for details), the starting dose was reduced to 300 mg. The applicant proposed pooling the data from patients who received either 300 mg or 400 mg starting dose of avapritinib in the efficacy evaluation. As seen in the following sections, FDA performed a similar analysis of efficacy and found no apparent differences in the demographics, baseline disease characteristics, or ORR between the 300 and 400 mg groups; therefore, FDA agreed with pooling of this data for the efficacy evaluation.

Efficacy Results for Patients with GIST with Exon 18 Mutations

The Applicant requested an indication for patients with GIST harboring any PDGFRα exon 18 mutation. The D842V mutation is the most common PDGFRα exon 18 mutation occurring in patients with GIST. The remaining exon 18 mutations are a diverse subset of mutations and

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occur at very low incidence rates. In Trial BLU-285-1101, the majority (38) of patients with a PDGFRα exon 18 mutation had a D842V mutation. An additional 5 patients with other PDGFRα exon 18 mutations were enrolled. These 5 patients do not represent the full spectrum of PDGFRα exon 18 mutations that may occur in patients with metastatic or unresectable GIST; however, according to FDA’s “Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease: Guidance for Industry”, patients with different rare molecular alterations may be grouped if it is reasonable to expect that the grouped patients will have similar responses and that drugs may be approved for a molecularly defined set of patients if clinical trials are successful irrespective of the extent to which patients with various rare molecular alterations were represented in the clinical trial. Extrapolation across multiple subsets may be possible despite the low frequency or absence of patients in some subsets. Therefore, FDA considered clinical data in the five patients with exon 18 mutations other than D842V and the preclinical data supporting that other exon 18 mutation are similarly inhibited by avapritinib supports the efficacy of avapritinib in patients with metastatic or unresectable GIST harboring a PDGFRA exon 18 mutation.

Patient Disposition for Patients with GIST with Exon 18 Mutations

The data cut-off date for analysis of Trial BLU-285-1101 was November 16, 2018. The first patient was enrolled on October 12, 2015. Of the 237 patients who received at least one dose of avapritinib on Trial BLU-285-1101, 204 received a starting dose of 300 or 400 mg of avapritinib and were included in the primary efficacy and safety analysis. The reasons for treatment discontinuation for all patients enrolled in BLU-285-1101 as well as for patients with GIST with exon 18 mutations included in the primary efficacy analysis are shown in Table 12.

Table 12. Treatment Discontinuation, BLU-285-1101

All Patients PDGFRA Exon 18 Enrolled in BLU- Efficacy Population 285-1101 N=43 N=237 Therapy ongoing 29 (67) 76 (32)

Discontinued treatment 14 (32) 161 (68) Adverse event 7 (16) 39 (16) Progressive disease 4 (9) 107 (45) Withdrawal of consent 1 (0.2) 5 (2.1) Investigator decision 2 (4.7) 7 (3.0) Subject noncompliance 0 1 (0.4) Other 0 2 (0.8) Source: Reviewer generated table – summarizing subject level analysis (ADSL, November 16, 2018 data cut-off date, submitted by Applicant)

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All patients were followed until withdrawal of consent, death, adverse event, protocol deviation, physician decision, pregnancy or loss to follow-up. Table 13 describes the reasons for study discontinuation.

Table 13. Study Discontinuation, BLU-285-1101

PDGFRA Exon 18 Efficacy All Patients Enrolled in Population BLU-285-1101 N=43 N=237 Follow up ongoing 35 (81) 130 (55) Discontinued study 8 (19) 107 (45) Death 5 (12) 80 (34) Adverse event 0 1 (0.4) Progressive disease 0 4 (1.7) Withdrawal of consent 1 (0.2) 13 (5) Investigator decision 1 (0.2) 6 (2.5) Lost to follow up 1 (0.2) 3 (1.3) Source: Reviewer generated table – summarizing subject level analysis (ADSL, November 16, 2018 data cut-off date, submitted by Applicant)

Demographics for GIST with a PDGFRα Exon 18 Mutation

Table 14 and Table 17 present baseline demographic characteristics for patients with GIST harboring a PDGFRα exon 18 mutation and the subset who had a D842V mutation, respectively. Mutations other than PDGFRα D842V included in the exon 18 population are deletion of D842_H845 (n=3); D842Y (n=1); and deletion of D842_H845 with insertion of V (n=1). Baseline disease characteristics for the corresponding populations are summarized in Table 15 and Table 18 while their prior therapy is detailed in Table 16 and Table 19, respectively.

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Table 14. Demographic Factors, GIST with a PDGFRα Exon 18 Mutation 300mg 400 mg 300 mg/ 400 mg N=32 N=11 N=43 Characteristic n (%) n (%) n (%) Sex

Female 11 (34) 3(27) 14(33)

Male 21 (66) 8(73) 29(67) Age Mean years (SD) 62.4 (12.5) 60.5 (10.2) 61.9 (11.8) Median years (Range) 63.5 (29, 90) 65 (35, 69) 64 (29, 90)

<65 years 19 (59) 5(45) 24(56)

≥65 years 13 (41) 6(55) 19(44)

Race

White 20 (62) 9(82) 29(67)

Asian 6 (19) 0(0) 6(14)

Black or African American 3 (9) 0(0) 3(7)

Other 1(3) 0(0) 1(2)

Unknown1 2(6) 2(18) 4(9)

Ethnicity

Not Hispanic or Latino 28(88) 9(82) 37(86)

Hispanic/Latino 1(3) 0(0) 1(2)

Not reporteda 3(9) 2(18) 5(12) Region

Europe 18(56) 7(64) 25(58)

United States 9(28) 4(36) 13(30)

Asia 5(16) 0(0) 5(12) Source: Reviewer generated table – summarizing subject level analysis datasets (ADSL, November 16, 2018 data cutoff date, submitted by Applicant) a Data on race and/or ethnicity were not collected in France country because of local regulations.

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Table 15. Baseline Disease Characteristics, GIST with a PDGFRα Exon 18 Mutation 300mg 400 mg 300 mg/ 400 mg N=32 N=11 N=43 Characteristic n (%) n (%) n (%) ECOG Performance Status 0 10 (31) 4 (36) 14 (33) 1 20 (62) 6 (55) 26 (60) 2 2 (6) 1 (9) 3 (7) Primary Tumor Site of GIST Stomach 22 (69) 8 (73) 30 (70) Peritoneum 4 (12) 0 (0) 4 (9) Small bowel 2 (6) 1 (9) 3 (7) Other 4 (13) 2 (18) 5 (14) Largest Baseline Tumor Mass

≤5 cm 15(47) 5(45) 20(47)

>5 cm to ≤10 cm 10(31) 4(36) 14(33)

>10 cm 7(22) 2(18) 9(21)

Metastatic Disease

Yes 31(97) 11(100) 42(98)

No 1(3) 0(0) 1(2)

Number of Metastatic Sites

1 20(62) 6(55) 26(60)

2 8(25) 4(36) 12(28)

3 3 (9) 1(9) 4 (9) >3 2 (6) 0 (0) 2 (5) Sites of Metastatic Diseasea,b Peritoneum 18 (56) 4 (36) 22 (51) Liver 13 (41) 7 (64) 20 (47) Abdomen/viscera 3 (9) 1 (9) 4 (9) Lymph nodes 1 (3) 1 (9) 2 (5%) Other 5 (16) 3 (27) 8 19) Source: Reviewer generated table – summarizing subject level analysis datasets (ADSL, November 16, 2018 data cutoff date, submitted by Applicant) a. May be greater than 100% as patients have more than one site of metastatic disease b. Other sites of metastatic disease include omentum, adrenals, colon, retroperitoneum, bone, appendix, and pancreas

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Table 16. Prior Therapy, GIST with a PDGFRα Exon 18 mutation 300mg 400 mg 300 mg/ 400 mg N=32 N=11 N=43 Characteristic n (%) n (%) n (%) Primary Surgical Resection

Yes 27 (84) 10 (91) 37 (86)

No 5 (16) 1 (9) 6 (14) Full Surgical Resection

Yes 9 (28) 5 (45) 14 (33)

No 23 (72) 6 (55) 29 (67) Prior TKI Therapy

Yes 28 (88) 10 (91) 38 (88)

No 4 (12) 1 (9) 5 (12)

Number of Prior Lines of TKI Median (min, max) 1 (0, 5) 1 (0, 3) 1 (0, 5)

0 4 (12) 1 (9) 5 (12)

1 13 (41) 6 (55) 19 (44)

2 6 (19) 2 (18) 8 (19)

3+ 9 (28) 2 (18) 11 (26) Best Response to Any TKI

Complete response 2(6) 0(0) 2(5) Partial response 2(6) 0(0) 2(5) Stable disease 8(25) 3(27) 11(26) Progressive disease 10(31) 3(27) 13(30) Not evaluable 5(16) 1(9) 6(14) Missing 5 (16) 4 (36) 9 (21) Prior TKI Receiveda,b Imatinib 26 (81) 9 (82) 35 (81) Sunitinib 12 (38) 3 (27) 15 (35) Regorafenib 5 (16) 2 (18) 7 (16) Other 10 (31) 0 (0) 10 (23) Source: Reviewer generated table – summarizing subject level analysis dataset and concomitant medications analysis dataset (ADSL and ADCM, November 16, 2018 data cutoff date, submitted by Applicant) a. May be greater than 100% as patients received more than one prior TKI b. Other TKIs include crenolanib, dasatinib, and sorafenib

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Table 17. Demographic Factors, GIST with a PDGFRα D842V Mutation 300mg 400 mg 300 mg/ 400 mg N=28 N=10 N=38 Characteristic n (%) n (%) n (%) Sex

Female 10 (36) 3 (30) 13 (34)

Male 18 (64) 7 (70) 25 (66) Age Mean years (SD) 61.5 (12.9) 61.3 (10.4) 61.4 (12.2) Median years (Range) 63 (29, 90) 66 (35, 69) 63.5 (29, 90)

<65 years 18 (64) 4 (40) 22 (58)

≥65 years 10 (36) 6 (60) 16 (42)

Race

White 17 (61) 8 (80) 25 (66)

Asian 6 (21) 0 (0) 6 (16)

Black or African American 3 (11) 0 (0) 3 (8)

Other 1 (4) 0 (0) 1 (3)

Unknown1 1 (4) 2 (20) 3 (8) Ethnicity

Not Hispanic or Latino 26 (93) 8 (80) 34 (89)

Hispanic/Latino 1 (4) 0 (0) 1 (3)

Not reporteda 1 (4) 2 (20) 3 (8)

Region

Europe 15 (54) 7 (70) 22 (58)

United States 8 (29) 3 (30) 11 (29)

Asia 5 (18) 0 (0) 5 (13) Source: Reviewer generated table – summarizing subject level analysis datasets (ADSL, November 16, 2018 data cutoff date, submitted by Applicant) a Data on race and/or ethnicity were not collected in France country because of local regulations.

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Table 18. Baseline Disease Characteristics, GIST with a PDGFRA D842V Mutation 300mg 400 mg 300 mg/ 400 mg N=28 N=10 N=38 Characteristic n (%) n (%) n (%) ECOG Performance Status 0 9 (32) 4 (40) 13 (34) 1 17 (61) 6 (60) 23 (61) 2 2 (7) 0 (0) 2 (5) Primary Tumor Site of GIST Stomach 21 (75) 8 (80) 29 (76) Peritoneum 3 (11) 0 (0) 3 (8) Small Bowel 1 (4) 1 (10) 2 (5) Other 3 (11) 1 (10) 4 (11)) Largest Baseline Tumor Mass

≤5 cm 13 (46) 4 (40) 17 (45)

>5 cm to ≤10 cm 6 (21) 2 (20) 8 (21)

>10 cm 9 (32) 4 (40) 13 (34)

Metastatic Disease

Yes 27 (96) 10 (100) 37 (97)

No 1 (4) 0 (0) 1 (3)

Number of Metastatic Sites

1 18 (64) 6 (60) 24 (63)

2 7 (25) 3 (30) 10 (26)

3+ 2 (7) 1 (10) 3 (8)

Sites of Metastatic Diseasea Peritoneum 17 (61) 3 (30) 20 (53) Liver 13 (46) 6 (60) 19 (50) Abdomen/viscera 1 (4) 1 (10) 2 (5) Lymph nodes 1 (4) 1 (10) 2 (5) Otherb 7 (25) 3 (30) 10 (26) Source: Reviewer generated table – summarizing subject level analysis datasets (ADSL, November 16, 2018 data cutoff date, submitted by Applicant) a. May be greater than 100% as patients have more than one site of metastatic disease b. Other sites of metastatic disease include omentum, adrenals, colon, retroperitoneum, bone, appendix, and pancreas

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Table 19. Prior Therapy, GIST with a PDGFRα D842V Mutation 300mg 400 mg 300 mg/ 400 mg N=28 N=10 N=38 Characteristic n (%) n (%) n (%) Primary Surgical Resection

Yes 25 (89) 9 (90) 34 (89)

No 3 (11) 1 (10) 4 (11) Full Surgical Resection

Yes 7 (25) 4 (40) 11 (29)

No 21 (75) 6 (60) 27 (71) Prior TKI Therapy

Yes 24 (86) 9 (90) 33 (87)

No 4 (14) 1 (10) 5 (13)

Number of Prior Lines of TKI Median (min, max) 1 (0, 5) 1 (0, 3) 1 (0, 5)

0 4 (14) 1 (10) 5 (13)

1 13 (46) 5 (50) 18 (47)

2 5 (18) 2 (20) 7 (18)

3+ 6 (21) 2 (20) 8 (21) Best Response to Any TKI

Complete response 1 (4) 0 (0) 1 (3) Partial response 1 (4) 0 (0) 1 (3) Stable disease 6 (21) 3 (30) 9 (24) Progressive disease 10 (36) 2 (20) 12 (32) Not evaluable 5 (18) 1 (10) 6 (16)

Missing 5 (18) 4 (40) 9 (24) Prior TKI Receiveda Imatinib 22 (79) 8 (80) 30 (79) Sunitinib 8 (29) 3 (30) 11 (29) Regorafenib 4 (14) 2 (20) 6 (16) Otherb 9 (32) 1 (10) 10 (26) Source: Reviewer generated table – summarizing subject level analysis dataset and concomitant medications analysis dataset (ADSL and ADCM, November 16, 2018 data cutoff date, submitted by Applicant) a. May be greater than 100% as patients received more than one prior TKI b. Other TKIs include crenolanib, dasatinib, sorafenib

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Primary Endpoint

The assessment of efficacy for patients with unresectable or metastatic GIST harboring a PDGFRα exon 18 mutation was based on a total of 43 patients, including 38 patients with PDGFRα D842V mutations, 3 patients with a deletion of D842_H845, 1 patient with D842Y, and one patient with deletion of D842_H845 and an insertion of V. The median duration of follow up for patients with PDGFRα exon 18 mutations was 10.6 months (range: 0.3 to 24.9 months). The ORR and DOR results for patients with GIST harboring PDGFRα exon 18 mutations are shown in Table 20.

Table 20. ORR and DOR Results for Patients with GIST Harboring a PDGFRα Exon 18 Mutation

PDGFRα Exon 18 PDGFRα D842V Efficacy Parameter N=43 N=38 Overall Response Rate (95% CI) 84% (69%, 93%) 89% (75%, 97%) Complete Response 7% 8% Partial Response 77% 82%

Duration of Response n=36 n=34 Median in months (Range) NR (1.9+, 20.3+) NR (1.9+, 20.3+) Patients with DOR ≥ 6 months 22 (61%) 20 (59%) Patients with DOR ≥ 12 months 8 (22%) 8 (23%) Source: Reviewer generated table – summarizing subject level analysis dataset and response analysis dataset (ADSL and ADRESP, November 16, 2018 data cutoff date, submitted by Applicant) NR- Not reached

Subgroup Analyses

Table 21 summarizes the reviewer’s subgroup analyses by key demographic characteristics. The results of subgroups analysis showed that the treatment effect was largely independent of gender, race, and age, although the small numbers limit conclusions that can be made in this subgroup analysis.

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Table 21. Subgroup Analyses by Age, Gender, and Race

PDGFRα Exon 18 PDGFRα D842V Group N=43 N=38 ORR 95% CI ORR 95% CI Sex F 13/14 (93) 66, 100 13/13 (100) 75, 100 M 23/29 (79) 79,92 21/25 (84 64, 95 Age <65 years 21/24 (88) 68, 97 20/22 (91) 71, 99 ≥65 years 15/19 (79) 54,94 14/16 (88) 62, 98 Race White 23/29 (79) 60,92 22/25 (88) 69, 97 Asian 6/6 (100) 54, 100 6/6 (100) 54, 100 Black 2/3 (67) 9, 99 2/3 (67) 9, 99 Other/Unknown 5/5 (100) 48, 100 4/4 (100) 40, 100 Region US 9/13 (69) 39,91 8/11 (73) 39, 94 Europe 22/25 (88) 69,97 21/22 (95) 77, 100 Asia 5/5 (100) 48,100 5/5 (100) 48, 100 Source: Reviewer generated table – summarizing subject level analysis dataset and response analysis dataset (ADSL and ADRESP, November 16, 2018 data cutoff date, submitted by Applicant)

Additionally, subgroup analyses were performed by baseline disease characteristics including ECOG performance status, largest baseline tumor mass, number of metastatic sites, prior TKI therapy, and number of lines of prior TKI therapies. The results of subgroups analysis showed that the treatment effect was largely independent of baseline characteristics, although the small numbers limit conclusions that can be made in this subgroup analysis.

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Table 22. Subgroup Analyses by Baseline Disease Characteristics

PDGFRα Exon 18 PDGFRα D842V Group N=43 N=38 ORR 95% CI ORR 95% CI ECOG Performance Status 0 13/14 (93) 66, 100 12/13 (92) 64, 100 1 21/26 (81) 61, 93 20/23 (87) 66, 97 2 2/3 (67) 9, 99 2/2 (100) 16, 100 Largest Baseline Tumor Mass ≤5 cm 16/20 (80) 56, 94 15/17 (88) 64, 99 >5 cm to ≤10 cm 13/14 (93) 66, 100 12/13 (92) 64, 100 >10 cm 7/9 (78) 40, 97 7/8 (88) 47, 100 Number of Metastatic Sites 0 1/1 (100) 3, 100 1/1 (100) 3, 100 1 22/26 (85) 65, 96 21/24 (88) 68, 97 2 10/12 (83) 52, 98 9/10 (90) 55, 100 3+ 3/4(75) 19,99 3/3 (100) 29, 100 Prior TKI Therapy N 5/5 (100) 48, 100 5/5 (100) 48, 100 Y 31/38 (82) 66, 92 29/33 (87) 72, 97 Number of Prior Line of TKI 0 5/5 (100) 48, 100 5/5 (100) 48, 100 1 17/19 (88) 67, 99 17/18 (94) 73, 100 2 6/8 (75) 35, 97 6/7 (86) 42, 100 3+ 8/11 (72) 39, 94 6/8 (100) 29, 100 Source: Reviewer generated table – summarizing subject level analysis dataset, concomitant medicines analysis dataset, and response analysis dataset (ADSL, ADCM, and ADRESP, November 16, 2018 data cutoff date, submitted by Applicant)

8.1.3 Integrated Review of Effectiveness

While Study BLU-285-1101 provided the only source of data to assess the efficacy of avapritinib in patients with GIST harboring a PDGFRα exon 18 mutation, the FDA reviewed published data and data provided by the Applicant from their natural history study BLU-285-1002 to understand the expected course of this subset of patients and their expected response to available therapies.

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Two retrospective analyses suggest that patients with PDGFRα D842V mutation-positive GIST respond poorly to imatinib, regorafenib, and sunitinib. These retrospective analyses genotyped 3,975 patients with GIST and identified 60 patients with PDGFRα mutations. Of these 60 patients, 32 tumors harbored a PDGFRα D842V mutation and the remainder had a mutation in PDGFRα exons 4, 12, or 18. Of the 32 patients with GIST harboring the PDGFRα D842V mutation, zero patients [95% confidence interval (CI): 0, 11%] had a response to imatinib according to Response Evaluation Criteria in Solid Tumors (RECIST). When the tyrosine kinase inhibitors imatinib, sunitinib, and others were used in second line treatment of patients with GIST tumors that harbor PDGFRα D842V mutation, the median PFS was only 2.1 months (Cassier PA, 2012). Additionally, in a study conducted by Yoo et. al., 18 patients with PDGFRα- mutant GIST patients were treated with imatinib, 9 of these patients had a PDGFRα D842V mutation and 5 of the patients with PDGFRA D842V mutations were evaluable for response. None of the 5 patients responded to imatinib as first-line treatment or to sunitinib as second- line treatment per RECIST(Yoo C, 2015). These retrospective analyses were conducted in Europe and Asia; there are no published studies describing U.S. patients who harbor a D842V mutation. To augment these data, the Applicant conducted a natural history study of unresectable or metastatic PDGFRα D842V mutated GIST, Trial BLU-285-1002.

BLU-285-1002 was a U.S. multicenter, retrospective, observation study using data collected from clinical charts to characterize the natural history of disease in patients with PDGFRα D842V driven GIST who were diagnosed from January 01, 2000, to July 01, 2016, and had been previously treated with a TKI; no treatments were administered on the study. The primary objectives were to assess the best response, duration of response (DOR), and progression free survival (PFS) for each therapy. Secondary objectives were to assess overall survival (OS), the spectrum of mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene and the methods used to identify the mutations, the time following complete resection of primary or metastatic disease to recurrence or progressive disease, and to describe site(s) of recurrence and metastasis for recurrent/metastatic PDGFRα D842-mutated GIST. For this trial best response included information about whether a patient achieve a complete response, a partial response, stable disease or progressive disease. Since each patient had whether they achieved a CR or PR recorded this can be translated into an ORR for each line of therapy they patient received.

Key inclusion criteria include • Patient ≥18 years of age at the time of diagnosis • Patient with GIST that harbors a D842 mutation in the PDGFRA gene • Patient treated with a commercially available kinase inhibitor for locally advanced, metastatic, or recurrent GIST • Patient received initial therapy between 01 January 2000 and 01 July 2016.

Statistical Analysis Plan

The primary efficacy endpoints characterized in this retrospective data collection study were best overall response, DOR, and PFS, with a secondary efficacy endpoint of OS.

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The following patient populations were evaluated and used for presentation and analysis of the data: • Intent-to-Treat (ITT) Population: All patients for whom data were collected. • First-line of Prior Treatment (FPT) Population: A subset of the ITT population that includes all patients who received a first-line treatment. • Second-line of Prior Treatment (SPT) Population: A subset of the ITT population that includes all patients who received a second-line treatment. • Third-line of Prior Treatment (TPT) Population: A subset of the ITT population that includes all patients who received a third-line treatment.

Results

Given the rarity of the PDGFRα D842V mutation, the number of patients in this natural history study is, as expected, small (N=22). Patient data was collected over a relevant time period. As seen in Table 23, the demographics and disease characteristics are representative of patients with GIST. The large tumor burden (65% had a primary tumor size >10 cm) is comparable to the patients with PDGFRα D842V-driven GIST in Study BLU-285-1101. To minimize the potential for confounding, data were only collected at 3 centers in the US where high-quality mutational analysis was done routinely. The results of this natural history study provide further information about the activity of currently available therapies in D842V-mutated GIST.

