CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

211288Orig1s000

MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA Multi-Disciplinary Review and Evaluation {NDA 211288} VIZIMPRO / dacomitinib

NDA/BLA Multi-Disciplinary Review and Evaluation Application Type New Drug Application-New Molecular Entity Application Number(s) 211288 Priority or Standard Priority Submit Date(s) January 31, 2018 Received Date(s) January 31, 2018 PDUFA Goal Date September 28, 2018 Division/Office OHOP / DOP2 Review Completion Date September 27, 2018 Established Name Dacomitinib (Proposed) Trade Name VIZIMPRO Pharmacologic Class Kinase Inhibitor Code name PF-00299804 Applicant Pfizer Pharmaceutical Company Formulation(s) 15 mg, 30 mg and 45 mg tablets Dosing Regimen 45 mg orally once daily (QD) with or without food Applicant Proposed VIZIMPRO is indicated for the first-line treatment of patients Indication(s)/Population(s) with (b) (4) metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)- (b) (4) mutations as detected by an FDA-approved test Recommendation on Approval Regulatory Action Recommended VIZIMPRO is indicated for the first-line treatment of patients Indication(s)/Population(s) with metastatic non-small cell lung cancer (NSCLC) with (if applicable) epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA- approved test

1 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

Reference ID: 4326788 NDA Multi-Disciplinary Review and Evaluation {NDA 211288} VIZIMPRO / dacomitinib

Table of Contents

Reviewers of Multi-Disciplinary Review and Evaluation...... 10

Additional Reviewers of Application (also see the Integrated Quality Assessment Review) ...... 10

Glossary ...... 11

1 Executive Summary...... 13 1.1 Product Introduction ...... 13 1.2 Conclusions on the Substantial Evidence of Effectiveness ...... 14 1.3 Benefit-Risk Assessment...... 14 1.4 Patient Experience Data ...... 19

2. Therapeutic Context ...... 21 2.1 Analysis of Condition ...... 21 2.2 Analysis of Current Treatment Options ...... 21

3 Regulatory Background ...... 23 3.1 U.S. Regulatory Actions and Marketing History...... 23 3.2 Summary of Pre-submission/Submission Regulatory Activity...... 23

4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ...... 24 4.1 Office of Scientific Investigations (OSI)...... 24 4.2 Product Quality...... 24 4.3 Clinical Microbiology ...... 25 4.4 Devices and Companion Diagnostic Issues ...... 25

5 Nonclinical Pharmacology/Toxicology...... 27 5.1 Executive Summary ...... 27 5.2 Referenced NDAs, BLAs, DMFs ...... 29 5.3 Pharmacology ...... 29 5.4 ADME/PK ...... 37 5.5 Toxicology...... 39 5.5.1 General Toxicology ...... 39 5.5.2 Genetic Toxicology...... 45 5.5.3 Carcinogenicity ...... 46

2 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

Reference ID: 4326788 NDA Multi-Disciplinary Review and Evaluation {NDA 211288} VIZIMPRO / dacomitinib

5.5.4 Reproductive and Developmental Toxicology ...... 47 5.5.5 Other Toxicology Studies ...... 51

6. Clinical Pharmacology ...... 53 6.1 Executive Summary ...... 53 6.2 Recommendations...... 53 6.4 Summary of Clinical Pharmacology Assessment ...... 55 6.5 Pharmacology and Clinical Pharmacokinetics...... 55 6.6 General Dosing and Therapeutic Individualization...... 55 6.7 Comprehensive Clinical Pharmacology Review ...... 57 6.7.1 General Pharmacology and Pharmacokinetic Characteristics ...... 57 6.7.2 Clinical Pharmacology Questions...... 61

7 Sources of Clinical Data and Review Strategy...... 81 7.1 Table of Clinical Studies ...... 82 7.2 Review Strategy ...... 88

8 Statistical and Clinical Evaluation ...... 88 8.1 Review of Relevant Individual Trials Used to Support Efficacy...... 88 8.1.1 ARCHER 1050: A randomized, open label, phase 3, efficacy and safety study of dacomitinib (PF-00299804) versus gefitinib for the first line treatment of locally advanced non-small cell lung cancer in subjects with epidermal growth factor receptor activating mutations...... 89 8.1.2 Study A741017 (Study 1017): A PHASE 2, OPEN LABEL, TRIAL OF DACOMITINIB (PF- 00299804) IN SELECTED PATIENTS WITH ADVANCED ADENOCARCINOMA OF THE LUNG 106 81.3 ARCHER 1009: A Randomized Double Blind Phase 3 Efficacy and Safety Study of PF- 00299804 (Dacomitinib) vs Erlotinib for the Treatment of Advanced Non-Small Cell Lung Cancer Following Progression After, or Intolerance to, at Least One Prior Chemotherapy 108 Study Results ARCHER 1009 ...... 110 8.1.4 Study A7471011 (Study 1011): A Double-Blind Placebo Controlled Randomized Trial of PF-804 In Patients With Incurable Stage IIIb/IV Non-Small Cell Lung Cancer After Failure Of Standard Therapy For Advanced Or Metastatic Disease...... 112 Study Results ...... 113 8.1.5 Integrated Assessment of Effectiveness...... 114 8.2 Review of Safety ...... 115