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Table 23. Demographics for Patients from Trial BLU-285-1002

Characteristic N=22

Sex

Female 7 (32) Source: Reviewer generated table – summarizing Male 15 (68) subject level analysis dataset, (ADSL, July 21, 2017 data cutoff date, submitted by Applicant) Age Mean years (SD) 56 (11.9) As shown in Table 24, only one patient had a response in any line Median years (Range) 57 (31, 72) of therapy in the retrospective Race study BLU-285-1002. This was a White 20 (91) complete response in the first line of therapy and the patient Black or African American 1 (4.5) received imatinib. Missing 1 (4.5) Table 24. ORR for Patients with Ethnicity GIST who Harbor a D842V Not Hispanic or Latino 20 (91) mutation from Study BLU-285-

Hispanic/Latino 0 (0) 1002

Missing 2 (9)

Primary Tumor Site of GIST Stomach 15 (68) Omentum 1 (4.5) Peritoneum 1 (4.5) Other 5 (23)

Largest Baseline Tumor Mass

≤5 cm 0

>5 cm to ≤10 cm 6 (27) >10 cm 11 (50) Missing 5 (23) First Line Second Line Third Line Efficacy Parameter N=22 N=19 N=16 Overall Response Rate (95% CI) 4.5 (0, 23) 0 (0, 18) 0 (0, 21) Complete Response 4.5 0 0 Partial Response 0 0 0 Source: Reviewer generated table – summarizing subject level analysis dataset and event analysis dataset,(ADSL and ADEVENT, July 21, 2017 data cutoff date, submitted by Applicant)

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8.1.4 Integrated Assessment of Effectiveness

The effectiveness of avapritinib 300 mg daily for treatment of patients with metastatic or unresectable GIST harboring a PDGFRα D842V mutation is established by the ORR of 89% (95% CI: 75, 97) with a 6-month duration of response of 88% (95% CI: 75, 100) and a 12-month duration of response of 68% (95% CI: 45, 91) as observed on trial BLU-285-1101. Patients with GIST harboring PDGFRα D842V mutations represent a rare patient population with a high unmet need that does not generally respond to any of the currently available therapies for GIST, as evidenced by two retrospective analysis from the literature and the natural history study BLU-285-1002 demonstrating that GIST harboring a PDGFRα D842V mutation responds poorly to available therapies including imatinib, regorafenib, and sunitinib. In the first retrospective study, 32 patients with PDGFRα D842V mutation positive GIST were identified; none had a response to imatinib [ORR=0% (95%CI: 0,11)]. Sunitinib and other TKIs were used as second line therapies; the ORR remained 0%. In the second retrospective study, no responses were seen with imatinib and sunitinib in 5 patients with PDGFRα D842V mutation-positive GIST for an ORR of 0% (95% CI: 0, 52). In the natural history study, of 22 patients with GIST harboring a PDGFRα D842V mutation, only one experienced a response, for an ORR of 4.5% (95% CI 0, 23).

The Applicant proposes that avapritinib is also effective in patients with GIST harboring any PDGFRα exon 18 mutation. The D842V mutation is the most common exon 18 mutation occurring in patients with GIST. The remaining exon 18 mutations are a diverse subset of mutations including substitutions, in-frame deletions, and deletions/insertions of various lengths. The Applicant submitted data from five patients with PDGFRα exon 18 mutations other than D842V; these patients do not represent the full spectrum of PDGFRα exon 18 mutations that may occur in patients with metastatic or unresectable GIST. Patients with PDGFRα exon 18 mutations other the D842V had an ORR of 40% (95% CI:5, 85). When these patients are included in the assessment, the ORR is similar to that observed in the PDGFRα D842V population: 84% (95%CI: 69, 93) with a 6-month duration of 89% (95% CI: 77, 100) and a 12- month duration of 65% (95% CI: 43, 88).

FDA’s “Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease: Guidance for Industry”, states that patients with different rare molecular alterations may be grouped if it is reasonable to expect that the grouped patients will have similar responses and that drugs may be approved for a molecularly defined set of patients if clinical trials are successful, irrespective of the extent to which patients with various rare molecular alterations were represented in the clinical trial. Extrapolation across multiple subsets may be possible despite the low frequency or absence of patients in some subsets. In order to support the expansion of the indication to the entire GIST harboring PDGFRα exon 18 mutations, the applicant submitted in vitro inhibitory activity data for avapritinib for 10 PDGFRα exon 18 mutations other than PDGFRα D842V (see Section 5.3). With the exception of one mutation, avapritinib demonstrated similar in vitro inhibitory activity against D842V mutated PGDFRα is it did PDGFRα with other exon 18 mutations. The clinical data in the five patients with exon 18 mutations other than D842V and the preclinical data supporting that other exon 18 mutation 91 Version date: April 2, 2018

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are similarly inhibited by avapritinib supports the efficacy of avapritinib in patients with metastatic or unresectable GIST harboring a PDGFRA exon 18 mutations.

Review of Safety

8.2.1 Safety Review Approach

Review of safety focused on the patients with unresectable or metastatic GIST who received 300 or 400 mg of avapritinib daily on Trial BLU-285-1101 (Primary Safety Population). Pooled safety data from all patients with unresectable or metastatic GIST who received avapritinib at any dose in both Trial BLU-285-1101 and Trial BLU-285-1303 was also evaluated (GIST Safety Population). This population provided information to evaluate dose-toxicity relationships in patients with GIST. Available safety data from all patients with advanced tumors included GIST and systemic mastocytosis were used to support the analysis of safety in a larger patient population (Pooled Safety Population).

The Applicant requested an approval for 300 mg once daily for patients with GIST. Trial BLU- 285-1101 initially determined 400 mg once daily to be the maximum tolerate dose of avapritinib and the dose expansion portion of the trial initially enrolled patients at a starting dose of 400 mg. Due to a high rate of central nervous system adverse events, the starting dose was reduced to 300 mg. FDA performed an efficacy analysis of both 300 mg and 400 mg and determined that pooling the data from both dose levels was appropriate (see section 8.1.2 for details). The Primary Safety Population in this review includes all patients from the efficacy evaluation. Although this includes both 300 and 400 mg dose levels and there is a clear dose- toxicity relationship shown by the reduction of the starting dose from 400 mg to 300 mg due to toxicity, the indicated dose will be the 300 mg and inclusion of the data from the 400 mg dose adds more information about the potential toxicities of avapritinib (and represents a conservative analysis of safety). Therefore, FDA agrees with pooling these dose levels for the safety evaluation. All safety analyses were conducted on the complete dataset provided by the Applicant for Trial BLU-285-1101, which used a data cutoff date of November 16, 2018.

8.2.2 Review of the Safety Database

Overall Exposure

A total of 204 patients with unresectable or metastatic GIST assigned a dose of 300 or 400 mg avapritinib daily received at least one dose of avapritinib on Trial BLU-284-1101 and were included in the Primary Safety Population. An additional 62 patients with unresectable or metastatic GIST who were treated at any dose (range 30 mg to 600mg once daily) on Trials BLU- 285-1101 and BLU-285-1303 were included in the GIST Safety Population. Finally, an additional 68 patients with systemic mastocysotsis treated at any dose of avapritinib in Trial BLU-285-2101 were included in the Pooled Safety Population (Table 25).

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Table 25. Safety Populations

Population Trial(s) n <300 mg 300/400mg >400 mg Primary Safety Population GIST BLU-285-1101 204 0 204 0

BLU-285-1101 GIST Safety Population GIST 267 30 234 3 BLU-285-1303 GIST BLU-285-1101 Pooled Safety Population Systemic BLU-285-1303 335 50 282 3 Mastocystosis BLU-285-2102 Source: Reviewer generated table – summarizing subject level analysis datasets (ADSL, November 16, 2018 data cutoff date, submitted by Applicant)

A summary of exposure to avapritinib is provided in Table 26. In the Primary Safety Population (n=204), the median duration of exposure to avapritinib was 5.4 months (mean 6.5 months), with a maximum exposure time of 24.6 months. In the GIST Safety Population (n=267), the median duration of exposure to avapritinib was 4.8 months (mean 7.2 months), with a maximum exposure time of 36.7 months. In the Pooled Safety Population pool (n=335), the median duration of exposure to avapritinib was 5.8 months (mean 8.4 months), with a maximum exposure time of 36.7 months. A total of 76 patients were exposed to avapritinib for more than 12 months and a total of 24 patients were exposed to avapritinib for more than 24 months.

Table 26. Duration of Exposure to Avapritinib in the Safety Population

0 to 3 >3 to 6 >6 to 9 >9 to 12 >12 to 18 >18 to 24 >24 months months months months months months months Primary Safety 73 41 35 27 15 12 1 Population (n=204) GIST Safety Population 104 49 36 30 18 18 12 (n=267) Pooled Safety 108 62 48 41 26 26 24 Population (n=335) Source: Reviewer generated table – summarizing subject level analysis datasets (ADSL, November 16, 2018 data cutoff date, submitted by Applicant)

Seventy-five percent (n=204) of the patients in the Primary Safety pool and 67% (n=337) of patients in the Pooled Safety Population received avapritinib 300 mg daily, which is the Applicant’s proposed dose for marketing. Another 60 (18%) in the Pooled Safety Population received >300 mg daily and 50 (15%) received <300 mg daily (Table 27).

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Table 27. Planned Total Daily Dose of Avapritinib in The Safety Population

Primary GIST Safety Pooled Safety Safety Population Population Population N=267 N=335 Planned Total Daily Dose N=204 30 mg 0 6 9 60 mg 0 6 12 90 mg 0 6 6 100 mg 0 0 3 130 mg 0 0 3 135 mg 0 6 6 200 mg 0 6 11 300 mg 154 184 225 400 mg 50 50 57 600 mg 0 3 3 Source: Reviewer generated table – summarizing subject level analysis datasets (ADSL, November 16, 2018 data cutoff date, submitted by Applicant)

Adequacy of the safety database:

Demographic information for patients analyzed for safety are summarized in Table 28.

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Table 28. Demographics of the Safety Populations

Primary GIST Safety Pooled Safety Safety Population Population Population N=267 N=335 N=204 n (%) n (%) Characteristic n (%) Sex Female 80 (39) 102 (38) 135 (40) Male 124 (61) 165 (62) 200 (60) Age Mean years (SD) 59.5 (11.1) 59.8 (11.2) 60.2 (11.4) Median years (Range) 62 (29,90) 62 (25, 91) 62 (25, 91) <65 years 122 (60) 160 (60) 194 (58) ≥65 years 82 (40) 107 (40) 138 (41) Race White 146 (72) 188 (70) 246 (73) Asian 21 (10) 29 (11) 31 (9) Black or African American 8 (3.9) 11 (4.1) 12 (3.6) Other 7 (3.4) 9 (3.4) 10 (3.0) Unknown1 22 (11) 30 (11) 36 (11) Ethnicity Not Hispanic or Latino 172 (84) 223 (84) 285 (85) Hispanic/Latino 6 (2.9) 6 (2.2) 9 (2.7) Not reported1 26 (13) 38 (14) 41 (12)

Region Europe 95 (47) 121 (45) 134 (40) United States 92 (45) 108 (40) 162 (48) North America 92 (45) 119 (45) 173 (52) Asia 17 (8) 27 (10) 28 (8) Source: Reviewer generated table – summarizing subject level analysis datasets (ADSL, November 16, 2018 data cutoff date, submitted by Applicant)

The size of the safety database is adequate to provide a reasonable estimate of adverse reactions that may be observed with avapritinib, and the duration of treatment is adequate to allow assessment of adverse reactions over time. There are no randomized data regarding the safety of avapritinib in comparison to either a standard of care agent or placebo, which would

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be helpful in understanding the contribution of the underlying disease to adverse reactions. The demographics of the patients included in the safety pool (Table 36) are representative of typical patients with GIST that participate on clinical trials.

8.2.3 Adequacy of Applicant’s Clinical Safety Assessments

Issues Regarding Data Integrity and Submission Quality

The quality of the safety data submitted was adequate to allow substantial primary review. The Applicant provided analysis-ready datasets for subjects on Trial BLU-285-1101, BLU-285-1303, and BLU-285-2101 as well as narratives for subjects on all clinical trials who: • Died within 30 days of last dose of study drug • Discontinued from study drug due to an adverse event • Experienced a treatment-related serious adverse event • Experienced an adverse event of special interest o Cognitive Effects o Intracranial hemorrhage A subset of safety data was traced back to the primary source (individual case report forms) and no discrepancies were identified.

Categorization of Adverse Events

Adverse events and severe adverse events were defined according to ICH E2A guidelines. Adverse events were reported down to the investigator’s verbatim term, graded by the investigator using the NCI-CTCAE for adverse events Version 4.03 for Studies BLU-285-1101 and BLU-285-2101 and version 5.0 for Study BLU-285-1303, and coded by the Applicant using MedDRA version 18.1. Terms that referred directly to relapse, persistence of disease or progression of GIST or systemic mastocytosis were excluded from the FDA’s analyses. Treatment-emergent adverse events (TEAE) excluded events that started before the start of the study drug or that started more than 30-days after the last dose of avapritinib. TEAEs were summarized by maximum grade per patient.

The FDA compared the verbatim adverse event term with the coded MedDRA preferred term for all adverse events reported on studies BLU-285-1101, BLU-285-1303, and BLU-285-2101 and did not identify any irregularities. The FDA grouped some related preferred terms for all analyses. SMQ analysis was also performed using MAED, and no additional safety signals were identified beyond those discussed below.

8.2.4 Safety Results

Deaths

Sixty-eight deaths were identified in the primary safety population (33%), 81 deaths were identified in the GIST Safety Population (30%), and 85 deaths were identified in the Pooled

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Safety Population (25%). Approximately half of all deaths on study occurred on or within 30 days after discontinuation of avapritinib (Table 29). The datasets provided by the applicant identified disease progression as the cause of death in 17 of the 24 deaths (71%) within 30 days and 52 of the 68 total deaths (76%) in the primary safety population. In the GIST Safety Population and the Pooled Safety Population, disease progression was identified as the cause of death in 21 of the 33 deaths (64%) and 24 of the 37 deaths (65%) that occurred within 30 days, respectively and 64 of the 81 total deaths (79%) and 66 of the 85 deaths (78%), respectively. Other reported causes of death that occurred in more than 1 patient within 30 days of treatment in any of the safety populations were sepsis (n=3) and tumor hemorrhage (n=2).

Table 29. Primary Reason for All Deaths

Primary GIST Safety Pooled Safety Safety Population Population Population N=267 N=335 Primary Cause of Death N=204 All deaths 68 (33) 81 (30) 85 (25) Disease progression 52 (25) 64 (24) 66 (20)

Adverse Events 7 (3.4) 12 (4.5) 15 (6) Unknown 9 (4.4) 10 (3.7) 12 (3.6)

Deaths within 30 Days of Treatment 24 (12) 33 (12) 37 (11) Disease progression 17 (8) 21 (8) 24 (7) Adverse Events 7 (3.4) 12 (4.5) 13 (4.5) Unknown 0 0 0 Source: Reviewer generated table – summarizing subject level analysis datasets (ADSL, November 16, 2018 data cutoff date, submitted by Applicant)

Reviewer Comment: This reviewer conducted analyses of the narrative summaries and adverse event listings to verify the cause of death described by the Applicant for all deaths attributed to a TEAE or other and deaths that occurred within 30 days of the last dose of avapritinib regardless of attributed cause.

Table 30 provides a tabular listing of the deaths that occurred within 30 days of receipt of avapritinib. Thirty-seven patients died within 30 days of the last dose of avapritinib. This review determined that the majority (n=23, 62%) of deaths that occurred within 30-day of the last dose of avapritinib were due to disease progression, and that another 6 (16% ) were clearly related to another underlying medical conditions. There were 8 deaths considered by this reviewer to be at least possibly related to avapritinib. The investigator did not assess any of these deaths as related to treatment with avapritinib.

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Table 30. Deaths Occurring within 30 Days of the Last Dose of Avapritinib Study Study Investigator Dose Patient ID Age/Sex Day of Day of Assessed Cause of Brief Description of Probable Cause of Death Related (mg) Last Dose Death Death

(b) (6) Patient died of hyperbilirubinemia in the setting N 61/F 30 78 97 Hyperbilirubinemia of metastatic disease to liver 68/M 60 330 348 Progressive disease Progressive Disease N 52/M 90 60 75 Progressive disease Progressive Disease N 59/M 90 745 754 Progressive disease Progressive Disease N Patient experienced unexplained hepatic failure Y 6 days after undergoing a laparotomy. The 77/M 135 547 554 Progressive disease patient died from hepatic failure leading to circulatory failure and respiratory collapse. 68/F 200 310 318 Progressive disease Progressive disease N Patient suddenly lost consciousness at home Y 73/M 300 243 243 Cardiac failure and was unable to be resuscitated. 76/F 300 56 61 Progressive disease Progressive disease N 62/M 300 56 84 Progressive disease Progressive disease N 64/M 300 42 44 Progressive disease Progressive disease N 55/F 300 56 60 Progressive disease Progressive disease N 62/M 300 213 224 Progressive disease Progressive disease N Patient experienced an event of anemia, N melena and coffee ground emesis which was 66/F 300 240 242 Progressive disease thought to be secondary to a tumor hemorrhage. This event was ongoing until drug was discontinued on day 240. The patient died

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from a tumor hemorrhage on day 242 of the study. (b) (6) 68/F 300 49 60 Progressive disease Progressive disease N 55/M 300 52 54 Progressive disease Progressive disease N 64/F 300 59 86 Progressive disease Progressive disease N 78/M 300 140 162 Progressive disease Progressive disease N 52/M 300 45 69 Progressive disease Progressive disease N Patient presented with generalized weakness Y and breathing problems on day 62. Chest x-ray was notable for right lower lobe pneumonia. 65/M 300 61 65 Sepsis Patient had a blood culture positive for E. coli. Patient developed hypotension and died on day 65 due to sepsis On day 163 patient presented with generalize Y weakness and was hospitalized with acute kidney injury, anemia, hypothermia, pneumonia, and sepsis. On day 165 patient had an MRI that showed a large multifocal 67/F 300 163 182 Progressive disease neoplastic liver mass consistent with metastatic disease. Patient was initially treated for sepsis; however, once new metastatic disease was diagnosed the patient was discharged to hospice and died on day 182 due to sepsis 65/M 300 29 31 Progressive disease Progressive disease N 42/M 300 226 249 Progressive disease Progressive disease N 61/F 400 105 121 Progressive disease Progressive disease N 63/F 400 23 37 Progressive disease Progressive disease N

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(b) (6) 67/F 400 195 200 On day 195 patient present with confusion, Y progressive asthenia and was hospitalized with hypotension, anemia and a blood culture was positive for methicillin-resistant Staphylococcus Sepsis aureus and urine culture was positive for E. coli. Additionally, chest xray was positive for pneumonia. Patient was treated with antibiotics. Patient died on day 200 from sepsis 65/F 400 46 52 On day 47 the patient was admitted to the N hospital secondary to tumor infiltration into the intestine, hypotension and severe anemia. An emergency gastroscopy revealed diffuse seepage of blood at several sites in the region of the tumor. The patient was treated with Tumor hemorrhage blood transfusion and argon plasma coagulation resulting in successful hemostasis; however, patient had recurrence of tumor hemorrhage and associated anemia on day 49 and was transition to palliative care. The patient died on day 52 secondary to tumor hemorrhage. 68/M 400 168 191 Progressive disease Progressive disease N 60/M 400 28 30 Patient died on day 30 due to respiratory Y Progressive disease failure. No pneumonia or other cause of respiratory failure was identified. 44/M 400 26 35 Progressive disease Progressive disease N 53/M 400 6 11 Progressive disease Progressive disease N 55/M 300 42 70 Progressive disease Progressive disease N 66/M 300 18 18 Patient was hospitalized on day 3 due to Y Pleural effusion abdominal pain and dyspnea. Patient remained in the hospital until day 17 of the study and was

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discharged. On day 18 patient died from a pleural effusion (b) (6) 71/M 300 66 67 Progressive disease leading to multi-organ N Multi-organ failure failure 82/M 30 193 197 On day 193 patient experienced a N Acute myeloid transformation of his systemic mastocytosis to leukemia acute myeloid leukemia and died 4 days later from acute myeloid leukemia 76/M 300 302 320 On day 302 patient discontinued drug due to Y thrombocytopenia. Six days after discontinuation patient was hospitalized for Staphylococcal vomiting initially through to be gastroenteritis sepsis but was found to have staphylococcal sepsis. Patients was treated with antibiotics, steroids and pressors. Patient died on day 320 from sepsis. 68/M 300 259 275 Day 247 patients with hospitalized due to N abdominal pain and an SAE of gastric hemorrhage secondary to gastric antral vascular ectasia and non-cirrhotic portal hypertensive Gastric hemorrhage gastropathy. During this hospitalization the patient continued treatment with avapritinib and as also related for sepsis; however gastric hemorrhage continued and worsened. Patient died on day 275 due to gastric hemorrhage. Source: Reviewer generated table – summarizing subject level analysis datasets (ADSL, November 16, 2018 data cutoff date, submitted by Applicant)

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Sepsis was clearly the root cause of death in 4 cases. Review of the narratives of these cases did no reveal any underlying immunosuppression, neutropenia or leukopenia that would make patients more susceptible to infection. However, in three of the four cases, the patient had underlying pneumonia that was likely the source of the infection. In at least two of these cases the pneumonia may have been due to progressive disease.

Reviewer Comment: There is not a clear causal relationship between avapritinib and sepsis; however, given that four patients had fatal outcomes from sepsis, and there are limitations of the data due to lack of randomization, this cause of death will be included in labeling in Section 6.1 (listed under SAEs).

The other four deaths considered by this reviewer to be at least possibly related to avapritinib all had different underlying causes including the following: • Pleural effusion • Respiratory failure • Cardiac failure • Hepatic failure

Reviewer Comment: All four of these events are considered at least possibly related to treatment with avapritinib, but since each occurred in only one patient in the safety population the relationship between avapritinib and these events cannot be determined. Given the rarity of these events and their uncertain relationship to avapritinib, these events will not be included in labeling.

Serious Adverse Events

A total of 106 (52%) of the patients in the Primary Safety Population, 137 (51%) of patients in the GIST Safety Population, and 172 (51%) of patients in the Pooled Safety Population experienced a treatment-emergent serious adverse event. The number of patients who experienced an SAE in each SOC are listed in Table 31.

Table 31. Serious Adverse Events by System Organ Class

Primary Safety GIST Safety Pooled Safety Population Population Population N=204 N=267 N=335 System Organ Class All Grades All Grades All Grades n (%) n (%) n (%) All patients with adverse event 106 (52) 137 (51) 172 (51) Gastrointestinal disorders 32 (16) 42 (16) 53 (16) Infections and Infestations 17 (8) 23 (9) 33 (10) Blood and lymphatic system disorders 19 (9) 23 (9) 29 (9) Respiratory, thoracic and mediastinal disorders 12 (6) 16 (6) 20 (6) Nervous system disorders 11 (5) 14 (5) 20 (6) General disorders and Administration site conditions 11 (5) 16 (6) 18 (5) Metabolism and nutrition disorders 9 (4.4) 9 (3.4) 12 (3.6)

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Primary Safety GIST Safety Pooled Safety Population Population Population N=204 N=267 N=335 System Organ Class All Grades All Grades All Grades n (%) n (%) n (%) Renal and urinary disorders 8 (3.9) 10 (3.7) 11 (3.3) Neoplasms benign, malignant and unspecified 5 (2.5) 9 (3.4) 12 (3.6) Cardiac disorders 5 (2.5) 6 (2.2) 6 (1.8) Psychiatric disorders 5 2.5) 8 (3.0) 10 (3.0) Hepatobiliary disorders 2 (1.0) 5 (1.9) 8 (2.4) Injury, poisoning and procedural complications 1 (0.5) 2 (0.7) 8 (2.4) Reproductive system and breast disorders 1 (0.5) 2 (0.7) 2 (0.6) Skin and subcutaneous tissue disorders 1 (0.5) 2 (0.7) 3 (0.9) Musculoskeletal and connective tissue disorders 0 1 (0.4) 3 (0.9) Ear and labyrinth disorders 0 2 (0.7) 2 (0.6) Endocrine disorders 0 2 (0.7) 2 (0.6) Eye disorders 0 1 (0.4) 2 (0.6) Immune system disorders 0 1 (0.4) 2 (0.6) Investigations 0 2 (0.7) 2 (0.6) Vascular disorders 0 1 (0.4) 1 (0.3) Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018, submitted by Applicant)

Table 32 displays the most frequent (> 1%) serious adverse events experienced by patients with metastatic or unresectable GIST who received avapritinib 300 or 400 mg daily (the Primary Safety Population).

Table 32: Serious Adverse Events by Preferred Term

Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) Anemiaa 19 (9) 18 (9) 23 (9) 22 (8) 29 (9) 27 (8) Gastrointestinal hemorrhageb 10 (4.9) 7 (3.4) 14 (5) 9 (3.4) 15 (4.4) 12 (3.6) Cognitive disorderc 7 (3.4) 5 (2.5) 9 (3.4) 6 (2.2) 10 (3.0) 8 (2.4) Abdominal paind 6 (2.9) 6 (2.9) 9 (3.4) 9 (3.4) 9 (2.7) 9 (2.7) Sepsis 5 (2.5) 5 (2.5) 5 (1.9) 5 (1.9) 5 (1.5) 5 (1.5) Pleural Effusion 5 (2.5) 3 (1.5) 7 (2.6) 5 (1.9) 10 (3.0) 6 (1.8) Acute kidney injury 4 (2.0) 3 (1.5) 6 (2.2) 5 (1.9) 7 (2.1) 6 (1.8) Vomiting 4 (2.0) 3 (1.5) 5 (1.9) 4 (1.5) 7 (2.1) 5 (1.5) Pneumonia 3 (1.5) 3 (1.5) 3 (1.1) 3 (1.1) 7 (2.1) 7 (2.1) Transient ischemic attack 3 (1.5) 1 (0.5) 3 (1.1) 1(0.4) 3 (0.9) 1 (0.3) Tumor hemorrhage 3 (1.5) 3 (1.5) 4 (1.5) 4 (1.5) 4 (1.2) 4 (1.2) Diarrhea 2 (1.0) 2 (1.0) 3 (1.1) 3 (1.1) 3 (0.9) 3 (0.9) Ascites 2 (1.0) 2 (1.0) 2 (0.8) 2 (0.8) 4 (1.2) 3 (0.9) Intestinal Obstruction 2 (1.0) 2 (1.0) 2 (0.8) 2 (0.8) 2 (0.6) 2 (0.6) Melaena 2 (1.0) 2 (1.0) 2 (0.8) 2 (0.8) 2 (0.6) 2 (0.6) Fatigue/asthenia 2 (1.0) 2 (1.0) 2 (0.8) 2 (0.8) 2 (0.6) 2 (0.6) Dyspnea 2 (1.0) 2 (1.0) 2 (0.8) 2 (0.8) 2 (0.6) 2 (0.6) Aspiration pneumonia 2 (1.0) 1 (0.5) 2 (0.8) 1 (0.4) 2 (0.6) 1 (0.3) Dehydration 2 (1.0) 1 (0.5) 2 (0.8) 1 (0.4) 2 (0.6) 1 (0.3)

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Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) Hypoglycemia 2 (1.0) 2 (1.0) 2 (0.8) 2 (0.8) 2 (0.6) 2 (0.6) Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018, submitted by Applicant) a Includes the PT terms of anemia and decreased hemoglobin b Includes PT terms of upper gastrointestinal hemorrhage, gastrointestinal hemorrhage c Includes PT terms of memory impairment, cognitive disorder, confusional state, disturbance in attention, mental impairment, somnolence, encephalopathy, mental status changes, disorientation, and abnormal thinking. d Includes PT terms of abdominal pain, upper abdominal, lower abdominal pain, abdominal discomfort, abdominal tenderness

Dropouts and/or Discontinuations Due to Adverse Effects

Overall, 75% of treated patients had a dose interruption, dose reduction, or permanent discontinuation due to an adverse event (Table 33).

Table 33. Treatment Interruptions, reductions or withdrawals

Primary GIST Safety Pooled Safety Safety Population Population Population N=267 N=335 N=204 Interruption 136 (67) 176 (66) 223 (67) Dose reduction 99 (49) 123 (46) 166 (50) Withdrawal 33 (17) 54 (20) 65 (19) Any of the above 154 (75) 196 (73) 251 (75) Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, submitted by Applicant)

The most common TEAE leading to interruption of avapritinib are shown in Table 34 in decreasing order. The table includes only those events that occurred in > 2% of subjects with metastatic or unresectable GIST who received 300 or 400 mg avapritinib daily in the Trial Blu- 285-1101 (Primary Safety Population).

Table 34. TEAEs Leading to Dose Interruption

Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) Cognitive disordera 25 (12) 3 (1.5) 31 (12) 4 (1.5) 36 (11) 7 (2.1) Anemia 22 (11) 17 (8) 26 (10) 20 (7) 34 (10) 28 (8) Fatigue/asthenia 21 (10) 7 (3.4) 26 (10) 8 (3.0) 28 (8) 9 (2.7) Edemab 18 (9) 2 (1.0) 23 (9) 4 (1.5) 25 (7) 5 (1.5) Nausea 14 (7) 1 (0.5) 20 (7) 2 (7) 23 (7) 3 (0.9) Hyperbilirubinemia 12 (6) 6 (2.9) 13 (5) 7 (2.6) 15 (4.5) 8 (2.3) Vomiting 12 (6) 2 (1.0) 15 (6) 3 (1.1) 18 (5) 4 (1.2)

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Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) Abdominal painc 10 (4.9) 4 (2.0) 12 (4.5) 6 (2.2) 15 (4.5) 5 (1.5) Diarrhea 9 (4.4) 4 (2.0) 11 (4.1) 5 (1.9) 12 (3.5) 6 (1.8) Neutropenia 7 (3.4) 7 (3.4) 8 (3.0) 8 (3.0) 8 (2.4) 8 (2.4) Pleural effusion 7 (3.4) 2 (1.0) 8 (3.0) 2 (0.8) 10 (3.0) 2 (0.6) Gastrointestinal hemorrhaged 7 (3.4) 5 (2.5) 12 (4.5) 8 (3.0) 18 (5) 14 (4.2) Increased creatinine 6 (2.9) 0 8 (3.0) 0 10 (3.0) 0 Dizziness 5 (2.5) 0 7 (2.6) 0 8 (2.4) 1 (0.3) Ascites 4 (2.0) 1 (0.5) 5 (1.9) 2 (0.7) 6 (1.8) 2 (0.6) Pneumonia 4 (2.0) 3 (1.5) 4 (1.5) 3 (1.1) 10 (3.0) 8 (2.4) Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018, submitted by Applicant) a.Includes PT terms memory impairment, cognitive disorder, confusional state, disturbance in attention, mental impairment, somnolence, encephalopathy, mental status changes, disorientation, and abnormal thinking. bInlcudes PT terms face swelling, conjunctival edema, eye edema, eyelid edema, orbital edema, periorbital edema, face edema, mouth edema, pharyngeal edema, peripheral edema, edema, generalized edema, localized edema, peripheral swelling, testicular edema. c Includes PT terms of abdominal pain, upper abdominal, lower abdominal pain, abdominal discomfort, abdominal tenderness dIncludes PT terms of upper gastrointestinal hemorrhage, gastrointestinal hemorrhage

The most common TEAE leading to dose reductions of avapritinib are shown in Table 35 in decreasing order. The table includes only those events that occurred in > 1 patient with metastatic or unresectable GIST who received 300 or 400 mg avapritinib daily in Trial BLU-285- 1101 (Primary Safety Population).

Table 35. TEAEs Leading to Dose Reductions

Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) Fatigue/Asthenia 21 (10) 5 (2.5) 26 (10) 6 (2.2) 30 (9) 8 (2.4) Cognitive effecta 18 (9) 1 (0.5) 22 (8) 1 (0.4) 29 (9) 2 (0.6) Edemab 16 (8) 0 19 (7) 2 (0.7) 30 (9) 3 (0.9) Anemia 11 (5) 11 (5) 15 (6) 13 (5) 24 (7) 19 (6) Hyperbilirubinemia 10 (5) 5 (2.5) 10 (3.7) 5 (1.9) 11 (3.3) 6 (1.8) Nausea 7 (3.4) 1 (0.5) 11 (4.1) 2 (0.7) 14 (4.2) 3 (0.9) Neutropenia 7 (3.4) 5 (2.5) 7 (2.6) 5 (1.9) 7 (2.1) 5 (1.5) Dyspnea 4 (2.0) 1 (0.5) 4 (1.5) 1 (0.4) 4 (1.2) 1 (0.3) Pleural effusion 4 (2.0) 2 (1.0) 4 (1.5) 2 (0.7) 6 (1.8) 2 (0.6) Vomiting 4 (2.0) 1 (0.5) 6 (2.2) 1 (0.4) 8 (2.4) 2 (0.6) Dizziness 3 (1.5) 1 (0.5) 4 (1.5) 1 (0.4) 4 (1.2) 1 (0.3) Hypokinesia 3 (1.5) 0 3 (1.1) 0 3 (0.9) 0 Abdominal painc 2 (1.0) 1 (0.5) 2 (0.7) 1 (0.4) 2 (0.6) 1 (0.3) Ascites 2 (1.0) 0 3 (1.1) 1 (0.4) 4 (1.2) 1 (0.3) Increased creatinine 2 (1.0) 0 3 1.1) 0 3 (0.9) 0 Diarrhea 2 (1.0) 2 (1.0) 3 (1.1) 2 (0.7) 5 (1.5) 2 (0.6) Hypophosphatemia 2 (1.0) 2 (1.0) 2 (0.7) 2 (0.7) 2 (0.6) 2 (0.6) Thrombocytopenia 2 (1.0) 1 (0.5) 2 (0.7) 1 (0.4) 7 (2.1) 5 (1.5) Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018, submitted by Applicant)

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a.Includes PT terms memory impairment, cognitive disorder, confusional state, disturbance in attention, mental impairment, somnolence, encephalopathy, mental status changes, disorientation, and abnormal thinking. b Inlcudes PT terms face swelling, conjunctival edema, eye edema, eyelid edema, orbital edema, periorbital edema, face edema, mouth edema, pharyngeal edema, peripheral edema, edema, generalized edema, localized edema, peripheral swelling, testicular edema c Includes PT terms of abdominal pain, upper abdominal, lower abdominal pain, abdominal discomfort, abdominal tenderness

The most common TEAE leading to dose discontinuations of avapritinib are shown in Table 36 in decreasing order. The table includes only those events that occurred in > 1 patient with metastatic or unresectable GIST who received 300 or 400 mg avapritinib daily in the Trial BLU- 285-1101 (Primary Safety Population).

Table 36. TEAEs Leading to Dose Discontinuations

Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) Cognitive effecta 4 (2.0) 4 (2.0) 6 (2.2) 4 (1.5) 8 (2.4) 5 (1.5) General Physical Health 3 (1.5) 3 (1.5) 3 (1.1) 3 (1.1) 3 (0.9) 3 (0.9) Deterioration Sepsis 3 (1.5) 3 (1.5) 3 (1.1) 3 (1.1) 3 (0.9) 3 (0.9) Fatigue/asthenia 2 (1.0) 1 (0.5) 2 (0.7) 1 (0.4) 2 (0.6) 1 (0.3) Abdominal painb 2 (1.0) 0 3 (1.1) 1 (0.4) 3 (0.9) 1 (0.3) Vomiting 2 (1.0) 0 2 (0.7) 0 2 (0.6) 0 Anemia 2 (1.0) 2 (1.0) 2 (0.7) 2 (0.7) 2 (0.6) 2 (0.6) Acute kidney injury 2 (1.0) 2 (1.0) 3 (1.1) 3 (1.1) 3 (0.9) 3 (0.9) Tumor hemorrhage 2 (1.0) 2 (1.0) 2 (0.7) 2 (0.7) 2 (0.6) 3 (0.6) Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018, submitted by Applicant) a .Includes PT terms memory impairment, cognitive disorder, confusional state, disturbance in attention, mental impairment, somnolence, encephalopathy, mental status changes, disorientation, and abnormal thinking. b Includes PT terms of abdominal pain, upper abdominal, lower abdominal pain, abdominal discomfort, abdominal tenderness

Significant Adverse Events

The applicant identified intracranial hemorrhage and cognitive effects as significant risks during development of avapritinib and provided analysis of these toxicities in Trials BLU-258-1101, 285-1303, and BLU-285-2101. FDA also conducted detailed analysis for the following additional safety concerns: KIT class effects and rash; the results of these analyses are described below.

Intracranial Bleeding

The applicant identified intracranial bleeding in preclinical studies when it was noted that death in the dog studies occurred at high doses due to multifocal hemorrhage in the spinal cord and brain. Intracranial bleeding also occurred in the clinical trials. In BLU-285-1101 and BLU-285- 2101, imaging of the brain by CT scan or MRI was performed at screening, and the first day of cycles 2 through 4. To further understand the relationship between avapritinib and intracranial bleeding, the FDA reviewed events of intracranial bleeding, including narratives.

The applicant and FDA review identified intracranial bleeding in 2 (1.0%) patients in the Primary

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Safety Population, 3 (1.1%) of patients in the GIST Safety Population, and 10 (3.0%) of patients in the Pooled Safety Population (Table 37). In the Primary Safety Population, 0.5% (n=1) of patients had Grade 3-4 intracranial bleeding. In the GIST Safety Population, 0.7% (n=2) of patients had Grade 3-4 intracranial bleeding. In the Pooled Safety Population, 1.5% (n=5) of patients had Grade 3-4 intracranial bleeding. Avapritinib was permanently discontinued in 1 (0.5%) patient in the Primary Safety Population, 2 (0.7%) patients in the GIST Safety Populations, and 3 (0.9%) of patients in the Pooled Safety Population due to intracranial bleeding. No patients in the Primary Safety Population or the GIST Safety Population had their dose interrupted or reduced due to intracranial bleeding. The dose of avapritinib was reduced in 1 (0.3%) patient and interrupted 4 (1.2%) patients in the Pooled Safety Population secondary to intracranial bleeding.

Table 37. Intracranial Bleeding

Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) Intracranial bleeding 2 (1.0) 1 (0.5) 3 (1.1) 2 (0.7) 10 (3.0) 5 (1.5) Intracranial hemorrhage 1 (0.5) 1 (0.5) 1 (0.4) 1 (0.4) 4 (1.2) 1 (0.3) Subdural hematoma 1 (0.5) 0 1 (0.4) 0 5 (1.5) 3 (0.9) Cerebral hemorrhage 0 0 1 (0.4) 1 (0.4) 1 (0.3) 1 (0.3) Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, submitted by Applicant)

The rate of intracranial hemorrhage was higher in the Pooled Safety Population than in either the Primary Safety Population or the GIST Safety Population. Intracranial bleeding occurred in 3 of 267 (1.1%) patients with GIST treated at any dose of avapritinib, while 7 of 68 (10.3%) patients with advanced systemic mastocytosis treated at any dose of avapritinib experienced intracranial bleeding. The applicant reports that confounding factors were present in all 7 patients with advanced systemic mastocytosis, including thrombocytopenia in 6 patients with platelet counts ranging from 22 x 109/L to 60 x 109/L, hypertension in 5 patients, aspirin use in 2 patients, and associated trauma in 1 patient. In the GIST Safety Population, confounding factors were found in 2 of the 3 patients with intracranial bleeding including hypertension, aspirin use and cavernous hemangioma in one patient and associated trauma in the other patient.

Reviewer Comment: Although confounding factors were identified in the majority of cases with intracranial bleeding, none of the confounding factors with the possible exception of trauma would lead to intracranial bleeding on their own. Platelet counts as low as 20 x 109/L generally are not sufficient to cause spontaneous intracranial bleeding in the absence of co-existing platelet dysfunction. Additionally, all of the patients with hypertension did not have malignant hypertension at the time of intracranial bleeding. Given preclinical studies showing intracranial bleeding as well as the occurrence of intracranial bleeding during the clinical trial of avapritinib, it is the conclusion of this reviewer that intracranial bleeding is associated with treatment with avapritinib and should be included in the warning and precautions of product labeling to inform providers of the potential risk of intracranial bleeding in patients with GIST who will receive avapritinib. Additionally, more information needs to be collected about the association between 107 Version date: April 2, 2018

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avapritinib and intracranial bleeding, this reviewer recommends a PMR to collect more information about intracranial bleeding in the ongoing Trial BLU-285-1303. This trial has recently been amended to include scheduled head imaging to evaluate patients for intracranial bleeding.

CNS Effects

In the original submission, the Applicant provided an evaluation of cognitive effects; in this evaluation the Applicant provided an evaluation of the four preferred terms of memory impairment, cognitive disorder, confusion state, and encephalopathy. To more comprehensively assess the full range of CNS adverse reactions in addition to the cognitive effects identified by the applicant, FDA evaluated the broader set of preferred terms in Table 38.

Table 38. Preferred terms included in CNS Effects

Group Term Preferred Term Cognitive Impairment Memory impairment Amnesia Cognitive disorder Confusional state Disturbance in attention Dementia Mental impairment Encephalopathy Mental disorder Mental status changes Abnormal thinking Retrograde amnesia Dizziness Dizziness Sleep disorders Sleep disorder Insomnia Somnolence Speech disorders Speech disorder Aphasia Dysarthria Slow Speech

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Hallucinations Auditory hallucination

Visual hallucination Hallucination Mood disorders Agitation Anxiety Depression Depressed mood Dysphoria Irritability Mood altered Nervousness Personality Changes Suicidal ideation

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The FDA reviewed all reported adverse events of CNS effects including narratives when available. As seen in Table 39, CNS effects occurred in 60% of patients in the Primary Safety Population, 5% of these events were Grade 3 or 4; 58% of patients in the GIST Safety Population, 6% were Grade 3 or 4; and 58% of the Pooled Safety Population, 6% were Grade 3 or 4. Avapritinib was permanently discontinued in 2.9% of patients in the Primary Safety Population, 3.4% of patients in the GIST Safety Population, and 3.9% of patients in the Pooled Safety Population due to a CNS effect. Avapritinib was dose reduced in 12% of patients in the Primary Safety Population,10% of patients in the GIST Safety Population, and 10% of patients in the Pooled Safety Population due to a CNS effect. Avapritinib was interrupted in 18% of patients in the Primary Safety Population, 19% of patients in the GIST Safety Population, and 17% of patients in the Pooled Safety Population due to a CNS effect. The subcategories of CNS effects as defined by the clinical reviewer are described in more detail below.

Table 39. CNS Effects

Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) CNS Effects 127 (62) 11 (5) 154 (58) 16 (6) 195 (58) 19 (6) Cognitive impairment 97 (48) 10 (4.9) 116 (43) 11 (4.1) 142 (42) 13 (3.9) Dizziness 45 (22) 1 (0.5) 53 (20) 1 (0.4) 66 (20) 2 (0.6) Sleep disorders 33 (16) 0 36 (13) 0 50 (15) 1 (0.3) Mood effects 26 (13) 2 (1.0) 37 (14) 5 (1.9) 44 (13) 5 (1.5) Speech disorders 16 (8) 0 18 (7) 0 21 (6.3) 0 Hallucinations 6 (2.9) 0 7 (2.6) 0 7 (2.1) 0 Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018, submitted by Applicant)

Cognitive Impairment

Cognitive impairment, defined by the preferred terms listed in Table 46, occurred in 48% of patients in Primary Safety Population, 4.9% of these events were Grade 3 or 4; 43% of patients in the GIST Safety Population, 4.1% were Grade 3 or 4; and 42% of the Pooled Safety Population, 3.9% were Grade 3 or 4. In the primary safety population, 4 (1.3%) patients required permanent discontinuation of avapritinib for cognitive impairment. Avapritinib was dose reduced in 10% of patients and interrupted in 14% of patients due to cognitive impairment in the primary safety population. In the pooled safety population, 10 (3.0%) patients required permanent discontinuation of avapritinib for cognitive impairment. Avapritinib was dose reduced in 9% of patients and interrupted in 8% of patients due to cognitive impairment. The most commonly occurring preferred terms related to cognitive impairment in all safety populations are displayed in Table 40.

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Table 40. Cognitive Impairment

Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) Cognitive impairment 97 (48) 10 (4.9) 116 (43) 11 (4.1) 142(42) 13 (3.9) Memory impairment 60 (29) 1 (0.5) 70 (26) 1 (0.4) 83 (25) 1 (0.3) Cognitive disorder 22 (11) 2 (1.0) 29 (11) 3 (1.3) 36 (11) 4 (1.2) Confusional state 15 (7) 4 (2.0) 17 (6) 4 (1.5) 22 (7) 4 (1.2) Disturbance in attention 15 (7) 0 17 (6) 0 20 (6) 0 Mental impairment 7 (3.4) 2 (1.0) 7 (2.6) 2 (0.7) 7 (2.1) 2 (0.6) Encephalopathy 3 (1.5) 2 (1.0) 3 (1.1) 2 (0.7) 6 (1.8) 5 (1.9) Mental status changes 2 (1.0) 1 (0.5) 2 (0.7) 1 (0.4) 3 (0.9) 2 (0.6) Amnesia 1 (0.5) 0 4 (1.5) 0 7 (2.1) 0 Mental disorder 1 (0.5) 0 1 (0.4) 0 1 (0.3) 0 Abnormal thinking 1 (0.5) 0 1 (0.4) 0 1 (0.3) 0 Retrograde amnesia 1 (0.5) 0 1 (0.4) 0 1 (0.3) 0 Dementia 0 0 0 0 1 (0.3) 0 Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018, submitted by Applicant)

The applicant provided narratives for the 11 patients in the pooled safety database who experienced a serious (Grade ≥3) adverse event of cognitive impairment after receiving 300 or 400 mg of avapritinib. Of these 11 patients, 10 had potential pre-existing confounding factors for the development of cognitive impairment including history of alcoholism, concomitant medications including zolpidem, benzodiazepine, and opioids, as well as a history of microangiopathic leukoencephalopathy. Despite the pre-existing conditions, three had positive de-challenge and re-challenge, and all patients who had preexisting symptoms of cognitive impairment experienced worsening of their symptoms after starting treatment with avapritinib.

The applicant and this reviewer also performed an analysis of age and cognitive effects. Cognitive impairment occurred at a higher rate in patients ≥65 years of age. Across all safety populations, the preferred term with the largest difference between those <65 years of age and those ≥65 years of age was confusional state (Table 41).