3 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

Reference ID: 4326788 NDA Multi-Disciplinary Review and Evaluation {NDA 211288} VIZIMPRO / dacomitinib

8.2.1 Safety Review Approach...... 115 8.2.2 Review of the Safety Database ...... 116 8.2.3 Adequacy of Pfizer’s Clinical Safety Assessments...... 119 8.2.5 Analysis of Submission-Specific Safety Issues...... 143 8.2.6 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ...... 144 8.2.7 Safety Analyses by Demographic Subgroups...... 145 8.2.8 Specific Safety Studies/Clinical Trials...... 149 8.2.9 Additional Safety Explorations...... 149 8.2.10 Safety in the Post Marketing Setting ...... 150

10 SUMMARY AND CONCLUSIONS...... 152 10.1 Statistical Issues...... 152 10.2 Conclusions and Recommendations...... 152

11. Advisory Committee Meeting and Other External Consultations ...... 154

12 Pediatrics ...... 155

13 Labeling Recommendations ...... 156 13.1 Prescription Drug Labeling...... 156

14 Risk Evaluation and Mitigation Strategies (REMS)...... 162

15 Post marketing Requirements and Commitment...... 163

16 Division Director (DHOT) ...... 163

17 Division Director (OCP) ...... 164

18 Division Director (OB) ...... 165

19 Division Director (Clinical) ...... 166

20 Office Director ...... 167

21 Appendices ...... 168 References...... 176 Financial Disclosure ...... 176 a. OCP Appendices (Technical documents supporting OCP recommendations) ...... 177

1. Summary of Findings...... 178

4 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

Reference ID: 4326788 NDA Multi-Disciplinary Review and Evaluation {NDA 211288} VIZIMPRO / dacomitinib

1.1 KEY REVIEW QUESTION...... 178 1.1.1 Is the proposed dosing regimen appropriate for the general patient population for which the indication is being sought? ...... 178 1.1.2 Is an alternative dosing regimen or management strategy required for subpopulations based on intrinsic patient factors?...... 179 1.2 RECOMMENDATIONS...... 180

2. Sponsor’s Population Pharmacokinetics and E-R Analysis ...... 180 2.1 PPK ANALYSIS...... 180 2.2 EXPOSURE RESPONSE (ER) ANALYSIS FOR EFFICACY...... 191 2.2 EXPOSURE RESPONSE (ER) ANALYSIS FOR SAFETY ...... 194 b. Additional Clinical Outcome Assessment Analyses...... 197

5 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

Reference ID: 4326788 NDA Multi-Disciplinary Review and Evaluation {NDA 211288} VIZIMPRO / dacomitinib