Table 41. Cognitive Impairment by Age Group

Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 <65 years ≥65 years <65 years ≥65 years <65 years ≥65 years N=122 N=82 N=160 N=107 N=194 N=138 Preferred Term n(%) n (%) n(%) n (%) n(%) n (%) Cognitive impairment 54 (44) 45 (55) 62 (39) 54 (50) 73 (38) 66 (48) Memory impairment 34 (28) 26 (32) 38 (24) 31 (29) 47 (24) 37 (27) Cognitive disorder 11 (9) 11 (13) 13 (8) 16 (15) 16 (8) 19 (14) Confusional state 6 (5) 9 (11) 7 (4.4) 10 (9) 9 (4.6) 12 (9) Disturbance in attention 4 (3.3) 11 (13) 5 (3.1) 12 (11) 7 (3.6) 12 (9) Somnolence 3 (2.5) 4 (4.9) 3 (1.9) 5 (4.7) 3 (1.5) 6 (4.3) Amnesia 0 1 (1.2) 3 (1.9) 1 (0.9) 5 (2.6) 2 (1.5) 111 Version date: April 2, 2018

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Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 <65 years ≥65 years <65 years ≥65 years <65 years ≥65 years N=122 N=82 N=160 N=107 N=194 N=138 Preferred Term n(%) n (%) n(%) n (%) n(%) n (%) Mental impairment 1 (0.8) 1 (1.2) 4 (2.5) 3 (2.8) 4 (2.1) 3 (2.2) Encephalopathy 1 (0.8) 2 (2.4) 1 (0.6) 2 (1.9) 2 (1.0) 3 (2.2) Mental status changes 1 (0.8) 1 (1.2) 1 (0.6) 0 1 (0.5) 1 (0.7) Mental disorder 1 (0.8) 0 1 (0.6) 0 1 (0.5) 0 Abnormal thinking 1 (0.8) 0 1 (0.6) 0 1 (0.5) 0 Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018, submitted by Applicant)

Reviewer Comment: Cognitive impairment was reported in 11% more patients ≥65 years old; however, individual preferred terms included in the group analysis had much smaller differences. Additionally, this is not a randomized trail so these differences may represent differences due to age only. Therefore, although cognitive impairment was more commonly reported in older patients; given the limitations of the data derived from single arm studies, additional data from RCT will be collected to further assess whether age may increase the risk of cognitive impairment.

Dizziness

Dizziness occurred in 22% of patients in the Primary Safety Population, 0.5% of these were Grade 3 or 4; 20% of patients in the GIST Safety Population, 0.3% were Grade 3 or 4; and 20% of the Pooled Safety Population, 0.6% were Grade 3 or 4. No patients in the Primary Safety Population, 1 (0.3%) patient in the GIST Safety Population, and 1 (0.3%) patient in the Pooled Safety Population required permanent discontinuation of avapritinib for dizziness. Avapritinib was dose reduced in 3 (1.5%) patients in the Primary Safety Population, 4 (1.5%) patients in the GIST Safety Population, and 4 (1.2%) patients in the Pooled Safety Population due to dizziness. Avapritinib was interrupted in 5 (2.5%) patients in the Primary Safety Population, 8 (3.0%) patients in the GIST Safety Population, and 8 (2.4%) patients in the Pooled Safety Population due to dizziness.

Speech Effects

Speech effects, defined by the preferred terms listed in Table 47, occurred in in 8% of patients in the Primary Safety Populations, 7% of patients in the GIST safety population, and 6% of patients in the Pooled Safety Population. Avapritinib was not permanently discontinued, dose reduced, or interrupted for any patient due to a speech effect. The most commonly experienced adverse event within the grouped preferred term are displayed in Table 42.

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Table 42. Speech Effects

Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) Speech effects 16 (8) 0 18 (7) 0 21 (6.3) 0 Speech disorder 9 (4.4) 0 11 (4.1) 0 11 (3.3) 0 Aphasia 8 (3.9) 0 8 (3.0) 0 11 (3.3) 0 Dysarthria 2 (1.0) 0 2 (0.7) 0 2 (0.6) 0 Slow Speech 1 (0.5) 0 1 (0.4) 0 1 (0.3) 0 Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018, submitted by Applicant)

Mood effects

Mood effects, defined by the preferred terms listed in Table 47, occurred in 13% of patients in the Primary Safety Populations, 14% of patients in the GIST Safety Population, and 12% of patients in the Pooled Safety Population. Avapritinib was not permanently discontinued for mood effects in any of the safety populations. Avapritinib was dose reduced in 2 (1.0%) patients in the Primary Safety Population, 2 (0.7%) patients in the GIST Safety Population, and 3 (1.5%) patients in the Pooled Safety Population due to mood effects. Avapritinib was interrupted in 3 (2.5%) of patients in the Primary Safety Population, 5 (3.1%) of patients in the GIST Safety Population, and 5 (2.5%) of patients in the Pooled Safety Population due to mood effects. The most commonly experienced adverse event within the grouped preferred term are displayed in Table 43.

Table 43. Mood Effects

Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) Mood effects 26 (13) 2 (1.0) 37 (14) 5 (1.9) 41 (12) 5 (1.5) Anxiety 15 (7) 1 (0.5) 19 (7) 2 (0.7) 21 (6) 2 (0.6) Depression 7 (1.5) 0 14 (5) 0 15 (5) 0 Depressed mood 3 (1.5) 0 4 (1.5) 1 (0.4) 4 (1.2) 1 (0.3) Agitation 1 (0.5) 0 1 (0.4) 0 1 (0.3) 0 Mood altered 1 (0.5) 0 3 (1.1) 1 (0.4) 3 (0.9) 1 (0.3) Nervousness 1 (0.5) 0 1 (0.4) 0 1 (0.3) 0 Personality change 1 (0.5) 1 (0.5) 1 (0.4) 1 (0.4) 1 (0.3) 1 (0.3) Dysphoria 0 0 0 0 1 (0.3) 0 Irritability 0 0 0 0 1 (0.3) 0 Suicidal ideation 0 0 0 0 0 0 Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018, submitted by Applicant)

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Sleep effects

Sleep effects, defined by the preferred terms listed in Table 47, occurred in 14% of patients in the Primary Safety Population, 13% of patients in the GIST Safety Population, and 13% of patients in the Pooled Safety Population. Avapritinib was not permanently discontinued, dose reduced, or interrupted for any patient due to a sleep effect. The most commonly experienced adverse event within the grouped preferred term are displayed in Table 44.

Table 44. Sleep Effects

Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) Sleep effects 33 (16) 0 36 (13) 0 44 (13) 1 (0.3) Insomnia 26 (13) 0 34 (13) 0 42 (13) 1 (0.3) Somnolence 7 (3.4) 0 8 (3.0) 0 9 (2.7) 0 Sleep disorder 2 (1.0) 0 2 (0.7) 0 2 (0.6) 0 Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018, submitted by Applicant)

Hallucinations

Hallucinations, defined by the preferred terms listed in Table 47, occurred in 2.9% of patients in the Primary Safety Population, 2.6% of patients in the GIST safety population, and 2.1% of patients in the Pooled Safety Population. One patient in the primary safety population required permanent discontinuation of avapritinib for hallucinations and one patient required dose interruption. The most commonly experienced adverse event within the preferred term are displayed in Table 45.

Table 45. Hallucinations

Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) Hallucinations 6 (2.9) 0 7 (2.6) 0 7 (2.1) 0 Visual hallucinations 2 (1.0) 0 3 (1.1) 0 3 (0.9) 0 Auditory hallucinations 2 (1.0) 0 1 (0.7) 0 3 (0.6) 0 Hallucinations 2 (1.0) 0 2 (0.7) 0 2 (0.6) 0 Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018, submitted by Applicant)

Reviewer Comment: CNS effects including cognitive impairment occurred in 62% of patients in the primary safety population. The majority of these adverse events were Grade 1 or 2; however, avapritinib was permanently discontinued in 2.9% of patients in the Primary Safety Population, 3.4% of patients in the GIST Safety Population, and 3.9% of patients in the Pooled Safety Population due to a CNS effect. Avapritinib was dose reduced in 12% of patients in the

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Primary Safety Population, 10% of patients in the GIST Safety Population, and 10% of patients in the Pooled Safety Population due to a CNS effect. Avapritinib was interrupted in 18% of patients in the Primary Safety Population, 19% of patients in the GIST Safety Population, and 17% of patients in the Pooled Safety Population due to a CNS effect. It is the conclusion of this reviewer that these CNS effects are associated with treatment with avapritinib and should be included in the warning and precautions of product labeling in order to inform providers of the potential risk of CNS effects in patients with GIST who will receive avapritinib. Additionally, more information needs to be collected about the association between avapritinib and CNS effects including incidence, severity, and out comes; this reviewer recommends a PMR to collect more information about CNS effects in the ongoing randomized Trial BLU-285-1303. This evaluation will also include information collected in the patient reported outcomes being collected in Trial BLU-285-1303.

KIT Class effects

Avapritinib is a tyrosine kinase inhibitor that targets PDGFRα, PDGFRα D842 mutants, and other exon 18 mutants, as well as KIT and multiple KIT exon 11, 11/17, and 17 mutants. Given that avapritinib has activity against KIT, FDA performed an analysis of adverse events associated with KIT inhibition. Table 46 displays the preferred terms used to evaluate KIT class effects of avapritinib.

Table 46. Preferred terms included in KIT Class Effects

Group Term Preferred Term Edema Conjunctival edema Angioedema Eye edema Eyelid edema Face edema Generalized edema Localized edema Edema Peripheral edema Mouth edema Orbital edema Papilledema Periorbital edema Pharyngeal edema Testicular edema

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Myelosupression Anemia

Neutropenia Neutrophil count decreased Thrombocytopenia Platelet count decreased Rash Rash Erythematous rash Follicular rash Generalized rash Macular rash Maculopapular rash Papular rash Pruritic rash Dermatitis Acneiform dermatitis Skin pigment changes Skin depigmentation Skin hyperpigmentation Skin discoloration Skin hypopigmentation Hair color changes Hair color changes Hypertension Hypertension Cardiac disorders Cardiac failure Cardiac disorder Cardiac failure congestive Cardiovascular disorder Angina pectoris Thyroid disorders Hypothyroidism Hyperthyroidism QT prolongation ECG QT prolongation Palmar-plantar erythrodysaesthesia Palmar-plantar erythrodysaesthesia syndrome

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The majority of patients (91% in the Primary Safety Population, 87% in the GIST Safety Population, and 90% in the Pooled Safety Population) experienced at least one adverse event associated with KIT inhibition. The majority of these were Grade 1 or 2. Additionally, the rates of these adverse events were consistent with other targeted therapies with KIT inhibition (Table 47). The subcategories of KIT inhibition are further evaluated below.

Table 47. KIT Associate Adverse Events

Primary Safety GIST Safety Pooled Safety Population Population Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) KIT effects 185 (91) 78 (39) 233 (87) 95 (36) 300 (90) 135 (40) Edema 147 (72) 4 (2.0) 186 (69) 7 (2.6) 248 (74) 10 (3.0) Myelosupression 114 (56) 67 (33) 140 (52) 79 (30) 186 (56) 113 (34) Hair pigmentation changes 43 (21) 1 (0.5) 55 (21) 1 (0.4) 75 (22) 2 (0.6) Rash 47 (23) 4 (2.1) 52 (19) 5 (1.9) 67 (20) 5 (1.5) Hypertension 17 (8) 6 (2.9) 25 (9) 7 (2.6) 30 (9) 10 (3) Skin pigmentation changes 6 (2.9) 0 10 (3.7) 0 13 (3.9) 0 Cardiac disorders 5 (2.5) 3 (1.5) 5 (1.9) 2 (0.7) 6 (1.8) 4 (1.2) Thyroid disorders 4 (2.0) 0 7 (2.6) 1 (0.4) 7 (2.1) 1 (0.3) QT Prolongation 3 (1.5) 0 3 (1.1) 0 7 (2.1) 1 (0.3) Palmar-plantar erythrodysaesthesia 3 (1.5) 0 3 (1.1) 0 3 (0.9) 0 Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018, submitted by Applicant)

Edema

As seen in Table 48, Edema occurred in 72% of patients in the Primary Safety Population, 2.0% were Grade 3 or 4; 69% of patients in the GIST Safety Population, 2.6% were Grade 3 or 4; and 74% of the Pooled Safety Population, 3.0% were Grade 3 or 4. Two (1.0%) patients in the Primary Safety Population required permanent discontinuation of avapritinib for edema. Avapritinib was dose reduced in 17 (8%) patients in the Primary Safety Population, 18 (7%) patients in the GIST Safety Populations, and 29 (9%) patients in the Pooled Safety Population due to edema. Avapritinib was interrupted in 19 (9%) patients in the Primary Safety Population, 20 (7%) patients in the GIST Safety Populations, and 21 (6%) patients in the Pooled Safety Population due to edema.

Table 48. Edema

Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) Edema 147 (72) 4 (2.0) 186 (69) 7 (2.6) 248 (74) 10 (3.0) Periorbital edema 83 (41) 1 (0.5) 104 (39) 2 (0.7) 154 (46) 5 (1.5) Peripheral edema 63 (31) 2 (1.0) 80 (30) 3 (1.1) 103 (31) 3 (0.9) 117 Version date: April 2, 2018

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Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) Facial edema 50 (25) 1 (0.5) 62 (23) 1 (0.4) 69 (21) 1 (0.3) Eyelid edema 18 (9) 0 22 (8) 0 23 (7) 0 Orbital edema 3 (1.5) 0 3 (1.1) 0 3 (0.9) 0 Generalized edema 2 (1.0) 1 (0.5) 3 (1.1) 1 (0.4) 4 (1.2) 1 (0.3) Papilledema 2 (1.0) 0 2 (0.7) 0 3 (0.9) 0 Conjunctival edema 1 (0.5) 0 2 (0.7) 0 4 (1.2) 0 Angioedema 1 (0.5) 0 1 (0.4) 0 1 (0.3) 0 Eye edema 1 (0.5) 0 2 (0.7) 0 2 (0.6) 0 Mouth edema 1 (0.5) 0 1 (0.4) 0 1 (0.3) 0 Testicular edema 1 (0.5) 0 2 (0.7) 0 2 (0.6) 0 Localized edema 0 0 1 (0.4) 0 2 (0.6) 0 Edema 0 0 1 (0.4) 0 3 (0.9) 0 Pharyngeal edema 0 0 0 0 1 (0.3) 0 Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018, submitted by Applicant)

Myelosuppression

As seen in Table 49, myelosuppression occurred in 56% of patients in the Primary Safety Population,33% were Grade 3 or 4; 52% of patients in the GIST Safety Population, 30% were Grade 3 or 4; and 56% of the Pooled Safety Population, 34% were Grade 3 or 4. Three (1.5%) patients in the Primary Safety Population, 3 (1.1%) patients in the GIST Safety Population, and 4 (1.2%) patients required permanent discontinuation of avapritinib for myelosuppression. Avapritinib was dose reduced in 21 (10%) patients in the Primary Safety Population, 24 (9%) patients in the GIST Safety Population, and 41 (12%) patients in the Pooled Safety Population due to myelosuppression. Avapritinib was interrupted in 37 (18%) patients in the Primary Safety Population, 43 (16%) patients in the GIST Safety Populations, and 59 (18%) patients in the Pooled Safety Population due to myelosuppression.

Table 49. Myelosuppression

Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) Myelosupression 114 (56) 67 (33) 140 (52) 79 (30) 186 (56) 113 (34) Anemia 102 (50) 58 (28) 126 (47) 68 (25) 162 (48) 86 (26) Neutropeniaa 28 (14) 11 (6) 34 (13) 14 (5) 43 (13) 22 (7) Thrombocytopeniab 17 (8) 1 (0.5) 18 (7) 1 (0.4) 42 (13) 16 (5) Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018, submitted by Applicant) aIncludes PT terms neutrophil count decreased, neutropenia bIncludes PT terms thrombocytopenia, platelet count decreased

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Hair Pigment Changes

Hair pigment changes occurred in 21% of patients in the Primary Safety Population; 21% of patients in the GIST Safety Population; and 22% of the Pooled Safety Population. No patients required permanent discontinuation of avapritinib for hair pigment changes. Avapritinib was dose reduced in 2 (1.0%) patients in the Primary Safety Population.

Rash

As seen in Table 50, rash occurred in 23% of patients in the Primary Safety Population, 2.1% were Grade 3 or 4; 19% of patients in the GIST Safety Population, 1.9% were Grade 3 or 4; and 20% of the Pooled Safety Population, 1.5% were Grade 3 or 4. No patients required permanent discontinuation due to rash. Avapritinib was dose reduced in 3 (1.5%) patients in the Primary Safety Population, 4 (1.5%) patients in the GIST Safety Populations, and 5 (1.5%) patients in the Pooled Safety Population due to rash. Avapritinib was interrupted in 5 (2.5%) patients in the Primary Safety Population, 7 (2.6%) patients in the GIST Safety Populations, and 9 (2.7%) patients in the Pooled Safety Population due to rash.

Table 50. Rash

Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) Rash 47 (23) 4 (2.1) 52 (19) 5 (1.9) 67 (20) 5 (1.5) Rash 26 (13) 1 (0.5) 33 (12) 2 (0.7) 42 (13) 2 (0.6) Maculopapular rash 10 (5) 2 (1.0) 14 (5) 2 (0.7) 16 (5) 2 (0.6) Erythematous rash 3 (1.5) 1 (0.5) 4 (1.5) 1 (0.4) 6 (1.8) 1 (0.3) Macular rash 3 (1.5) 0 3 (1.1) 0 3 (0.9) 0 Follicular rash 1 (0.5) 0 2 (0.7) 0 2 (0.6) 0 Generalized rash 1 (0.5) 0 1 (0.4) 0 1 (0.3) 0 Papular rash 1 (0.5) 0 1 (0.4) 0 4 (1.2) 0 Pruritic rash 0 0 1 (0.4) 0 5 (1.5) 0 Dermatitis 0 0 0 0 1 (0.3) 0 Acneiform dermatitis 0 0 3 (1.1) 0 5 (1.5) 0 Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018 submitted by Applicant)

Reviewer Comment: Given the risk of Stevens-Johnson syndrome (SJS)/ toxic epidermologic necrolysis (TEN) that has been observed with other KIT inhibitors, this reviewer requested narratives for all Grade 3 rashes experienced by patients treated at any dose of avapritinib. These narratives were reviewed and there was no evidence that any of the rashes were SJS or TEN.

Hypertension

Hypertension occurred in 8% of patients in the Primary Safety Population, 2.9% were Grade 3

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or 4; 9% of patients in the GIST Safety Population, 2.6% were Grade 3 or 4; and 9% of the Pooled Safety Population, 1.5% were Grade 3 or 4. No patients required permanent discontinuation of avapritinib for hypertension. Avapritinib was dose reduced in 1 (0.3%) patient and was interrupted in 4 (1.2%) patients in the Pooled Safety Population secondary to hypertension.

Skin Pigment Changes

As seen in Table 51, skin pigment changes occurred in 2.9% of patients in the Primary Safety Population, 3.7% of patients in the GIST Safety Population, and 3.9% of the Pooled Safety Population. No action was taken with avapritinib for skin pigment changes.

Table 51. Skin Pigment Changes

Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) Skin Pigment Changes 6 (2.9) 0 10 (3.7) 0 13 (3.9) 0 Skin hypopigmentation 4 (2.0) 0 6 (2.2) 0 8 (2.4) 0 Skin discoloration 2 (1.0) 0 3 (1.1) 0 4 (1.2) 0 Skin depigmentation 0 0 0 0 1 (0.3) 0 Skin hyperpigmentation 0 0 1 (0.4) 0 1 (0.3) 0 Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018, submitted by Applicant)

Cardiac Disorders

As seen in Table 52, cardiac disorders occurred in 2.5% of patients in the Primary Safety Population, 1.0 % were Grade 3 or 4; 1.9% of patients in the GIST Safety Population, 2.6% were Grade 3 or 4; and 1.8% of the Pooled Safety Population, 0.9% were Grade 3 or 4. There was one fatal event of cardiac failure, see Section 8.2.4 for more information. One (0.3%) patient in the Pooled Safety Population required permanent discontinuation and 4 (1.2%) patients in the Pooled Safety Population were dose reduced due to cardiac disorders.

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Table 52. Cardiac Disorders

Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) Cardiac disorders 5 (2.5) 3 (1.5) 5 (1.9) 3 (1.1) 6 (1.8) 4 (1.2) Cardiac disorder 1 (0.5) 1 (0.5) 1 (0.4) 1 (0.4) 1 (0.3) 1 (0.3) Cardiac failure 1 (0.5) 1 (0.5) 1 (0.4) 1 (0.4) 2 (0.6) 2 (0.6) Congestive cardiac failure 1 (0.5) 1 (0.5) 1 (0.4) 1 (0.4) 1 (0.3) 1 (0.3) Cardiovascular disorder 1 (0.5) 0 1 (0.4) 0 1 (0.3) 0 Angina pectoris 1 (0.5) 0 1 (0.4) 0 1 (0.3) 0 Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018, submitted by Applicant)

Thyroid disorders

As seen in , thyroid disorders occurred in 2.0% of patients in the Primary Safety Population, none were Grade 3 or 4; 2.6 % of patients in the GIST Safety Population, 0.4% were Grade 3 or 4; and 2.1% of the Pooled Safety Population, 0.3% were Grade 3 or 4. No action was taken with avapritinib due to thyroid disorders.

Table 53. Thyroid disorders

Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade≥ 3 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) Thyroid disorders 4 (2.0) 0 7 (2.6) 1 (0.4) 7 (2.1) 1 (0.3) Hyperthyroidism 2 (1.0) 0 3 (1.1) 0 3 (0.9) 0 Hypothyroidism 2 (1.0) 0 4 (1.5) 1 (0.4) 4 (1.2) 1 (0.3) Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018, submitted by Applicant)

QT Prolongation

QT prolongation occurred in 1.5% of patients in the Primary Safety Population, none were Grade 3 or 4; 1.1% of patients in the GIST Safety Population, none were Grade 3 or 4; and 2.1% of the Pooled Safety Population, 0.3% were Grade 3 or 4. In the Pooled Safety Population, no patients required permanent discontinuation or dose reduction of avapritinib for QT prolongation. Avapritinib was interrupted in 2 (0.6%) patients in The Pooled Safety Population due to QT prolongation.

Palmar-Plantar Erythrodysesthesia

Palmar-plantar erythrodysesthesia occurred in 1.5% of patients in the Primary Safety Population, none were Grade 3 or 4; 1.1% of patients in the GIST Safety Population, none of Grade 3 or ;, and 0.9% of the Pooled Safety Population, none Grade 3 or 4. No action was taken with avapritinib due to palmar-plantar erythrodysesthesia.

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Treatment Emergent Adverse Events and Adverse Reactions

Common (in ≥ 10% of patients with metastatic or unresectable GIST who received 300 mg or 400mg of avapritinib daily) TEAEs occurring either on avapritinib or within 30 days after discontinuation of avapritinib are summarized by preferred term and system organ class in Table 54. No additional common adverse events were detected in the analysis of the GIST Safety Population or the Pooled Safety Population.

Table 54. Common Treatment Emergent Adverse Events

Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 System Organ Class All Grades Grade 3-4 All Grades Grade 3-4 All Grades Grade 3-4 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) All patients with adverse event 202 (99) 123 (60) 263 (99) 186 (70) 331 (99) 248 (74) General disorders and administration site conditions Edemaa 147 (72) 4 (2.0) 186 (69) 7 (2.6) 248 (74) 10 (3.0) Fatigue/asthenia 124 (61) 18 (9) 163 (61) 21 (8) 191 (57) 26 (8) Pyrexia 29 (14) 1 (0.5) 31 (12) 1 (0.4) 37 (11) 3 (0.9) Gastrointestinal disorders Nausea 131 (64) 5 (2.5) 164 (61) 8 (3.0) 189 (56) 11 (3.3) Vomiting 78 (38) 4 (2.0) 99 (37) 5 (1.9) 120 (36) 7 (2.1) Diarrhea 75 (37) 10 (4.9) 97 (36) 11 (4.1) 121 (36) 12 (3.6) Abdominal painb 63 (31) 23 (6) 83 (31) 18 (7) 106 (32) 20 (6) Constipation 47 (23) 3 (1.5) 62 (23) 3 (1.1) 72 (21) 3 (0.9) Dyspepsia 33 (16) 0 43 (16) 0 47 (14) 0 Blood and lymphatic system disorders Anemia 102 (50) 53 (26) 128 (48) 69 (26) 164 (49) 87 (26) Nervous system disorders

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Primary Safety Population GIST Safety Population Pooled Safety Population N=204 N=267 N=335 System Organ Class All Grades Grade 3-4 All Grades Grade 3-4 All Grades Grade 3-4 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) Cogntive impairmentc 99 (49) 9 (4.4) 118 (44) 10 (3.7) 144(43) 12 (3.6) Dizziness 45 (22) 1 (0.5) 54 (20) 1 (0.4) 67 (20) 2 (0.6) Headache 35 (17) 1 (0.5) 48 (18) 1 (0.4) 58 (17) 2 (0.6) Taste effectd 31 (15) 0 55 (16) 0 Metabolism and nutritional disorders Decreased appetite 78 (38) 6 (2.9) 97 (36) 9 (3.4) 108 (32) 9 (2.7) Hypokalemia 32 (16) 6 (2.9) 40 (15) 7 (2.6) 49 (15) 9 (2.7) Hypophasphatemia 28 (14) 9 (4.4) 36 (13) 12 (4.5) 44 (13) 17 (5) Hypomagnesemia 22 (11) 1 (0.5) 26 (10) 2 (0.7) 26 (8) 2 (0.6) Eye disorders Increased lacrimation 67 (33) 0 83 (31) 0 90 (27) 0 Skin and subcutaneous tissue disorders Rashe 47 (23) 4 (2.1) 52 (19) 5 (1.9) 67 (20) 5 (1.5) Hair color changes 43 (21) 1 (0.5) 55 (21) 1 (0.4) 75 (22) 2 (0.6) Alopecia 27 (13) NA 33 (12) NA 41 (12) NA Respiratory, thoracic, and mediastinal disorders Dyspnea 35 (17) 5 (2.5) 42 (16) 7 (2.6) 50 (15) 7 (2.1) Pleural effusion 25 (12) 4 (2.0) 31 (12) 6 (2.2) 38 (11) 7 (2.1) Investigations Hyperbiliarubaenmia 43 (21) 9 (4.4) 55 (21) 11 (4.1) 64 (19) 13 (3.9) Weight decreased 27 (13) 2 (1.0) 35 (13) 2 (0.7) 38 (11) 3 (0.9) AST increased 28 (14) 1 (0.5) 32 (12) 1 (0.4) 36 (11) 3 (0.9) Psychiatric disorders Insomnia 27 (13) 0 34 (13) 0 42 (13) 1 (0.3) Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018 submitted by Applicant) aIncludes PT terms face swelling, conjunctival edema, eye edema, eyelid edema, orbital edema, periorbital edema, face edema, mouth edema, pharyngeal edema, peripheral edema, edema, generalized edema, localized edema, peripheral swelling, testicular edema. b Includes PT terms of abdominal pain, upper abdominal, lower abdominal pain, abdominal discomfort, abdominal tenderness cIncludes PT terms memory impairment, cognitive disorder, confusional state, disturbance in attention, mental impairment, somnolence, encephalopathy, mental status changes, disorientation, and abnormal thinking. dIncludes PT terms dysgeusia and ageusia eIncludes PT terms rash, rash maculo-papular, rash erythematous, rash macular, rash generalized, and rash papular

Laboratory Findings

BLU-285-1101, BLU-285-1303, and BLU-285-2101 required laboratory testing at baseline and at regularly scheduled intervals. The incidence of laboratory abnormalities is based on a denominator consisting of patients with a baseline and at least one on-study test for each of the laboratory tests. Table 55 summarizes the incidence of laboratory abnormalities. Only patients with treatment-emergent laboratory abnormalities are included in the numerator in the calculation of incidence.

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Table 55. Laboratory Abnormalities Occurring in >10% of Patients

Primary Safety GIST Safety Pooled Safety Population Population Population N=204 N=267 N=335 All Grade All Grade All Grade 3- Grades 3-4 Grades 3-4 Grades 4 n n (%) n (%) n n (%) n (%) n n (%) n (%) Hematologic Decreased hemoglobin 201 162 (81) 56 (28) 257 198 (77) 65 (25) 325 250 (77) 88 (27) Decreased leukocytes 201 125 (62) 10 (5) 257 156 (61) 12 (4.7) 324 194 (60) 21 (6) Decreased neutrophils 201 85 (42) 12 (6) 257 101 (39) 17 (7) 325 138 (42) 30 (9) Decreased platelets 201 54 (27) 1 (0.5) 257 67 (26) 1 (0.4) 325 113 (35) 23 (7) Increased INR 154 37 (24) 1 (0.6) 183 42 (23) 1 (0.5) 246 54 (22) 1 (0.4) Increased activated partial 198 26 (13) 0 237 31 (13) 2 (0.8) 305 39 (13) 3 (1.0) thromboplastin time Chemistry Increased bilirubin 201 138 (69) 18 (9) 257 172 (67) 23 (9) 325 210 (65) 29 (9) Decreased aspartate 201 103 (51) 3 (1.5) 256 134 (52) 3 (1.2) 324 164 (51) 5 (1.5) aminotransferase Decreased phosphate 199 93 (47) 26 (13) 231 111 (48) 31 (13) 299 137 (46) 39 (13) Decreases potassium 201 71 (35) 13 (6) 256 87 (34) 16 (6) 324 114 (35) 18 (6) Decreased albumin 201 63 (31) 4 (2.0) 257 75 (29) 4 (1.6) 325 84 (26) 5 (1.5) Decreased magnesium 200 58 (29) 2 (1.0) 256 68 (27) 4 (1.6) 324 78 (24) 4 (1.2) Increased creatinine 201 59 (29) 0 257 78 (30) 1 (3.9) 325 96 (30) 1 (0.3) Decreased sodium 201 57 (28) 14 (7) 257 70 (27) 16 (6) 325 79 (24) 18 (6) Increased alanine aminotransferase 201 38 (19) 1 (0.5) 257 46 (18) 1 (0.4) 325 64 (20) 3 (0.9) Increased alkaline phosphatase 201 29 (14) 2 (1.0) 257 35 (14) 3 (1.2) 325 64 (20) 3 (0.9) Source: Reviewer generated table – summarizing laboratory analysis dataset (ADLB, November 16, 2018, data cutoff date, submitted by Applicant)

Vital Signs

This review identified potentially clinically significant post-baseline systolic blood pressure elevations, defined as value ≥ 120 mmHg with an increase from baseline of ≥20 mmHg, were observed in 28% (n=57) of the primary safety population and 33% (n=111) of the pooled safety population (Table 56). Hypertension was reported as an adverse event in 8% (n=17) of subjects in the primary safety population and was Grade ≥ 3 in 2.9% (n=6).

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Table 56. Vital Sign Abnormalities

Primary Safety Population GIST Safety Population Pooled Safety Population Vital Sign N=204 N=267 N=335 Systolic blood pressure (mmHg)a High 57 (28) 81 (30) 111 (33) Low 10 (4.9) 10 (3.7) 15 (4.5) Diastolic blood pressure (mmHg)b High 21 (10) 29 (11) 36 (11) Low 7 (3.4) 8 (3.0) 12 (3.6) Pulse (beats per minute)c High 3 (1.5) 5 (1.9) 7 (2.1) Low 6 (2.9) 9 (3.4) 14 (4.2) Weight (kg)d High 36 (18) 42 (16) 69 (21) Low 36 (18) 49 (18) 61 (18) Body temperature (⁰C)e High 30 (15) 35 (13) 48 (14) Low 7 (3.4) 9 (2.7) 11 (3.3) Source: Reviewer generated table – summarizing vital signs analysis dataset (ADVS, November 16, 2018 data cutoff date, submitted by Applicant) a High/Low systolic blood pressure: ≥120 mmHg with increase from baseline ≥20 mm Hg/≤ 90 mmHg with decrease from baseline of ≥20 mmHg b High/Low diastolic blood pressure: ≥80 mmHg with increase from baseline ≥20 mmHg/≤ 50 mmHg with decrease from baseline of ≥20 mmHg c High/Low pulse rate: ≥120 beats per minute with increase from baseline of ≥15 beats per minute/≤50 bpm with decrease from baseline of ≥15 bpm d High/Low weight (kilograms): ≥10% increase from baseline/ ≥10% decrease from baseline e High/Low body temperature: ≥37.50C/≤350C

QT

The effect of avapritinib was evaluated in a subset of 27 patients in Study BLU-285- 1101. The highest dose that was evaluated was 400 mg once daily (QD), which covers the therapeutic exposure at the 300 mg QD dose. The data were analyzed using exposure-response analysis as the primary analysis, which did not suggest that avapritinib is associated with large mean increases in the QTc interval (Table 57) 1 for overall results. The findings of this analysis are further supported by the available nonclinical data, central tendency analysis and categorical analysis.

Table 57. Point Estimates and the 90% CIs

ECG parameter Treatment Concentration ∆QTcF 90% CI (ms) 90%CI Avapritinib 400 mg QD 885.9 ng/mL 5.7 0.9, 10.6

The 400 mg QD dose is the maximum tolerated dose in the target patient population. The proposed label recommends dosing on an empty stomach. At this stage, the maximum effect by intrinsic/extrinsic factors on Cmax is that with a high fat meal (i.e. 60% increase in Cmax). The sponsor’s population PK analysis indicates that there are no clinically relevant effects of age, sex, race and body weight on the PK of avapritinib, and no dose adjustment is recommended

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for patients with mild or moderate hepatic and renal impairment. The effects of severe hepatic and renal impairment on avapritinib PK have not been evaluated.

8.2.5 Analysis of Submission-Specific Safety Issues

As avapritinib is a new molecular entity, there are no submission-specific safety issues. All adverse events are discussed in Section 8.2.4.

8.2.6 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability

No COA Analyses informing safety or tolerability were submitted.

8.2.7 Safety Analyses by Demographic Subgroups

The applicant conducted an analysis of TEAE by age and identified only five TEAEs with a difference in incidence across the age group (Source SCS Section 5.1.1): • Periorbital edema was more common (46%) in patients ≥65 years old than in patients < 65 years old (32%) • Decreased appetite was more common (42%) in patients ≥65 years old than in patients < 65 years old (31%) • Diarrhea was more common (42%) in patients ≥65 years old than in patients < 65 years old (28%) • Increased lacrimation was more common (39%) in patients ≥65 years old than in patients < 65 years old (25%) • Peripheral edema was more common (39%) in patients ≥65 years old than in patients < 65 years old (20%)

The applicant found no differences in TEAEs that led to study drug discontinuation or dose modification by age.

Reviewer Comment: In Trial BLU-285-1101, there were five preferred terms that occurred in a higher proportion (≥10% greater) of patients ≥ 65 years old. However, this is not a randomized trail so these differences may represent differences due to age only. Therefore, given the limitations of the data derived from single arm studies, additional data from RCT will be collected to further assess whether age may increase the risk of cognitive impairment. The applicant conducted an analysis of TEAEs by sex and found no clinically relevant differences in the spectrum or severity of TEAEs by sex. They also found no differences in TEAEs that led to study drug discontinuation or dose modification by sex (Source SCS Section 5.1.2).

The applicant conducted an analysis of TEAEs by race and identified eight TEAES with potential differences in rates incidence across race (Table 58). Given the limited number of non-White patients (or unknown patients); inferences regarding these analyses are limited.

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Table 58. TEAES with a Difference of Incidence Among Racial groups

Primary Safety Population GIST Safety Population Pooled Safety Population White Other Unknown White Other Unknown White Other Unknown N=146 N=36 N=22 N=188 N=49 N=30 N=246 N=53 N=36 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Fatigue 85 (58) 11 (31) 17 (77) 113 (60) 15 (31) 20 (67) 133 (54) 16 (30) 24 (67) Periorbital edema 64 (44) 11 (31) 7 (36) 81 (43) 13 (27) 10 (33) 122 (50) 17 (32) 15 (42) Decreased Appetite 60 (41) 7 (19) 10 (45) 75 (40) 11 (22) 11 (37) 83 (34) 12 (23) 13 (36) Vomiting 58 (40) 9 (25) 11 (50) 74 (39) 12 (24) 13 (43) 93 (38) 13 (25) 14 (39) Diarrhea 57 (39) 11 (31) 8 (36) 74 (39) 13 (27) 10 (33) 93 (38) 15 (28) 13 (36) Increased lacrimation 53 (36) 5 (14) 9 (41) 65 (35) 6 (12) 12 (40) 70 (28) 7 (13) 13 (36) Peripheral edema 49 (34) 7 (19) 7 (32) 63 (33) 9 (18) 8 (27) 83 (34) 10 (19) 10 (28) Abdominal pain 27 (18) 10 (27) 5 (23) 35 (19) 14 (29) 10 (33) 46 (19) 15 (28) 12 (33) Source: Reviewer generated table – summarizing ISS adverse event analysis dataset (ADAE, data cut off date November 16, 2018, submitted by Applicant)

Few subjects were Hispanic and Latino, safety was not analyzed by these variables (Source SCS Section 5.1.3).

8.2.8 Specific Safety Studies/Clinical Trials

No specific safety studies or clinical trials were submitted

8.2.9 Additional Safety Explorations

Human Carcinogenicity or Tumor Development

The applicant did not conduct studies investigating the carcinogenic potential of avapritinib as such studies are not needed to support a marketing application for patients with advanced cancer. Avapritinib was not mutagenic in a bacterial reverse mutation (Ames) assay. Avapritinib was clastogenic in the in vitro chromosome aberration test in human peripheral blood lymphocytes at concentrations ≥ 5 μg/mL (22-hour incubation); these aberrations appeared structural rather than numerical. Avapritinib was, however, not clastogenic in the in vivo rat bone marrow micronucleus test at doses up to 150 mg/kg). Based on the weight of evidence, avapritinib was not considered genotoxic (Section 5.5.5).

Pediatrics and Assessment of Effects on Growth

The applicant was granted Orphan Designation for avapritinib for the treatment of patients with metastatic or unresectable GIST and is therefore not required to conduct pediatric studies under the Pediatric Research Equity Act (PREA).

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Overdose, Drug Abuse Potential, Withdrawal, and Rebound

The applicant did not provide any reported cases of overdose of avapritinib in the GIST population. Avapritinib does not appear to have abuse potential.

8.2.10 Safety in the Postmarket Setting

Safety Concerns Identified Through Postmarket Experience

Avapritinib is not marketed in any country, and there is no postmarket experience.

Expectations on Safety in the Postmarket Setting

Safety in the postmarket setting will be further assessed in randomized controlled trials. These trials are active comparator trials, however, so there still may be limitations regarding the attribution of certain adverse effects (i.e., over a theoretical placebo).

8.2.11 Integrated Assessment of Safety

The safety of avapritinib was evaluated in three different safety populations. The Primary Safety Population consisted of 204 patients with unresectable or metastatic GIST who received 300 or 400 mg of avapritinib daily on Trial BLU-285-1101. The GIST Safety Population consisted of 267 patients with unresectable or metastatic GIST who received avapritinib at any dose in both Trial BLU-285-1101 and Trial BLU-285-1303. The Pooled Safety Population consisted of 335 patients with either unresectable or metastatic GIST or advanced systemic mastocytosis who received avapritinib at any dose on Trial BLU-285-1101, Trial BLU-285-1303, or Trial BLU-285-2101. In the Primary Safety Population (n=204), the median duration of exposure to avapritinib was 5.4 months (mean 6.5 months), with a maximum exposure time of 24.6 months. In the GIST Safety Population (n=267), the median duration of exposure to avapritinib was 4.8 months (mean 7.2 months), with a maximum exposure time of 36.7 months. In the Pooled Safety Population, (N=335), the median duration of exposure to avapritinib was 5.8 months (mean 8.4 months), with a maximum exposure time of 36.7 months.

In the Primary Safety Population 12% of patients died within 30 days of receiving avapritinib. The majority (8%) of these died due to disease progression; however, 3.4% of patients died due to an adverse event. Sepsis and Tumor hemorrhage were the only adverse events leading to death that occurred in more than one patient. The events of sepsis were considered at least possibly related to treatment with avapritinib.

The majority (99%) of patients in the Primary Safety Population experienced at least one adverse event, of these 60% were Grade 3-4. This rate was similar in both the GIST Safety Population and the Pooled Safety Population. The most common (>20%) adverse events, including laboratory abnormalities, in patients in the Primary Safety Population were edema,

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nausea, fatigue/asthenia, cognitive effects, vomiting, diarrhea, decreased appetite, abdominal pain, increased lacrimation, constipation, rash, and dizziness.

Serious adverse events were reported in 52% of patients in the Primary Safety Population; the most frequent (occurring ≥1% of patients) included anemia (9%), gastrointestinal hemorrhage (3.9%), abdominal pain (3.4%), pleural effusion and sepsis (2.5%, each), vomiting and acute kidney injury (2%, each), pneumonia and tumor hemorrhage (1.5%, each). Permanent discontinuation of avapritinib due to an adverse events occurred in 16% of the Primary Safety Population; the most frequent adverse events (occurring in more than 1 patient) requiring permanent discontinuation included fatigue, abdominal pain, vomiting, sepsis, anemia, acute kidney injury, and encephalopathy. Dose reductions occurred in 49% of patients in the Primary Safety Population; the most frequent adverse events (occurring in ≥2% of patients) requiring a dosage reduction were fatigue, anemia, hyperbilirubinemia, memory impairment, nausea and periorbital edema. Dose interruptions occurred in 57% of patients in the Primary Safety Population; the most frequent adverse events (occurring in ≥2% of patients) requiring dose interruptions were anemia, fatigue, nausea, vomiting, hyperbilirubinemia, memory impairment, diarrhea, cognitive disorder, and abdominal pain. Evaluation of the GIST Safety Population and the Pooled Safety Population did not reveal any adverse events that were not identified in the evaluation of the Primary Safety Population.

Two adverse events merit close consideration: • Intracranial hemorrhage: Intracranial hemorrhage (e.g. subdural hematoma, intracranial hemorrhage, and cerebral hemorrhage) occurred in 3% of the 335 patients who received avapritinib; 1.2% of these events were Grade 3 or 4. Intracranial hemorrhage can be spontaneous and can occur in patients with normal platelet counts. Events of intracranial hemorrhage occurred in a range from 1.7 months to 19.3 months after initiating avapritinib. Overall, 0.9% of patients receiving avapritinib required permanent discontinuation for an intracranial hemorrhage; 1.2% required dosage interruption followed by dose reduction. • CNS Effects: CNS effects, including cognitive impairment, dizziness, sleep disorders, mood disorders, speech disorders, encephalopathy, and hallucinations, occurred in 122 (60%) patients in the Primary Safety Population, and 4.9% (n=10) of these patients had a Grade 3-4 CNS effect. Avapritinib was permanently discontinued in 1.5% of patients, dose reduced in 11% of patients, and dose was interrupted in 16% of patients in the Primary Safety Population due to a CNS effect. Cognitive impairment occurred in 49% of patients in the Primary Safety Population, dizziness occurred in 22% of patients in the Primary Safety Population, sleep effects occurred in 14% of patients in the Primary Safety Population, and hallucinations occurred in 2.9% of patients in the Primary Safety Population. The median time to onset of the first CNS adverse reaction was 7.9 weeks (range <1 day to 22.6 months).

The review team recommends a warning and precaution for both intracranial hemorrhage and CNS effects. The review team also recommends that the Applicant, as a postmarketing requirement, submit a final analysis of intracranial hemorrhage from the ongoing Trial BLU-285- 129 Version date: April 2, 2018

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1303 to provide more information about the predisposing factors, incidence, severity, and timing of intracranial hemorrhage in patients with receive avapritinib. Additionally, the review team recommends the Applicant, as a postmarketing requirement, submit a final analysis of CNS effects from the ongoing Trial BLU-285-1303 including adverse events rates, timing, predisposing factors and clinical outcome assessments of CNS effects in patients treated with avapritinib.

8.3 Statistical Issues

There are no outstanding statistical issues with the study design, statistical analysis plan, or efficacy analyses of Trial BLU-285-1101. While the statistical analysis plan of the trial included summary statistics of PFS as a secondary efficacy endpoint, these results were not presented in this review, as analyses of time-to-event endpoints are not interpretable in single arm trials.

8.4 Conclusions and Recommendations

The efficacy of avapritinib for the treatment of adults with unresectable or metastatic GIST harboring a PDGFRα D842V mutation was established on the basis of a durable response rate of 89% (95%CI: 75,97) with a 6-month duration of response of 88% (95% CI: 75, 100) and a 12 month duration of response of 68% (95% CI: 45, 91) in patients with PDFGRα D842V mutations in Trial BLU-285-1101. To support the expansion of the indication to all patients with a PDGFRα exon 18 mutation, the Applicant provided data in five patients with other PDGFRα exon 18 mutations and the ORR in this patient population was 40% (95% CI:5, 85). The ORR in this population was 84% (95%CI: 69, 93) with a 6-month duration of 89% (95% CI: 77, 100) and a 12- month duration of 65% (95% CI: 43, 88). Additionally, the Applicant provided in vivo data showing that other PDGRα exon 18 mutations are expected to respond similarly to avapritinib. Although the ORR in the patients with PDGFRα exon 18 mutations is numerically lower than that observed in the PDGFRAα D842V mutation population and has large confidence intervals, it is appropriate to include all patients with PDGFRα exon 18 mutations in the efficacy analysis and approved indication. According to FDA’s “Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease: Guidance for Industry” guidance, patients with different rare molecular alterations may be grouped if it is reasonable to expect that the grouped patients will have similar responses and that drugs may be approved for a molecularly defined set of patients if clinical trials are successful, irrespective of the extent to which patients with various rare molecular alterations were represented in the clinical trial. Although there is no data provided to show that currently approved therapies are not effective in other PDGFRα exon 18 mutations, the applicant did provide data from in vitro inhibitory activity data for avapritinib for 10 PDGFRα exon 18 mutations other than PDGFRα D842V that showed with one exception avapritinib has similar in vitro inhibitory activity against D842V mutated PGDFRα and other PDGFRα exon 18 mutations. Therefore, the clinical data in the five patients with exon 18 mutations other than D842V and the preclinical data supporting that other exon 18 mutation are similarly inhibited by avapritinib supports the efficacy of avapritinib in patients with metastatic or unresectable GIST harboring a PDGFRA exon 18.

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Avapritinib was well-tolerated, with 17% of patients in the primary safety population discontinuing due to adverse events and only 3.4% of patients died due to an adverse event. The majority (99%) of patients experienced at least one adverse event; 60% of patients experienced at least one Grade 3 or 4 adverse event. The two most serious adverse events associated with avapritinib treatment are intracranial hemorrhage and central nervous system effects. These risks have been included as Warnings and Precautions in labeling. The Warnings and Precautions include information about incidence, severity and outcome of these serious adverse events as well as action to be taken with avapritinib when these adverse events occur. The inclusion of intracranial hemorrhage and nervous system effects as Warnings and Precautions in labeling will allow for informed treatment decisions for patients with GIST and PDGFRα exon 18 mutations.

In view of the clinical benefit demonstrated by the durable response rate in patients with unresectable or metastatic GIST who harbor a PDGFRα exon 18 mutations in addition to the tolerability of avapritinib, the review team recommends regular approval of avapritinib for patients with unresectable or metastatic GIST who harbor a PDGFRα exon 18 mutations.