Table of Tables

Table 1: Summary of Treatment Armamentarium Relevant to Proposed Indication...... 22 Table 2: Calculation of PDE for 2-Methyltetrahydrofuran...... 25 Table 3: Tumor Growth Inhibition in Various Human Tumor Cell Lines ...... 31 Table 4: Plasma Levels of Dacomitinib and PF-05199265 in Rats, Rabbits, and Dogs ...... 44 Table 5: Human Lymphocyte Assay: 24-Hour Treatment without Metabolic Activation...... 46 Table 6: Geometric Mean (%CV) PK Parameters of Dacomitinib on Day 1 After Single-Dose Administration (Study 1001) ...... 62 Table 7: Geometric Mean (%CV) PK Parameters of Dacomitinib on Day 14 After Once Daily Dosing (Study 1001)...... 62 Table 8: Geometric (%CV) Trough Plasma Concentrations (Ctrough, ng/mL) for Dacomitinib and PF-05199265 following Once Daily 45 mg Oral Doses of Dacomitinib ...... 63 Table 9: Point Estimates and 90% CIs Corresponding to the Largest Upper Bounds for Dacomitinib in ΔQTcF (FDA Analysis)...... 64 Table 10: Summary of Steady State Exposure Data after 45 mg Once Daily doses of dacomitinib by CYP2D6 phenotype Groups (Studies 1042 and 1050)...... 66 Table 11: NCI Criteria of Hepatic Function ...... 67 Table 12: Dacomitinib Individual CLs in the Dataset by Hepatic Function (NCI Criteria)...... 68 Table 13: Geometric Mean (%CV) PK Parameters for Total and Unbound Dacomitinib after a Single 30 mg Oral Dose...... 68 Table 14: Geometric Mean (%CV) PK Parameters for Total and Unbound PF-05199265 after a Single 30 mg Oral Dose of Dacomitinib ...... 69 Table 15: Statistical Summary of Hepatic Group Comparison for Total and Unbound Dacomitinib ...... 69 Table 16: Geometric Mean (%CV) PK Parameters for Dacomitinib after a Single 45 mg Oral Dose to Healthy Subjects (Study 1015) ...... 71 Table 17: Geometric Mean (%CV) PK Parameters for PF-05199265 after a Single 30 mg Oral Dose of Dacomitinib in Healthy Subjects (Study 1015) ...... 71 Table 18: Statistical Summary of Treatment Comparison for Food Effect (Study 1015)...... 71 Table 19: Geometric Mean (%CV) PK Parameters for Dacomitinib after a Single 45 mg Oral Dose With or Without Rabeprazole 40 mg Once Daily for 7 Days to Healthy Subjects (Study 1015) ...73 Table 20: Geometric Mean (%CV) PK Parameters for PF-05199265 after a Single 45 mg Oral Dose of Dacomitinib in Healthy Subjects With or Without Rabeprazole 40 mg Once Daily for 7 Days to Healthy Subjects (Study 1015)...... 73 Table 21: Statistical Summary of Treatment Comparison for Rabeprazole Effect (Study 1015)..73 Table 22: Geometric Mean (%CV) PK Parameters for Dacomitinib after a Single 45 mg Oral Dose With or Without 20 mL of Maalox® (400 mg/5 mL) to Patients with Solid Tumors (Study 1001)74 Table 23: Statistical Summary of Treatment Comparison for Maalox® Effect (Study 1001) ...... 74 Table 24: Geometric Mean (%CV) PK Parameters for Dacomitinib after a Single 45 mg Oral Dose in the Presence or Absence of Paroxetine 30 mg Once Daily for 10 Days to Healthy Subjects (Study 1021) ...... 76

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Reference ID: 4326788 NDA Multi-Disciplinary Review and Evaluation {NDA 211288} VIZIMPRO / dacomitinib

Table 25: Geometric Mean (%CV) PK Parameters for PF-05199265 after a Single 45 mg Oral Dose of Dacomitinib in Healthy Subjects With or Without Paroxetine 30 mg Once Daily for 10 Days to Healthy Subjects (Study 1021)...... 76 Table 26: Statistical Summary of Treatment Comparison for Paroxetine Effect (Study 1021).....76 Table 27: Summary of Statistical Treatment Comparisons of Total Drug Moiety (Dacomitinib + PF-05199265) ...... 77 Table 28: Geometric Mean (%CV) PK Parameters for Paroxetine 30 mg Once Daily Oral Doses (Study 1021) Compared to Historical Data...... 78 Table 29: Geometric Mean (%CV) PK Parameters for Dextromethorphan after a Single 30 mg Oral Dose With or Without Dacomitinib 45 mg Single Dose in Healthy Subjects (Study 1039) ...79 Table 30: Geometric Mean (%CV) PK Parameters for Dextrorphan after a Single 45 mg Oral Dose of Dacomitinib in Healthy Subjects With or Without Dacomitinib 45 mg Single Dose in Healthy Subjects (Study 1039) ...... 79 Table 31: Statistical Summary of Treatment Comparison for Effect of Dacomitinib on Dextromethorphan (Study 1039) ...... 79 Table 32: Listing of Clinical Trials Relevant to this NDA...... 83 Table 33. ARCHER 1050 Patient Disposition...... 92 Table 34: ACRCHER 1050: Protocol Deviations...... 92 Table 35. ARCHER 1050: Demographic Characteristics ...... 93 Table 36. ARCHER 1050: Baseline characteristics...... 94 Table 37. ARCHER 1050: PFS Primary Analysis ...... 95 Table 38. ARCHER 1050: ORR and DoR Analyses...... 97 Table 39. ARCHER 1050: OS Analysis...... 97 Table 40. Subgroup Analysis of OS by OS Time <12 Months vs ≥12 Months...... 98 Table 41. ARCHER 1050: Baseline Characteristics by OS Time <12 Months vs ≥12 Months ...... 99 Table 42. ARCHER 1050: PRO Completion Rates...... 101 Table 43. ARCHER 1050: PFS Subgroup Analyses ...... 105 Table 44. ARCHER 1050: OS Subgroup Analyses ...... 106 Table 45. ARCHER 1009: PFS results in Patients with EGFR Exon 19 Deletion or Exon 21 L858R ...... 111 Table 46. ARCHER 1009: OS and ORR results in Patients with EGFR Exon 19 Deletion or Exon 21 L858R...... 112 Table 47. Study 1011: OS Analysis in Patients with EGFR Exon 19 Deletion or Exon 21 L858R..114 Table 48. Study 1011: PFS and OS Results in Patients with EGFR Exon 19 Deletion or Exon 21 L858R...... 114 Table 49. ARCHER 1050 Exposure Summary ...... 116 Table 50. ARCHER 1050 Demographics ...... 118 Table 51. ARCHER 1050 Overview of Safety...... 121 Table 52. All Deaths ARCHER 1050 Study ...... 122 Table 53. Adverse Events Leading to Death on the Dacomitinib Arm of ARCHER 1050...... 122 Table 54. Death Due to Treatment Emergent Adverse Events (TEAE) ...... 132 Table 55. ARCHER 1050 SAE in >1% Patients on the Dacomitinib Arm...... 133 Table 56. Dacomitinib Drug Interruptions Due to AE by Preferred Term (PT)...... 134