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X Yutao Gong, PhD Safety Analyst

X X

Pourab Roy, PhD Pallavi Mishra-Kalyani, PhD Primary Statistical Reviewer Statistical Team Leader

X X

Christy Osgood, MD Ashley Ward, MD Primary Clinical Reviewer Clinical Team Leader

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9 Advisory Committee Meeting and Other External Consultations

This Application was not presented to the oncologic Drug Advisory Committee or any other external consultants.

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10 Pediatrics

The Applicant was granted Orphan Designation for avapritinib for the treatment of patients with unresectable or metastatic GIST and is therefore exempt from pediatric studies under the Pediatric Research Equity Act (PREA). There are no data regarding the use of avapritinib in children.

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11 Labeling Recommendations

11.2 Prescription Drug Labeling

The table below summarizes changes to the proposed prescribing information made by FDA. See the final approved prescribing information for AYVAKIT (avapritinib) accompanying the approval letter for more information.

Section Proposed Labeling Approved Labeling Highlights Modified based on changes made to the Full Prescribing Information. Full Prescribing Information Indications and Usage … Removed regardless of prior line of therapy from indication of patients with PDFGRα Exon 18 Mutation-Positive Unresectable or Metastatic Gastrointestinal Stromal Tumor (GIST) Dosage and … Revised patient selection to correspond Administration, to changes made to the indication and Patient Selection usage statement. Dosage and … Omitted statement (b) (4) Administration, Recommended Dosage Dosage and Included two dose reductions. Expanded to provide dosage Administration, Dosage modification for patients unable to Modifications for tolerate a reduced dose. Adverse Reactions Included dosage modifications for Expanded to include dosage cognitive effects and other. modifications for intracranial hemorrhage and CNS effects to correspond to changes made to W&P. Dosage and … Added dosage modifications for strong Administration, and moderate CYP3A inhibitors. Concomitant Use of Strong or Moderate CYP3A Inhibitors Warnings and Included W&P for cognitive effects. Expanded W&P to describe a broad Precautions, Central spectrum of CNS adverse reactions Nervous System Effects based on those observed in safety population of 335 patients. Adverse Reactions, Described the safety population of 335 Revised to separately describe the Clinical Trails Experience patients which informed the W&P and pooled safety population of 335 patients the 204 patients which informed the used to inform the W&P and the safety clinical trials experience. population of 204 patients used to inform the clinical trials experience. Added overall exposure to avapritinib for 6 months and one year and a description of fatal adverse reactions and dosage interruptions in the safety

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population of 204 patients.

Expanded to list adverse reactions and laboratory abnormalities that occurred above a specified rate regardless of attribution as the safety of avapritinib was evaluated in a single arm trial. Drug Interactions … Based on evidence from model-based approaches, expanded to a describe the effect of moderate CYP3A inhibitors on the pharmacokinetics of avapritinib and provide dosage modifications; and omitted the information regarding a drug interaction with CYP3A and CYP2C9 substrates. Specific Populations, Recommended avoid breastfeeding Modified to avoid breastfeeding during Lactation during treatment and for (b) (4) after treatment and for 2 weeks after the final the final dose. dose based on the elimination half-life. Specific Populations, … Added recommendations for Females and Males of contraception for males with female Reproductive Potential partners of reproductive potential based on evidence from nonclinical studies. Clinical Pharmacology, … Added a description of exposure- Pharmacodynamics response relationship based on 21 CFR 201.57(c)(13)(i)(B). Clinical Studies … Patient Counseling … Revised based on changes made to the Information Full Prescribing Information. W&P – Warnings and Precautions; CNS – central nervous system

Other Prescription Drug Labeling

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12 Risk Evaluation and Mitigation Strategies (REMS)

The risks of avapritinib, including intracranial hemorrhage and CNS effects, can be adequately managed in the post-marketing setting through product presentation and labeling. No additional risk management strategies are recommended. The Division of Risk Management in the Office of Surveillance and Epidemiology concurs with this assessment.

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13 Postmarketing Requirements and Commitment

During the review of the NDA, FDA identified the following postmarketing commitments (PMCs) and postmarketing requirement (PMRs):

• PMR- 1: Conduct an analysis characterizing avapritinib-associated CNS adverse reactions including cognitive impairment, dizziness, sleep disorders, mood disorders, speech disorders, and hallucinations including incidence, timing, appropriate diagnostic criteria, action taken with avapritinib, and outcome of cognitive effects to provide additional data that may inform product labeling. Include patient-level data, clinical outcome assessments and pooled analyses of data from completed and on-going trials in patients with gastrointestinal stromal tumor and advanced systemic mastocytosis, including trials BLU-285-1101, BLU252-2102, and BLU-285-1303. Submit the analysis, datasets, the results of any related clinical outcome assessments and patient narratives for cognitive effects in the final report.

• PMR-2: Conduct an analysis characterizing avapritinib-associated intracranial hemorrhage, including incidence, timing, appropriate diagnostic criteria, action taken with avapritinib, predisposing concomitant medications and comorbidities and outcome of intracranial hemorrhage to provide additional data that may inform product labeling. Include patient-level data and pooled analyses of data from completed and on-going trials in patients with gastrointestinal stromal tumor and advanced systemic mastocytosis, including trials BLU-285-1101, BLU-252- 2102, and BLU-285-1303. Submit the analysis, datasets, and patient narratives for intracranial hemorrhage events in the final report.

• PMR-3 Complete a pharmacokinetic trial to determine an appropriate dose of avapritinib to minimize toxicity in patients with severe hepatic impairment in accordance with the FDA Guidance for Industry entitled “Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling” found at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gu idances/UCM072123.pdf.

• PMC-1: Develop and submit the report of a valid companion diagnostic to detect PDGFRα D842V somatic variants for identifying patients with GIST who may benefit from avapritinib using clinical trial data from study BLU-285-1101 titled, “A Phase 1 Study of BLU-285 in Patients with Gastrointestinal Stromal Tumors (GIST) and other Relapsed and Refractory Solid Tumors”, to inform product labeling. The analytical validation should consist of precision, limit of detection and accuracy studies for the

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PDGFRα D842V somatic variant indication. Support the clinical validation by a clinical bridging study comparing the nucleic acid based in-vitro diagnostic device and the clinical trial enrollment assay.

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14 Division Director (Clinical) Comments

I agree with the review teams and recommend approval of avapritinib for the treatment of adults with unresectable or metastatic GIST harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations. Given the rarity of PDGFRA-mutant GIST and given the observed 84% ORR (per mRECIST) in the NAVIGATOR clinical trial, I do not believe that a randomized clinical trial would be feasible (e.g., to assess for an effect on overall survival or progression free survival). There are no other effective therapies for patients with these PDGFRA mutations, and it is unlikely that a patient with PDGFRA-mutant GIST would elect to be randomized to receive placebo.

Steven Lemery

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15 Office Director (or designated signatory authority) Comments

This application was reviewed by the Oncology Center of Excellence (OCE) per the OCE Intercenter Agreement. My signature below represents an approval recommendation for the clinical portion of this application under the OCE.

X

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16 Appendices

19.1 References

Cassier PA, Fumagalli E, Rutlkowski P, et al. (2012). Outcome of Patients with Platelet-Derived Growth Factor Recepto ALpha Mutated Gastrointestinal Stromal Tumors in the Tyrosine Kinase Inhibiutor Era. Clinical Cancer Research, 2012; 18 (16): 4458-4464.

CioffiA, MR and Maki RG. GI Stromal Tumors: 15 Years of Lessons from A Rare Cancer. Journal of Clinical Oncology, 2015; 33(16): 1849-1854.

Cohen MH, Cortazar P, Justice R, and Pazdar, R. Approval Summary: Imatinib Mesylate in the Treatment of Metastatic and/or Unresectable Malignant Gastrointestinal Stromal Tumors. The Oncologist, 2010; 15(3): 300-307.

Demehri S, Corbin A, Loriaux M, et al. Establishment of a murine model of aggressive systemic mastocytosis/mast cell leukemia. Experimental Hematology, 2006; 34(3):284-288.

Fruttiger M, Karlsson L, Hall AC, et al. Defective oligodendrocyte development and severe hypomyelination in PDGF-A knockout mice. Development 1999; 126(3):457-467.

Garner AP, Gozgit JM, Anjum A, et al. Ponatinib Inhibits Polyclonal Drug-Resistant KIT Oncoproteins and Shows Therapeutic Potential in Heavily Pretreated Gastrointestinal Stromal Tumor (GIST) Patients. Clinical Cancer Research 2014; 20(22):5745-5755.

Gnessi L, Basciani S, Mariani S, et al. Leydig cell loss and spermatogenic arrest in platelet- derived growth factor (PDGF)-A-deficient mice. J Cell Biology 2000; 149:1019-1025.

Heinrich MC, Griffith D, McKinley A, et al. Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors. Clinical Cancer Research 2012; 18(16):4375-4384.

Heron SE, Crossland KM, Andermann E, et al. Sodium-channel defects in benign familial neonatal-infantile seizures. Lancet 2002; 360(9344):1520.

Hoch RV, Soriano P. Roles of PDGF in animal development. Development 2003; 130(20):4769- 4784.

Künstlinger H, Binot E, Merkelbach-Bruse S, Huss S, Wardelmann E, Buettner R, Schildhaus HU. High-resolution melting analysis is a sensitive diagnostic tool to detect imatinib-resistant and imatinib-sensitive PDGFRA exon 18 mutations in gastrointestinal stromal tumors. Human pathology. 2014 Mar 1;45(3):573-82.

Lasota J, Dansonka-Mieszkowska A, Sobin LH, Miettinen M. A great majority of GISTs with

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PDGFRA mutations represent gastric tumors of low or no malignant potential. Laboratory Investigation. 2004 Jul;84(7):874.

Ma G, Murphy JD, Martinez ME, and Sicklick JK. Epidemiology of gastrointestinal tumors in the era of histology codes; results of population-based study. Cancer Epidemiology, Biomarkers and Prevention 2015; 24(1):298-302.

Miettinen M, and Losota J. Gastrointestinal stromal tumors-definition, clinical, histological, immunohistocheical, and molecular genetic features and differentail diagnosis. Virchows Archive 2001; 438(1): 1-12.

Nannini M, Urbini M, Astolfi A, Biasco G, Pantaleo MA. The progressive fragmentation of the KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors (GIST). Journal of translational medicine. 2017 Dec;15(1):113.

Schwarz N, Bast T, Gaily E, et al. Clinical and genetic spectrum of SCN2A-associated episodic ataxia. European Journal of Paediatric Neurology 2019; 23(3):438-447.

Sugawara T, Tsurubuchi Y, Agarwala KL, et al. A missense mutation of the Na+ channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction. Proc Natl Acad Sci USA 2001; 98(18):10515.

Yoo C, Ryu MH, Jo J, et al. Efficacy of Imatinib in Patients with Platelet-Derived Growth Factor Receptor Alpha-Mutated Gastrointestinal Tumors. Cancer Research and Treatment 2016; 48(2): 546-552.

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19.2 Financial Disclosure

Covered Clinical Study (Name and/or Number): BLU-285-1101 (NAVIGATOR)

Was a list of clinical investigators provided: Yes No (Request list from Applicant) Total number of investigators identified: 186 Number of investigators who are Sponsor employees (including both full-time and part-time employees): 0

Number of investigators with disclosable financial interests/arrangements (Form FDA 3455): 2 If there are investigators with disclosable financial interests/arrangements, identify the number of investigators with interests/arrangements in each category (as defined in 21 CFR 54.2(a), (b), (c) and (f)): Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: Significant payments of other sorts: 2 Proprietary interest in the product tested held by investigator: Significant equity interest held by investigator in S Sponsor of covered study: Is an attachment provided with details Yes No (Request details from of the disclosable financial Applicant) interests/arrangements: Is a description of the steps taken to Yes No (Request information minimize potential bias provided: from Applicant) Number of investigators with certification of due diligence (Form FDA 3454, box 3) 2 Is an attachment provided with the Yes No (Request explanation reason: from Applicant)

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19.3 OCP Appendices (Technical documents supporting OCP recommendations)

19.3.1 Summary of Bioanalytical Method Validation and Performance

Were relevant metabolite concentrations measured in the clinical pharmacology and biopharmaceutics studies?

Yes, plasma and urine concentrations of the active parent, avapritinib and the major metabolites, BLU111207 and BLU111208 (the constitutive enantiomers of the metabolite M499), were measured in the clinical pharmacology and biopharmaceutics studies. Following oral administration of avapritinib 300 mg once daily in patients with GIST, the major metabolites are BLU111207 and BLU111208. The steady state AUC of BLU111207 and BLU111208 were approximately 35% and 42% of the AUC of avapritinib, respectively. Based on the mass-balance Study BLU-285-0103, unchanged avapritinib (49%) and metabolites M690 (hydroxy glucuronide; 35%) and M499 (oxidative deamination; 14%) were the major circulating radioactive components. All other metabolites were detected in trace amounts.

For all moieties measured, is free, bound, or total measured? What is the basis for that decision, if any, and is it appropriate?

The total plasma concentrations of avapritinib, BLU111207 and BLU111208 were measured in the clinical trials. This was appropriate due to the constant plasma protein binding of avapritinib, BLU111207 and BLU111208 over the clinically relevant concentration range studied. The average fraction unbound (fu) values in human plasma proteins of avapritinib, BLU111207 and BLU111208 were 1.2%, 0.6% and 0.7%, respectively. The fu values for avapritinib, BLU111207 or BLU111208 were independent of concentrations (1 to 10 µM for avapritinib; 0.5 to 10 µM for BLU111207 or BLU111208).

What bioanalytical methods are used to assess concentrations?

Three methods for analysis human plasma samples are described below.

Avapritinib (BLU-285) (b) (4) (b) (4) Method 1963 (Validation Report: BLU-R4448R2): Method 1963 is an LC-MS/MS method for the determination of BLU-285 in K2EDTA human plasma using BLU-285-d8 as the internal standard. concentrations were calculated with a 1/x2 linear regression over a concentration range of 2.00 (LLOQ) to 3000 ng/mL with 8 calibration standards. Dilution integrity is validated for 22500 ng/mL (Dilution QC) 10-fold diluted BLU-285. This method was used in Study BLU-285-0101, Study BLU-285-0102, Study BLU-285-0104, Study BLU-285-0105, and Study BLU-285-1101. BLU111207 and BLU111208 (b) (4) (b) (4) Method 2713-R0 (Validation Report: 805-R9148R3): Method 2713-R0 is an LC- MS/MS method for the determination of BLU111207 and BLU111208 in K2EDTA human plasma

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using BLU111207-d8 and BLU111208-d8 as the respective internal standards. BLU111207 and BLU111208 concentrations were calculated with a 1/x2 linear regression over a concentration range of 1.00 (LLOQ) to 1000 ng/mL with 8 calibration standards. Dilution integrity is validated for 7500 ng/mL (Dilution QC) 10-fold diluted for both BLU111207 and BLU111208. This method was used in Study BLU-285-1101 (b) (4) (b) (4) Method 2676-R0 (Validation Report: BLU-R8894R2): Method 2676-R0 is an LC- MS/MS method for the determination of BLU111207 and BLU111208 in K2EDTA human plasma using BLU111207-d8 and BLU111208-d8 as the respective internal standards. BLU111207 and BLU111208 concentrations were calculated with a 1/x2 linear regression over a concentration range of 0.0100 (LLOQ) to 10.0 ng/mL with 8 calibration standards. Dilution integrity is validated for 75 ng/mL (Dilution QC) 10-fold diluted for both BLU111207 and BLU111208. This method was used in Study BLU-285-1101. 19.3.2 Clinical PK Six Clinical Pharmacokinetic studies in this submission are summarized in Table 59. Only the to- be-marketed immediate-release 100 mg tablet and the drug-in-capsule formulation were used in patients with GIST (Study BLU-285-1101). The patients were switched to the 100 mg tablet during the expansion phase (Part 2) from the capsule formulation in the dose escalation phase (Part 1) of Study BLU-285-1101. Table 59. Clinical PK Studies in NDA 212608 Submission

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Source: Summary of Clinical Pharmacology Studies Table 1 (Section 2.7.2)

Formulation Effect The applicant developed immediate-release tablet formulation with four strengths: 100 mg, 200 mg, 300 mg and 400 mg. No clinically relevant difference was expected due to tablet strength as well as between the tablet and the capsule formulation based on following data. In Study BLU-285-0101, no clinically relevant difference was observed between 1 × 200 mg tablets and 2 × 100 mg capsules under fasted conditions in healthy volunteer. The study was an open-label, randomized, 2-way crossover study in 30 healthy adult male subjects. Each subject was administrated with 1 × 200 mg tablet and 2 × 100 mg capsules with a 3-week washout period between treatments under fasted conditions.

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Table 60. Summary and Statistical Comparison of Avapritinib Pharmacokinetic Parameters After Administration of Avapritinib 200 mg as 1 × 200 mg Tablet or 2 × 100 mg Capsules Under Fasted Conditions (Study BLU-285-0101)

Source: Summary of Clinical Pharmacology Studies Table7 (Section 2.7.1)

In patients with GIST in Study BLU-285-1101, the dose-normalized median Cmax and AUC0-24 values were similar between the capsule and 100 mg tablet formulations on C1D1 and C1D15, Figure 7. (b) (4) All tablet strengths the same percentage composition of drug and excipients. The applicant used in vivo bioequivalence study BLU-285-0105 to demonstrate BE for the 100 and 400 mg strength tablets. The applicant submitted a strength-based waiver of in vivo bioavailability/bioequivalence studies for the 200 and 300 mg strength tablets based on in vitro data.

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Figure 7: Effect of Formulation (Capsule versus 100 mg Tablet) on Avapritinib Dose-normalized Cmax and AUC (Study BLU-285-1101)

Source: Summary of Clinical Pharmacology Studies Figure 5 (Section 2.7.2)

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PK Dose Proportionality In patients with GIST in Study BLU-285-1101, avapritinib, its major metabolites BLU111207 and BLU111208 PK profiles are shown in Figure 8 and Figure 9. Avapritinib, BLU111207 and BLU111208 PK characteristics were evaluated after the first dose (C1D1) and after multiple doses (C1D15), Table 61 to Table 63. Dose proportionality in Cmax and AUC of avapritinib was evaluated using a power model across the dose range of 30 to 400 mg on C1D1 and C1D15, Figure 10. The power model indicated dose-proportional PK from 30 to 400 mg. Similar power model analyses suggested dose-proportional PK for BLU111207 and BLU111208 from 30 to 400 mg of avapritinib. Tmax of avapritinib ranged from 2.0 to 4.1 hours following single doses of avapritinib 30 mg to 400 mg following multiple doses in Study BLU-285-1101, the geometric mean Cmax and AUC of avapritinib is 813 ng/mL (1.63 µM) and 15400 ng•h/mL, respectively. Steady state concentration of avapritinib was reached by day 15 following daily dosing and the mean accumulation ratio was 3.1 to 4.6 after repeated dosing. At 300 mg, the AUC ratio for BLU111207 and BLU111208 to parent drug was approximately 19% and 23%, respectively, on C1D1, and approximately 35% and 42%, respectively, at steady state on C1D15.

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Table 61. Summary of Avapritinib PK on Cycle 1 Day 1 Following Avapritinib Single-dose (Upper Table) and on Cycle 1 Day 15 Following Repeat-dose (Lower Table) in Patients with GIST (Study BLU-285-1101) a. Avapritinib PK parameters on Cycle 1 Day 1

b. Avapritinib PK parameters on Cycle 1 Day 15

Source: Summary of Clinical Pharmacology Studies Table 3 and 4 (Section 2.7.2)

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Table 62. Summary of BLU111207 PK on Cycle 1 Day 1 Following Avapritinib Single-dose (Upper Table) and on Cycle 1 Day 15 Following Repeat-dose (Lower Table) in Patients with GIST (Study BLU-285-1101) a. BLU111207 PK parameters on Cycle 1 Day 1

b. BLU111207 PK parameters on Cycle 1 Day 15

Source: Summary of Clinical Pharmacology Studies Table 7 and 8 (Section 2.7.2)

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Table 63. Summary of BLU111208 PK on Cycle 1 Day 1 Following Avapritinib Single-dose (Upper Table) and on Cycle 1 Day 15 Following Repeat-dose (Lower Table) in Patients with GIST (Study BLU-285-1101) a. BLU111208 PK parameters on Cycle 1 Day 1

b. BLU111208 PK parameters on Cycle 1 Day 15

Source: Summary of Clinical Pharmacology Studies Table 9 and 10 (Section 2.7.2)

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Figure 8: Mean (+Standard Deviation) Plasma Concentration-Time Profiles of Avapritinib in Patients with GIST (Study BLU-285-1101)

Source: Summary of Clinical Pharmacology Studies Figure 2 (Section 2.7.2)

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Figure 9: Mean (+ Standard Deviation) Plasma Concentration-Time Profiles of BLU111207 and BLU111208 in Patients with GIST (Study BLU-285-1101)

Source: Summary of Clinical Pharmacology Studies Figure 6 (Section 2.7.2)

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Figure 10: Power Analysis of Avapritinib Systemic Exposure vs Dose Following Administration of Avapritinib in Patients With GIST (Study BLU-285-1101)

Source: Summary of Clinical Pharmacology Studies Figure 4and Table 5 (Section 2.7.2)

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19.3.3 Population PK and/or PD Analyses The goal of population PK analysis (popPK) was to develop a population pharmacokinetic (PK) model to assess sources of variability (intrinsic and extrinsic covariates) of avapritinib in healthy volunteers and patients.

The population PK model included 4 clinical trials, comprising 122 healthy subjects and 221 patients with gastrointestinal stromal tumors (GIST). The popPK analysis was conducted by the applicant. The PK of avapritinib was characterized by a two-compartment model with absorption modelled via 4 or 5 transit compartments that was dependent on tablet or capsule formulation. The rate of absorption was modelled in terms of absorption transit rate constant for tablets (KTRT) and absorption transit rate constant for capsules (KTRC). Disposition of avapritinib was modelled in terms of apparent oral clearance (CL/F), apparent volume of distribution for the central compartment (Vc/F), apparent inter-compartmental clearance (Q/F), and apparent volume of distribution for the peripheral compartment (Vp/F). Between-subject variability (BSV) was included on the absorption rate constant (KTR), CL/F, and Vc/F. Between- occasion variability (BOV) was included on KTR and relative bioavailability (F). A proportional error model was used to describe residual unexplained variability (RUV) for avapritinib. A schematic of the base model is shown in Figure 11.

Figure 11: Schematic of the Base Population PK Model.

Source: Applicant’s poppk report, Page 11

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The final model has been evaluated by the reviewer. No signs of model misspecification were identified in the goodness-of-fit plots (Figure 12). Prediction-corrected visual predictive check showed that the final model adequately described the observed PK profile of avapritinib in healthy subjects and patients with GIST tumor (Figure 13). The shrinkage in the eta residual is 8% for CL and 5% for V.

Figure 12: Goodness of Fit Plots of the Final Model

Source: Reviewer’s Analysis based on “blu-285-all-20190206-1232.csv”

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Figure 13: Visual Predictive Checks of Avapritinib Concentration-Time Data Stratified by Population.

Source: Reviewer’s Analysis based on “blu-285-all-20190206-1232.csv”

The influence of continuous and categorical covariates was tested for their statistical significance on PK parameters in the model. Covariates were selected based on known or hypothetical factors that could affect the PK. Concomitant administration of a proton pump inhibitor (PPI) was defined using an event-level (time-varying) criteria, where there was no concomitant PPI use if there is 0 to less than 5 consecutive days of PPI use prior to the PK sample, and concomitant PPI use if there was equal or more than 5 consecutive days of PPI use prior to the PK sample. Parameter estimates of final covariate model including significant covariates developed by the applicant were provided in Table 64. The final model included effects of lean body weight on Vc/F, formulation effect on absorption rate as well as an effect of disease status (GIST) and PPI comedication on bioavailability. The effects of all evaluated covariates on the avapritinib exposure (AUC from time 0 to 35 days and Cmax) were illustrated in the forest plot (Figure 14). Overall, no intrinsic or extrinsic factors appear to have clinically relevant effects on avapritinib exposure. The magnitude of the effect of evaluated covariates on avapritinib exposure was minor (<0.5-fold change).

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Table 64: Parameter Estimates of the Final PopPK Model

Source: Applicant’s poppk report, Table 12, Page 78

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Figure 14: Covariate Effects on avapritinib Exposuer (AUC0-35 days or Cmax)

Source: Applicant’s poppk report, Page 17

PopPK analysis indicates that age (range: 18-90 years old), race (255 white, 25 black and 22 Asian people), sex (246 males and 97 females), body weight (range: 39.5-156.3 kg) and albumin concentration (range: 19-51 g/L) have no clinically meaningful effect of the pharmacokinetics of avapritinib.

The post-hoc avapritinib CL were similar between subjects with normal liver function, subjects with mild hepatic impairment and subjects with moderate hepatic impairment (Figure 15). Among 343 patients in the pooled analysis, 284 subjects had normal hepatic function, 53 subjects had mild hepatic impairment (total bilirubin within upper limit of normal [ULN] and AST>ULN or total bilirubin >1 to 1.5 times ULN and any AST), and 6 subjects had moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN and any AST). As there were 63 PK samples from 6 patients with moderate HI and the shrinkage for eta residual for CL is small, the comparison based on individual post-hoc CL is not expected to be biased. FDA agrees with the

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Applicant’s labeling claim that no dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase (AST) > ULN or total bilirubin greater than 1 to 1.5 times ULN and any AST) and moderate hepatic impairment (total bilirubin >1.5 to 3.0 times ULN and any AST).

Figure 15: Comparison of post-hoc CL across hepatic function.

Source: Reviewer’s Analysis based on “blu-285-all-20190206-1232.csv”

In the same population, 230 had normal renal function (creatinine clearance (Clcr>= 90)), 88 had mild renal impairment (Clcr>=60 & Clcr<90), and 24 had moderate renal impairment (Clcr>=30 & Clcr<60). The post-hoc avapritinib CL were similar between subjects with normal renal function, those with mild renal impairment and those with moderate renal impairment (Figure 16). FDA agrees with Applicant’s labeling claim that no dose adjustment is recommended for patients with mild and moderate renal impairment [creatinine clearance (CLcr) 30-89 mL/min estimated by Cockcroft-Gault)].

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Figure 16: Comparison of post-hoc CL across renal function.

Source: Reviewer’s Analysis based on “blu-285-all-20190206-1232.csv”

The effect of PPI use on avapritinib PK was also evaluated. During PK sample collection, 77 patients had 5 full days of PPI use, 7 patients had some use of PPI use in prior 5 days and 259 patients never used PPI use in prior 5 days. The effect of PPI use on relative bioavailability F1 is estimated to be 0.77. As there are 77 patients with 5 full days of PPI use in the analysis dataset and sufficient PK samples (433 out of 718) were collected in the absorption phase within 4 hours of last dose (Figure 17), FDA agrees that this estimate should be relatively reliable and that the effect of gastric acid reducing agents on the bioavailability of avapritinib is not clinically relevant.

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Figure 17: Observed Avapritinib Concentration-Time Profile across PPI Usage.

Source: Reviewer’s Analysis based on “blu-285-all-20190206-1232.csv”

19.3.4 Exposure-Response Analyses

Dose-Response Analyses Part 2 of study 1101 was initiated at the MTD of 400mg; however, based on the emerging data which suggested a trend toward higher incidence of Grade 3 neurologic AEs and more dose reductions at 400 mg QD, 300 mg was chosen by the Applicant as the recommended dose. Because of the dose change during the trial, a dose-response analysis for efficacy and safety can be tested between 300 mg and 400 mg QD. In patients with PDGFRα exon 18 mutation, the overall response rate in patients treated with 300 mg as starting dose was 87.5% (95% CI: 71%, 96.5%), which was comparable to the ORR in patients treated with 400 mg (Table 65). In the Applicant’s primary efficacy analysis for avapritinib in patients with 4L+ GIST tumors, 8 patients had a D842V mutation and were excluded from the analysis as they were already counted in the mutation positive population. In the remaining 4L+ GIST patients without a D842V

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mutation, the overall response rate in patients treated with 300 mg as starting dose was 15.4% (95% CI: 8.2%, 25.3%), which was also comparable to the ORR (14.3% (95% CI: 4.8%, 30.3%)) in patients treated with 400 mg. It should be noted that this comparison should be interpreted with caution because of nonrandomization and small sample size.

Table 65: Primary Analysis: Summary of Best Response by Central Radiology per mRECIST 1.1 (Safety Population: PDGFRA Exon 18 Patients)

Source: Applicant’s Clinical Overview Table 9, Page 42

Analysis of the overall safety data suggested better tolerability with avapritinib 300 mg QD relative to 400 mg QD. Specifically, there was a higher incidence of Grade 3+ AEs (82% vs 67%), AE leading to dose reduction (66% vs 41%), and AESIs of cognitive effects (48% vs 35%) in the 400 mg starting dose group compared to 300 mg group.

Concentration-Response Analyses Exposure-response analyses were conducted by the Applicant to explore the relationship between exposure of avapritinib and efficacy and safety in patients who received avapritinib.

Exposure-ORR relationship was evaluated in 62 patients with PDGFRα exon 18.

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Exposure safety analyses were performed to investigate whether the adverse events could be attributed to the variability in avapritinib. The markers of safety events include time to first all grade 3+ adverse events and time to first cognitive events. The exposure-safety analyses were conducted in 221 patients from study 1101.

The primary exposure metrics for exposure-efficacy assessment are individual predicted average, trough concentration for avapritinib at steady state. The primary exposure metrics for exposure-safety assessment are individual predicted average, maximum concentration for avapritinib at steady state. Graphical quartile analyses were used to investigate the exposure- ORR and exposure-AE relationships.

1) Concentration-efficacy relationship Overall, there shows to be no trend of exposure-ORR relationship in patients with a PDGFRα exon 18 mutation. Patients who had CR or PR appeared to have lower average concentration at steady state compared to patients with SD (Figure 18). However, because of the high response rate in patients with a PDGFRα exon 18 mutation and small sample size, this result should be interpreted with caution.

Figure 18: Boxplot of Best Overall Response vs Cave_ss.

Source: Reviewer’s Analysis based on “exposure-ep-master-20190312-1012.xpt”, “adsl.xpt” and “adresp.xpt”

2) Exposure-safety Relationships Graphical quartile analyses suggest higher avapritinib average concentration at steady state were associated with faster onset and higher incidence of Grade 3/4 AEs and AESI (AE of special interest) of cognitive effects (Figure 19).

Statistically significant relationships were found between average avapritinib concentration at steady state and Grade 3/4 AEs and AESI (AE of special interest) of cognitive effects (p-

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value<0.0001). The baseline covariates across all exposure quartiles in the exposure-AE analyses (Table 66) appear to be balanced.

Figure 19: Relationship between Avapritinib Exposure and Grade 3/4 AE and Cognitive Effects.

Source: Reviewer’s Analysis based on “exposure-ep-master-20190312-1012.csv”

Table 66: Baseline Covariates across 4 Exposure Quartiles in the Exposure-Safety Analyses.

Covariate Value Q1 Q2 Q3 Q4 Number of Subjects 55 55 55 56 Weight 76.8 (26.1) 71.2 (16.3) 77.5 (20.5) 73.4 (21.3) BSA 1.9 (0.3) 1.9 (0.2) 1.9 (0.3) 1.9 (0.3) Age <65 years 40 (72.7%) 28 (50.9%) 30 (54.5%) 36 (64.3%) >=65 Age 15 (27.3%) 27 (49.1%) 25 (45.5%) 20 (35.7%) years ECOG 0 19 (34.5%) 22 (40%) 23 (41.8%) 23 (41.1%) ECOG 1 33 (60%) 29 (52.7%) 32 (58.2%) 32 (57.1%) ECOG 2 3 (5.5%) 4 (7.3%) NA 1 (1.8%) Non- Race 6 (10.9%) 7 (12.7%) 4 (7.3%) 19 (33.9%) White Race Unknown 6 (10.9%) 9 (16.4%) 6 (10.9%) 4 (7.1%) Race White 43 (78.2%) 39 (70.9%) 45 (81.8%) 33 (58.9%) Sex F 22 (40%) 17 (30.9%) 18 (32.7%) 26 (46.4%)

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Sex M 33 (60%) 38 (69.1%) 37 (67.3%) 30 (53.6%) Tumor Mass <=10 cm 42 (76.4%) 42 (76.4%) 40 (72.7%) 49 (87.5%) Tumor Mass >10 cm 13 (23.6%) 13 (23.6%) 15 (27.3%) 7 (12.5%) Source: Reviewer’s Analysis based on “exposure-ep-master-20190312-1012.csv”

19.3.5 Physiologically-based Pharmacokinetic Review

Executive Summary The aim of this review is to evaluate the adequacy of the Applicant’s PBPK report titled “Development of a PBPK model for avapritinib using the SIMCYP population-based simulator and subsequent evaluation of the drug-drug interaction with inhibitors and inducers of CYP3A4 in patients with gastrointestinal stromal tumors (GIST)” to support the intended uses.

Specifically, the Applicant applied the PBPK modeling approach to prospectively estimate: • Effects of coadministration of a strong CYP3A4 inhibitor (such as ketoconazole) on the PK of avapritinib; • Effects of coadministration of a moderate CYP3A4 inhibitor (such as erythromycin, verapamil, and fluconazole) on the PK of avapritinib; • Effects of coadministration of a weak CYP3A4 inhibitor (such as cimetidine) on the PK of avapritinib; • Effects of coadministration of a moderate CYP3A4 inducer (such as efavirenz) on the PK of avapritinib.

The Division of Pharmacometrics has reviewed the original PBPK report, the amendment to the report, supporting modeling files, and the Applicant’s response to FDA request for information dated 23 August 2019, and concluded the following: • PBPK modeling is adequate to predict the PK of avapritinib in healthy volunteers and patients with GIST, following single and multiple dose administration. • PBPK analyses are adequate to predict the effect of CYP3A4 inhibitors on avapritinib exposure. Based on the inhibitors and dosage evaluated, the model predicted avapritinib AUCtau may increase from 4.4- to 10-fold with co-administration of a strong CYP3A4 inhibitor (such as itraconazole, and ketoconazole). Avapritinib AUCtau may increase by around 2.8-fold (range from 2.5-to 3.1-fold) with co-administration of a moderate CYP3A4 inhibitor (such as erythromycin, verapamil or fluconazole); while no significant interaction is predicted with a weak CYP3A4 inhibitor (such as cimetidine) at steady-state. • PBPK analyses are adequate to predict the effect of a moderate CYP3A4 inducer on avapritinib exposure. The model predicted that a moderate CYP3A4 inducer (such as efavirenz) may decrease the steady-state AUC of avapritinib by 62%. • PBPK analyses are adequate to support labeling language for avapritinib interaction with CYP3A4 modulators.

Background

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Avapritinib proposed dosing regimen is 300 mg once daily (QD) as immediate-release film- coated tablets. After single dose (SD) administration of avapritinib in patients with GIST, median Tmax ranged from 2 to 4 hours. Following single and multiple once daily dosing, avapritinib exposure (Cmax and AUC) was dose-proportional across the dose range of 30 to 400 mg. Following multiple once-daily (QD) administration, the geometric mean accumulation ratio was 3.1 to 4.6 in plasma. The geometric mean CL/F ranged between 17.2 and 28.6 L/h after single- dose administration and between 17.3 to 24.6 L/h after QD administration. The interindividual variability (%CV) for PK parameters (Cmax, AUC24h, C24h) ranged between 20% to 73% in patients following SD and QD dosing [BLU-285-1101].

In vitro data showed the isoforms CYP3A4 (major) and CYP2C9 (minor) contribute to the oxidative metabolism of avapritinib. Metabolic pathways of avapritinib included oxidation, glucuronidation, oxidative deamination and N-dealkylation. Based on the ADME study in healthy subjects [BLU-285-0103], unchanged avapritinib (49%) and metabolites M690 (hydroxy glucuronide; 35%) and M499 (oxidative deamination; 14%) were the major circulating radioactive components. In patients with GIST, the steady state AUC of BLU111207 and BLU111208, the enantiomers of the active metabolite M499, were 35% and 42% of avapritinib AUC, respectively. Those metabolites are reported to be less potent than avapritinib against KIT D816V in vitro. Of note, these metabolites were not incorporated in the PBPK analyses. Fecal excretion is the major elimination pathway for avapritinib and metabolites. Unchanged avapritinib accounted for 11% and 0.23% of the administered radioactive dose excreted in feces and urine, respectively [BLU-R7561].

The exposure to avapritinib increased when administered under fed conditions (high fat meal): Cmax and AUCinf increased by 59% and 29%, respectively, compared to fasted state [BLU-285- 0102]. Avapritinib is proposed to be administered under fasted conditions (patients will be instructed not to eat for at least 2 hours before and at least 1 hour after taking avapritinib).

In vitro, avapritinib was determined to be a competitive inhibitor, time-dependent inhibitor and inducer of CYP3A4 [Report 1709171, CYP-0915-R4 and CYP0915-R3]. Avapritinib was not determined to be a substrate of the efflux transporters P-gp or BCRP in vitro [Report OPT-2018- 549].

Methods PBPK model structure and development The PBPK analyses were performed using the population-based PBPK software Simcyp® (V17R1, Simcyp Ltd., a Certara Company, Sheffield, United Kingdom). The avapritinib PBPK model was developed based on in vitro, human ADME study and clinical PK and DDI data.

Briefly, a first-order absorption model and a minimal PBPK model were used to describe the PK of avapritinib. The first-order absorption rate (ka=1.3 1/h) with a lag time of 0.5 h was optimized to capture the avapritinib PK profile and Tmax value observed in healthy subjects administered 200 mg SD [BLU-285-0102]. The fraction absorbed (fa) was assumed to be 0.78 based on food effect study data (BLU-285-0102). This assumption was supported also by the

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percentage recovered of unchanged avapritinib in feces (mean 11%, range: 4-18%) from metabolic profiling of human mass balance data [BLU-285-0103, BLU-R7561]. In vitro Caco-2 (b) (4) (b) (4) permeability data [Reports P13-8376 and P14-8616] were used to estimate the human intestinal effective permeability (Peff human 1.59 x 10-4 cm/s) value and the hybrid intestinal blood flow parameter (QGut=8.76 L/h). The unbound fraction in enterocytes (fuGut) was assumed equal to unbound fraction in plasma.

The unbound fraction in plasma (fup=0.012) and blood to plasma concentration ratio (b) (4) (B/P=0.95) values were determined in vitro [Reports BPM-0013 and P14_9193]. Albumin was assumed to be the main binding protein (no data available). The volume of distribution parameter Vss (=8.42 L/kg) was estimated using allometric scaling of Vss values reported in animal species accounting for species differences in plasma protein binding.

The enzyme kinetics (Clint,u) for CYP3A4 and CYPC9 were determined using the retrograde approach, based on the relative contribution of each enzyme to the clearance of avapritinib. In vitro data from recombinant CYP enzymes, corrected for “Inter System Extrapolation Factors”, were used to assign the relative contribution [Report 140415]. The estimates of fm were 0.90 and 0.10 for CYP3A4 and CYP2C9 respectively. The CL/F value of 18.4 L/h, reported in healthy subjects following a single 200 mg oral dose of avapritinib [BLU-285-0102], was used in the retrograde model. Based on the human ADME data, 0.23% of the avapritinib dose is excreted unchanged in urine resulting in an estimated renal clearance (CLr) of 0.042 L/h [BLU-285-0103].

In-vitro data showed avapritinib is a competitive inhibitor, a time-dependent inhibitor (TDI) and an inducer for CYP3A4. The CYP3A4 Indmax and IndC50 values were 5.7-fold and 0.36 μM, respectively, based mRNA data [Report 1709171]. The CYP3A4 TDI parameters, KI (inhibitor -1 concentration causing half-maximal inactivation) and Kinact values were 12.3 μM and 1.8 h , respectively [Report CYP-0915-R4]. The Ki value for competitive inhibition of CYP3A4 was 10.3 μM [Report CYP0915-R3]. Due to uncertainty in the non-specific microsomal binding (fumic; applied to CYP3A4 KI value) and non-specific binding in hepatocyte incubations (fuinc; applied to CYP3A4 IndC50 value), the impact of these values on the predicted net effect on CYP3A4 activity (auto-induction and auto-inhibition) was investigated during development of avapritinib PBPK model. The Applicant reported the in-vitro TDI (corrected for the observed fumic value) and induction parameters (assumed no non-specific binding), when incorporated in the avapritinib PBPK model, would over-predict the steady-state drug exposure. Accordingly, the Applicant adjusted the observed fumic value to a predicted value of 0.91 based on protein concentration of 0.1 mg/mL used in the in vitro study and used a predicted value of 0.53 for fuinc.

Simulations were performed using the default healthy virtual population models. For simulations involving GIST patients the North European Caucasian population (“Sim- N Eur Caucasian”) was used to accommodate the wider age range observed in this population (29 to 90 years; median 62 years; Study BLU-285-1101). The Applicant also proposed to develop a virtual “GIST” population model based on the lower levels of albumin (37 g/L) observed in patients with GIST [BLU-285-1101] compared to those reported in healthy subjects (45 g/L). To

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reflect this observation, albumin levels were adjusted in the healthy population model. The resulting “GIST” population model had a predicted mean avapritinib fu value of 0.015, slightly (b) (4) higher than the measured value of 0.012 in plasma from healthy individuals [Report P14- 9193]. Simulations were conducted using both the default healthy population model and “GIST” for comparison. Simulations were conducted in the fasted state, consistent with the proposed usage.

The default compound models for ketoconazole, itraconazole, erythromycin, diltiazem, verapamil, fluconazole, cimetidine, and efavirenz were used in the PBPK simulations for the respective DDIs. For rifampicin DDI, the default library model (v17) and a modified model based on published literature were used1. The maximum fold induction (Indmax, expressed as a fold over vehicle control) for rifampicin default model was increased from 16 to 37.1 based on rifampicin-mediated DDI predictions involving 17 clinical studies substrates of differing fmCYP3A4 (range of 0.18 to 1). Accordingly, two sets of simulations with rifampicin were conducted: one using the default CYP3A4 induction parameters for rifampicin (Indmax=16 and IndC50= 0.32 µM) and the other using the modified Indmax value of 37 (and IndC50=0.32 µM).

PBPK model verification The performance of avapritinib PBPK model was evaluated by comparison of simulated and reported clinical PK data, following single and multiple dose administration in healthy volunteers and patients with GIST [BLU-285-0102 and BLU-285-1101]. Clinical DDI data avapritinib-itraconazole and avapritinib-rifampin were used to verify the contribution of CYP3A4 to the overall clearance of avapritinib [BLU-285-0104].

PBPK model application The PBPK analyses was applied prospectively to estimate the following: • Effects of coadministration of a strong CYP3A4 inhibitor (such as ketoconazole and itraconazole) on the PK of avapritinib; • Effects of coadministration of a moderate CYP3A4 inhibitor (such as erythromycin, verapamil, and fluconazole) on the PK of avapritinib; • Effects of coadministration of a weak CYP3A4 inhibitor (such as cimetidine) on the PK of avapritinib; • Effects of coadministration of a moderate CYP3A4 inducer (such as efavirenz) on the PK of avapritinib.

Results Q1. Can PBPK analyses provide a reasonable description of the PK of avapritinib? Yes, PBPK simulations described the PK profile of avapritinib following single dose administration (200 and 400 mg) in healthy subjects [BLU-285-0102, BLU-285-0105], and

1 Yamashita F et al. Modeling of rifampicin-induced CYP3A4 activation dynamics for the prediction of clinical drug-drug interactions from in vitro data. PLoS One, vol. 8, no. 9, p. e70330, 2013.

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multiple dose (90, 135, 200 and 300 mg QD) in patients with GIST [BLU-285-1101]. Comparison of observed PK profile versus PBPK predicted are shown in Figure 20 .

There was reasonable agreement between PBPK predicted and observed exposures in healthy volunteer PK data. Overall, the predicted geometric mean values for AUC (AUCinf or AUCtau), Cmax and Tmax were within ± 30% of the observed parameters (Table 67).

Figure 20. PBPK predicted and observed PK profiles of avapritinib

A B

C D

PBPK predicted mean (lines) and observed mean (circles) plasma concentration-time profiles of avapritinib following (A) a single oral dose of avapritinib 200 mg in healthy subjects [n=30, Study BLU-285-0102]; (B) a single oral dose of avapritinib 400 mg in healthy subjects [n=62, Study BLU-285-0105]; 300 mg QD for 15 days (C) on day 1, and (D) on day 15 in patients with GIST [mean, n=110 individuals, Study BLU-285-1101]. The solid black line is the mean data for the simulated population and the gray dashed lines represent the 5% and 95% percentiles. Simulations were conducted using the healthy population models “Sim- Healthy” or “Sim-N Eur Caucasian”. (Source: Avapritinib PBPK DDI Report and Avapritinib PBPK DDI Report -Revision 1).

The performance of the PBPK model for avapritinib to describe the PK in GIST patient population was evaluated by comparison with the observed data in patients with GIST (Study BLU-285-1101), using both the default healthy subject population model (“Sim-N Eur Caucasian”) and the Applicant’s proposed “GIST” population model. Overall predicted PK parameter values for avapritinib for both population models were within ±50% of the observed clinical data (Table 67). There was a prediction bias for slightly higher exposure using the healthy volunteer population compared to GIST population model, due to lower predicted CL/F.

Considering the interindividual variability in the steady-state PK of avapritinib (%CV for Cmax and

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AUC of 52.2% and 48.3%, respectively), the healthy subject population model was considered adequate to predict the PK profile of avapritinib for patients with GIST.

Table 67. Comparison of PBPK predicted and observed PK parameters for avapritinib Avapritinib Observed Predicted Study Dosing Cmax Tmax AUC CL/F Cmin Virtual Cmax Tmax AUC CL/F Cmin Population Regimen (ng/mL) (h) (ng.hr/mL) (L/h) (ng/mL) population (ng/mL) (h) (ng.hr/mL) (L/h) (ng/mL) 200 mg SD Healthy 209.5 4.4 11500 19.6 NA Healthy 192.3 4.5 12187 21.3 NA BLU-285-0102 400 mg SD Healthy 473.2 4.0 26120 18.4 NA Healthy 384 4.5 25460 21.4 NA BLU-285-0105 90 mg QD Patients NA GIST 80.3 4.9 1564 23.8 NA 86.5 2.0 1310 19.6 Day 1 with GIST *Healthy 88 4.7 1761 19.0 NA BLU-285-1101 90 mg QD Patients GIST 248 3.4 5193 24.9 180 239 4.0 4660 20.2 161 Day 15 with GIST *Healthy 291 3.5 6158 20.0 216 BLU-285-1101 135 mg QD Patients GIST 119 4.6 2326 22.5 NA 132 4.0 1980 22.9 NA Day 1 with GIST *Healthy 126 4.7 2536 18.0 NA BLU-285-1101 135 mg QD Patients GIST 373 3.4 7826 23.9 272 435 2.0 8030 17.7 283 Day 15 with GIST *Healthy 415 3.4 8771 19.4 307 BLU-285-1101 200 mg QD Patients GIST 197 4.5 3821 22.1 NA 229 3.0 3170 23.3 NA Day 1 with GIST *Healthy 212 4.7 4253 17.4 NA BLU-285-1101 200 mg QD Patients GIST 598 3.5 12457 23.7 469 526 4.0 10100 22.3 334 Day 15 with GIST *Healthy 691 3.8 14589 18.9 510 BLU-285-1101 300 mg QD Patients GIST 307 4.5 5987 19.7 NA 305 4.0 4510 31.5 NA Day 1 with GIST *Healthy 310 5.3 6160 14.9 NA BLU-285-1101 300 mg QD Patients GIST 907 3.5 18874 21.8 648 905 4.0 16900 21.8 593 Day 15 with GIST *Healthy 969 3.8 20361 19.6 706 BLU-285-1101 400 mg QD Patients GIST 407 4.5 7957 19.1 NA 343 4.0 5310 29.9 NA Day 1 with GIST *Healthy 414 5.4 8259 17.4 NA BLU-285-1101 400 mg QD Patients GIST 1197 3.5 24935 22.8 854 1140 4.0 21300 22.8 760 Day 15 with GIST *Healthy 1292 3.8 27204 19.8 942 BLU-285-1101 Data are presented as Mean. *Simulations were conducted with the default Healthy volunteer population model “Sim-N Eur Caucasian” to allow coverage of the age range of the clinical study. NA: Not applicable; SD: single dose; QD: once-daily dosing; AUC0-24h for SD, AUCtau for QD. (Source: CSRs, simulation output files).

Reviewer’s comments: The Applicant proposed to build a virtual “GIST” population model based on the lower levels of albumin (37 g/L) reported in patients with GIST [BLU-285-1101] compared to healthy subjects (45 g/L). Albumin was assumed as the main binding protein and levels were reduced in the GIST population model. Consequently, the GIST population model predicted higher fraction unbound in plasma (fu=0.015) in patients with GIST compared to healthy subjects (fu= 0.012). The increase in the unbound fraction resulted in a higher apparent clearance (CL/F) for the patients with GIST. The Applicant noted that the resulting CL/F were consistent with the slightly higher CL/F values reported in patients with GIST (CL/F= 18-28 L/h GIST) compared to healthy subjects (CL/F=15-18 L/h).

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Refining physiological parameters using clinical observations (i.e., laboratory data) is an important approach in PBPK modeling to reflect its population of interest. However, in the case of avapritinib, other mechanisms for the higher CL/F, reported in patients with GIST in the trial BLU-285-1101, were not considered in the proposed GIST population model.

For instance, avapritinib showed pH-dependent solubility in vitro (lower solubility at higher pH). Thus, there is a potential for reduced bioavailability in higher gastric pH. The Applicant stated patients with gastric/intestinal cancer (n = 89) may have higher gastric pH values compared to healthy subjects (2.9 vs 6.6). Gastric pH value specific for the GIST population is not available. There is a potential for GIST patients have lower bioavailability of avapritinib compared to healthy subjects. Nonetheless, the changes in avapritinib PK related to GIST disease status were not considered to be clinically relevant due to the observed interindividual variability in the PK. Therefore, the healthy population PBPK model was considered adequate to predict the PK profile of avapritinib for patients with GIST.

Q2. Can available data combined with PBPK analyses be used to estimate the interaction effect of avapritinib on CYP3A? Yes. Multiple dose PK data of avapritinib at 300 mg dose level was used to optimize the interaction effect of avapritinib on CYP3A pathway. Comparison of predicted and observed plasma concentrations of avapritinib following multiple oral doses of avapritinib (300 mg QD) is shown in Figure 21A.

The CYP3A4 inactivation (KI and kinact) and induction data (Indmax and IndC50) of avapritinib fairly estimated the steady-state drug exposure. The predicted mean Cmax and AUC values for avapritinib 300 mg QD on Day 15 were within ±20% of the observed values (Table 67). The predicted accumulation ratio (Rac=geo mean of AUC24h Day 15/ AUC24h Day 1) was 3.3-fold compared to the observed ratio of 3.6 [BLU-285-1101].

The optimized CYP3A4 interaction parameters (fumic and fuinc values) were then applied prospectively and verified in the other dosage regimens tested in the clinical study BLU-285- 1101. Following once daily dosing of avapritinib 90 mg, 135 mg, 200 mg or 400 mg for 15 days to patients with GIST, the simulated avapritinib Cmax, AUC and Cmin values were within ±50% of the observed values [BLU-285-1101]. Comparison of simulated and observed plasma concentrations of avapritinib following 400 mg QD dosing is shown in Figure 21B.

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Figure 21. PBPK predicted and observed PK profiles of avapritinib following multiple dosing

A B

PBPK Predicted (lines) and observed (circles, Study BLU-285-1101) plasma concentration-time profiles of avapritinib following once-daily dosing of (A) 300 mg (mean of n=110 individuals) or (B) 400 mg (individual data n=38) avapritinib for 15 days. The solid black line is the mean data for the simulated population (10 trials of 110 subjects per trial, N=1100) and the dashed lines are the 5th and 95th percentiles. Gray lines are the mean data for the individual simulated trials. (Source: Avapritinib PBPK DDI Report, Simulation output files).

Simulations were conducted to predict changes in hepatic and intestinal CYP3A4 levels during once daily dosing of avapritinib 90 to 400 mg for 15 days in patients with GIST, using both healthy volunteer and GIST population models (Figure 22). There were minor differences in predicted CYP3A4 enzyme levels in the two populations. Overall, the predicted effect of multiple dosing of avapritinib on CYP3A4 activity was a net increase in CYP3A4 hepatic enzyme level. The predicted increase in CYP3A4 activity on Day 15 varied with dose from around 6% following 90 mg QD dosing to around 20% following 400 mg QD dosing.

Figure 22. PBPK predicted hepatic CYP3A4 values following multiple dosing of avapritinib

PBPK predicted values of active hepatic CYP3A4 enzyme compared to baseline, over time, across avapritinib dose levels (90 mg to 400 mg QD for 15 days). Simulations were conducted using (a) the proposed GIST population model and (b) Sim-N Eur Caucasian population model (Source: Avapritinib PBPK DDI Report -Revision 1)

Reviewer’s comments: Based on recombinant CYP assay [Report 140415] and clinical DDI study with itraconazole [BLU- 285-1104], the Applicant proposed CYP3A4 is the main isoform contributing to avapritinib metabolism. PBPK simulations predicted a mild induction of CYP3A4 activity (6-20% increase in

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CYP3A activities in the liver at steady state), following multiple doses of 90-400 mg avapritinib QD, when CYP3A4 induction and TDI parameters were incorporated in avapritinib PBPK model.

The reviewer considered the use of the multiple dose PK data of avapritinib to optimize the interaction effect of avapritinib on CYP3A pathway sufficient for the intended purposes. Reasons are: 1) avapritinib is a sensitive CYP3A4 substrate (fmCYP3A4 >0.8); and 2) avapritinib showed dose and time-independent PK.

Q3. Can PBPK analyses predict the interaction effect of a CYP3A4 inhibitor on the PK of avapritinib? Yes. PBPK simulations predicted the clinically observed DDI between avapritinib and itraconazole in healthy volunteers given a single dose of 200 mg avapritinib and repeated doses of 200 mg QD itraconazole (Figure 23). The predicted geometric mean PK parameters (Cmax, AUC, and ratios) for avapritinib were within 10% of the observed values (Table 68). These results suggest avapritinib PBPK model provided a reasonable estimate of the metabolic contribution of CYP3A4 (fmCYP3A4=0.9) to avapritinib overall clearance at single-dose in vivo.

Table 68. PBPK predicted and observed Cmax and AUC values of avapritinib in absence and presence of itraconazole Cmax (ng/mL) AUCinf (ng.h/mL) Cmax Ratio (90%CI) AUCinf Ratio (90%CI) Treatment Pred Obs Pred Obs Pred Obs Pred Obs

Control 198 271 12729 13660 1.24 1.38 4.20 4.21 with ITZ 246 361 54460 58950 (1.23-1.25) (1.21-1.57) (4.07-4.34) (3.66-4.84) PK data are presented as mean values. Observed and predicted Cmax ratio and AUC ratio presented as geometric means, and expressed as with inhibitor/without inhibitor. Observed values (N=19-20) from study BLU-285-0104. Trial design simulation: a single oral dose of avapritinib (200 mg) in the absence of itraconazole (ITZ) and co-administered with ITZ on the 4th day of 14 days of dosing (200 mg BID day 1; 200 mg QD day 2-14). Simulations were conducted using the “Sim-Heathy” population model (Source: Table 9 of avapritinib-PBPK-DDI-report).

Figure 23. PBPK predicted and observed PK profile of avapritinib in absence and presence of itraconazole

A B

PBPK predicted (lines) and observed (circles, Study BLU-285-0104) mean plasma concentration-time profiles (A) and corresponding log-linear profile (B) of avapritinib following a single dose of avapritinib (200 mg) in the absence of itraconazole (solid line) and on the 4th day of 14 days of dosing of itraconazole (day 1 200 mg BID; day 2-14 200 mg QD; dashed line). Lines

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represent the mean for the simulated population (n = 200). Simulations were conducted using the “Sim-Heathy” population model. (Source: Avapritinib-PBPK-DDI-report).

Reviewer’s comment The design of the clinical DDI study was not fully optimized to evaluate the interaction effect with itraconazole. For instance, avapritinib PK data were not collected long enough to capture the entirety of avapritinib PK curve in the presence of a perpetrator (as illustrated in Figure 23). Clinically, the mean half-life of avapritinib increased 3-fold from 52 h to 169 h with itraconazole coadministration, and the percent AUC extrapolated was higher than 20% for most subjects, suggesting that estimations of AUCinf, CL/F and half-life were potentially not robust [Clinical Pharmacology Summary].

PBPK simulations were then conducted to evaluate the interaction effect of itraconazole on avapritinib following single-dose and multiple-dose scenarios. Refer to Q5 for results.

Q4. Can PBPK analyses predict the interaction effect of a CYP3A4 inducer on the PK of avapritinib? Yes. For simulations of the DDI effect with rifampin, application of the default value for Indmax resulted in 2-fold under-prediction of the decrease in exposure of avapritinib (400 mg SD) when co-administered with rifampicin (600 mg QD). The predicted and observed geometric mean Cmax and AUC ratios for avapritinib in the presence of rifampin were 0.57 and 0.20 versus 0.26 and 0.08, respectively.

However, application of a higher Indmax value (37 instead of 16) (modified rifampin model) resulted in predicted geometric mean Cmax and AUC ratios for avapritinib in the presence of rifampin within 1.4 and 1.2-fold of observed values [BLU-285-0104]. A comparison of predicted and observed PK of avapritinib (400 mg SD) in the absence and presence of rifampin are shown in Table 69.

Table 69. PBPK predicted and observed Cmax and AUC values of avapritinib in absence and presence of rifampin Cmax (ng/mL) AUCinf (ng.h/mL) Cmax Ratio (90%CI) AUCinf Ratio (90%CI) Treatment Pred Obs Pred Obs Pred Obs Pred Obs

Control 398.5 480.4 25288 26630 0.35 0.26 0.09 0.08 With RIF 153.0 139.5 2577 2196 (0.33-0.37) (0.20-0.34) (0.09-0.10) (0.07-0.10) PK data are presented as means. Observed and predicted Cmax ratio and AUC ratio presented as geometric means, and expressed as with inducer/without inducer. Observed values (N=19-20) from clinical study BLU-285-0104.Trial design simulation: a single oral dose of avapritinib (400 mg) in the absence of rifampicin (RIF), and co-administered on the 9th day of 18 days of dosing of RIF. *Simulations using RIF Indmax of CYP3A4= 37 (modified rifampin model). Simulations were conducted using the “Sim-Heathy” population model. (Source: Table 12 of avapritinib-PBPK-DDI-report).

Reviewer’s comments: Current analysis used the default enzyme induction model, which assumes when multiple inducers are co-administered the highest induction factor of the interacting drugs to predict the net-induction effect. Prediction of drug interactions involving multiple inducers for the same

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enzyme is complex, as multiple inducers may affect the same or different transcription factors. The reviewer tested other induction models available in the PBPK software, namely additive and multiplicative, to evaluate the differential effects on the net induction effect of rifampin- avapritinib DDI. Selection of multiple enzyme induction model (additive or multiplicative) had minimal impact on predicted values of avapritinib Cmax and AUC ratio in the presence of rifampin (data not shown).

Q5. Can PBPK analyses be used to estimate the effects of CYP3A4 inhibitors on the PK of avapritinib? Yes. The DDI liabilities of avapritinib as a victim of strong, moderate and weak inhibitors of CYP3A4 were estimated by PBPK analyses. Predicted avapritinib exposure at single-dose and steady state in the presence of CYP3A4 inhibitors are summarized in Table 70.

At single-dose, PBPK analyses show that the drug interaction effect, in terms of predicted geometric mean ratios for avapritinib AUCinf, ranged from 4- to 9.5-fold across different strong CYP3A4 inhibitors, ranged from 3- to 3.5-fold across different moderate CYP3A4 inhibitors, and was 1.2-fold with a weak CYP3A4 inhibitor.

Compared with the single-dose scenario, PBPK analyses predicted similar increase on avapritinib AUC following repeated doses of avapritinib in presence of CYP3A4 inhibitors. At steady-state, the predicted geometric mean ratios for avapritinib AUCtau ranged from 4.4 to 10- fold with a strong CYP3A4 inhibitor, 2.5 to 3.1-fold with a moderate CYP3A4 inhibitor, and 1.2- fold with a weak CYP3A4 inhibitor. These predictions are in line with the minor effect of CYP3A4 auto-induction to avapritinib clearance at steady-state. Nonetheless, there was a higher interaction effect on avapritinib Cmax (higher Cmax ratio) at steady-state compared to single-dose scenario.

Table 70. PBPK predicted Cmax and AUC ratios for avapritinib following single-dose and at steady-state in the presence of CYP3A4 inhibitors using healthy population model Perpetrator Avapritinib 300 mg SD Avapritinib 300 mg QD Cmax Ratio AUCinf Ratio Cmax Ratio AUCtau Ratio Dosing Class (90% CI) (90% CI) (90% CI) (90% CI) Regimen [Trial Min-Max] [Trial Min-Max] [Trial Min-Max] [Trial Min-Max] 1.22 4.16 3.91 4.36 CYP3A4 strong Ketoconazole (1.20-1.23) (3.94-4.38) (3.69-4.13) (4.12-4.62) inhibitor 400 mg QD [1.17-1.26] [3.73-4.41] [3.47-4.35] [3.88-4.80] 1.22 7.41 6.21 7.00 CYP3A4 strong Itraconazole (1.20-1.23) (6.99-7.86) (5.77-6.68) (6.51-7.53) inhibitor 200 mg QD [1.20-1.28] [6.44-8.42] [5.06-7.24] [5.67-8.19] 1.22 9.58 8.86 10.12 CYP3A4 strong Itraconazole (1.20-1.28) (9.02-10.2) (8.30-9.46) (9.47-10.8) inhibitor 200 mg BID [1.21-1.24] [6.44-10.6] [7.93-10.16] [9.14-11.4] 1.15 2.98 2.30 2.49 CYP3A4 moderate Erythromycin (1.14-1.16) (2.85-3.13) (2.22-2.39) (2.40-2.60) inhibitor 500 mg TID [1.11-1.18] [2.43-3.37] [1.97-2.50] [2.10-2.75] 1.16 3.45 2.47 2.69 CYP3A4 moderate Verapamil (1.15-1.17) (3.28-3.61) (2.38-2.56) (2.59-2.79) inhibitor 80 mg TID [1.20-1.28] [6.44-4.29] [2.17-2.82] [2.36-3.16]

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1.17 3.08 2.77 3.05 CYP3A4/CYP2C9 Fluconazole (1.16-1.17) (3.03-3.14) (2.70-2.84) (2.98-3.12) moderate inhibitor 200 mg QD [1.14-1.20] [2.89-3.23] [2.53-3.07] [2.74-3.42] 1.05 1.17 1.14 1.16 CYP3A4 weak Cimetidine (1.04-1.05) (1.17-1.18) (1.14-1.15) (1.16-1.17) inhibitor 400 mg TID [1.04-1.05] [1.15-1.19] [1.13-1.16] [1.14-1.17] Data are presented as population geometric mean values for exposure ratios (AUC and Cmax) expressed as the fold change in the in the presence versus absence of a perpetrator (90% confidence interval). Values in brackets are the trial range: maximum and minimum values from 10 simulated trials. Simulations were conducted using “Sim N Eur Caucasian” population model. (Source: Avapritinib PBPK DDI Report-Revision 1).

The interaction effect of CYP3A4 modulators on avapritinib were also predicted using the Applicant’s proposed GIST population model. No significant impact on predicted values of avapritinib Cmax and AUC ratio were obtained. The DDI simulations results (multiple dosing of avapritinib 300 mg QD) using the GIST population compared to healthy population is listed in Table 71.

Table 71. Comparison of population model predictions for Cmax and AUC ratios for avapritinib steady-state in the presence of CYP3A4 modulators Perpetrator GIST population model Healthy population model Dosing Cmax Ratio AUCtau Ratio Cmax Ratio AUCtau Ratio Class Regimen (90% CI) (90% CI) (90% CI) (90% CI) CYP3A4 strong Ketoconazole 4.24 4.79 3.91 4.36 inhibitor 400 mg QD (4.00-4.49) (4.51-5.08) (3.69-4.13) (4.12-4.62) CYP3A4 strong Itraconazole 6.91 7.90 6.21 7.00 inhibitor 200 mg QD (6.42-7.44) (7.33-8.51) (5.77-6.68) (6.51-7.53) CYP3A4 strong Itraconazole 9.23 10.66 8.86 10.12 inhibitor 200 mg BID (8.62-9.89) (9.94-11.43) (8.30-9.46) (9.47-10.8) CYP3A4 moderate Erythromycin 2.28 2.48 2.30 2.49 inhibitor 500 mg TID (6.42-7.44) (6.42-7.44) (2.22-2.39) (2.40-2.60) CYP3A4 moderate Verapamil 2.55 2.80 2.47 2.69 inhibitor 80 mg TID (2.46-2.65) (2.70-2.92) (2.38-2.56) (2.59-2.79) CYP3A4/CYP2C9 Fluconazole 2.85 3.16 2.77 3.05 moderate inhibitor 200 mg QD (2.78-2.92) (3.08-3.24) (2.70-2.84) (2.98-3.12) CYP3A4 weak Cimetidine 1.16 1.18 1.14 1.16 inhibitor 400 mg TID (1.16-1.17) (1.18-1.19) (1.14-1.15) (1.16-1.17) CYP3A4 moderate Efavirenz 0.42 0.36 0.45 0.38 inducer 600 mg QD (0.41-0.44) (0.34-0.37) (0.43-0.47) (0.36-0.40) Data are presented as population geometric mean values for exposure ratios (AUC and Cmax) expressed as the fold change in the in the presence versus absence of a perpetrator (90% confidence interval). DDI effect following multiple oral dosing of avapritinib (300 mg QD co-administered with multiple dosing of the perpetrators. Simulations were conducted using the “Sim N Eur Caucasian” and “GIST” population models. (Source: Avapritinib PBPK DDI Report-Revision 1).

Reviewer’s comment: Cimetidine is likely to be reclassified as a weak CYP3A inhibitor in the revised FDA DDI table. For the purpose of this review, we consider cimetidine to be a weak CYP3A4 inhibitor.

Q6. Can PBPK analyses be used to estimate the effects of CYP3A4 inducers on the PK of avapritinib? Yes. The DDI liabilities of avapritinib as a victim of a moderate inducer of CYP3A4 were estimated by PBPK analyses. Multiple dosing of efavirenz (600 mg QD for 40 days) significantly decreased the exposure to single-dose avapritinib (300 mg on day 28): the predicted geometric 179 Version date: April 2, 2018

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mean (90% CI) ratios for Cmax and AUCinf were 0.71 (0.70-0.73) and 0.31 (0.30-0.33), respectively. At steady-state (300 mg QD, 29 days), the predicted geometric mean (90% CI) ratios for avapritinib Cmax and AUCtau were 0.45 (0.43-0.47) and 0.38 (0.36-0.40) respectively, following multiple-dose of efavirenz (600 mg QD for 29 days).

The predicted interaction effect of efavirenz on avapritinib steady-state using the GIST population model was not different than that of the healthy population model (Table 71).

Conclusions In summary, PBPK analysis are adequate to predict the PK of avapritinib in healthy volunteers and patients with GIST, following single- and multiple-dose administration.

PBPK analyses are adequate to predict the effect of CYP3A4 inhibitors on avapritinib exposure. The model predicted avapritinib steady-state AUCtau may increase from 4.4- to 10-fold with co- administration of a strong CYP3A4 inhibitor (such as itraconazole and ketoconazole). A moderate CYP3A4 inhibitor (such as erythromycin, verapamil and fluconazole) may increase avapritinib AUCtau by around 2.8-fold (range from 2.5-to 3.1-fold); while no significant interaction is predicted with a weak CYP3A4 inhibitor (such as cimetidine). The PBPK analyses are adequate to support labeling language for avapritinib interaction with CYP3A4 inhibitors.

PBPK analyses are adequate to predict the effect of a moderate CYP3A4 inducer on avapritinib exposure. The model predicted that a moderate CYP3A4 inducer (such as efavirenz) may decrease the steady-state AUCtau of avapritinib by 62%. PBPK analyses are adequate to support labeling language for avapritinib interaction with a moderate CYP3A4 inducer.

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Signatures

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!Signature: C>igitally signed by Pal!avr S. Mshra-k.alyam -S 0Noc·us.• • u.s.G... •mmco1.ou•HHs.... ,0Aou·•eopl• . Palla VI· 5 • Mishra - kalyani - 5 0.9.2342.19200300.100.1.1 "' 2?° 1, 675542, cnz:Pall.J\liS. Mishra·kalyani ·S Oat~: 2020.01.09 08:39:26 -OS 00 ShenghuiTang Office of Biostatistics, Select one: Division Director (OB) Division of Biometrics Sections: 8 - Authored 5 _L_Approved

!Signature: Sh h • T s ~~~~~~~~~~oum f[M.

Signature: Digitally signed by Stt'vt'n J. Lfmery-S ON: c=US, o=U.S. Govl!"mment, ou,.HHS, 01.1,,,FOA, oo=People, 0.9.2142.19200300.100.1.1,,.1300392067. Steven J. Lemery -S cn,.Stl!"ven J. Lemery-S Date: 2020.01.0817'.ll '.05 -05'00

!Steven Lemery Office of Oncologic Select one: Division Director Disease, Division of Sections: All JS. Authored (Section (Clinical) Oncology 3 17)

X Annroved Signature: °"~'~"'f \1..-- Jl..-f)I·~ Steven J. Lemery -S E!~~~~~~,;:::r:}9=;.~~:-,:::~ .~

Reference ID: 4543562 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

IDARA UDOH 01/09/2020 12:16:45 PM

STACY S SHORD 01/09/2020 12:20:49 PM

STEVEN J LEMERY on behalf of ASHLEY F WARD 01/09/2020 01:14:31 PM

MARC R THEORET 01/09/2020 01:42:45 PM

Reference ID: 4543562