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Reference ID: 4326788 NDA Multi-Disciplinary Review and Evaluation {NDA 211288} VIZIMPRO / dacomitinib

Table 57. ARCHER 1050 Dose Reductions ...... 135 Table 58. TEAE Leading to Dose Reduction in at least 2% of Patients by...... 136 Table 59. ARCHER 1050 Permanent Discontinuation for AE in at Least 1...... 137 Table 60. Treatment Emergent Adverse Events for ARCHER, Pool A and Pool B...... 140 Table 61. Laboratory abnormalities Worsening from Baseline in ≥20% of Patients ...... 142 Table 62. ARCHER 1050: Adverse Events by Gender...... 146 Table 63. ARCHER 1050: Adverse Events by Race...... 147 Table 64. ARCHER 1050: Adverse Events by Age ...... 148 Table 65. Overview of TEAEs in Dacomitinib – Treated Patients ...... 149 Table 66. Adverse Events ≥30% in ARCHER 1050 and Safety Pool B ...... 151 Table 67. Summary of Labeling Changes...... 156 Table 68. Summary of Included Studies ...... 181 Table 69. Summary of Continuous Covariates Age and Baseline Body Weight...... 181 Table 70. Summary of Continuous Covariates Creatinine Clearance and Albumin...... 182 Table 71. Summary of Baseline Continuous Covariates Alanine Transaminase Aspartate Transaminase and Total Bilirubin ...... 182 Table 72. Summary of Categorical Covariates (1 of 3)...... 183 Table 73. Summary of Categorical Covariates (2 of 3)...... 184 Table 74. Summary of Categorical Covariates (3 of 3)...... 185 Table 75. Covariates Tested in the Population PK Analysis ...... 186 Table 76. Dacomitinib Final Model PK Parameter Estimate Summary...... 186 Table 77. Dacomitinib Individual Clearances by Renal Function ...... 189 Table 78. Dacomitinib Individual Clearances by Hepatic Function (NCI Criteria) ...... 190 Table 79. Potential Covariates...... 191 Table 80. Final Model for Dacomitinib Exposure-Response Analysis of ORR ...... 192 Table 81. Table of Potential Covariates...... 194 Table 82. Summary of Adverse Events Frequency ...... 194

8 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

Reference ID: 4326788 NDA Multi-Disciplinary Review and Evaluation {NDA 211288} VIZIMPRO / dacomitinib

Table of Figures

Figure 1. Dacomitinib (PF-00299804) Inhibition of EGFR Activity in A431 Cells...... 30 Figure 2. Anti-tumor Activity of Dacomitinib (PF-00299804) or Erlotinib...... 32 Figure 3. In vivo Anti-tumor Activity of Dacomitinib (PF-00299804) or Gefitinib...... 33 Figure 4. Anti-tumor Activity of Dacomitinib (PF-00299804) in a Mouse Model of Ovarian Carcinoma...... 34 Figure 5. Anti-tumor Activity of Dacomitinib (PF-00299804) in a Mouse Model of Glioblastoma Multiforme...... 35 Figure 6. ARCHER 1050: Kaplan Meier Curves for PFS...... 96 Figure 7. ARCHER 1050: Kaplan Meier Curves of OS ...... 98 Figure 8. ARCHER 1050: PRO Chest Pain ...... 102 Figure 9. ARCHER 1050: PRO Shortness of Breath...... 103 Figure 10. ARCHER 1050: Cough...... 104 Figure 11. ARCHER 1050 Hy’s Law Plot...... 138 Figure 12. Effect of Renal Impairment on Dacomitinib CL...... 179 Figure 13. Effect of Hepatic Impairment on Dacomitinib CL ...... 180 Figure 14. Goodness-of-fit Plots for the Final Model ...... 187 Figure 15. VPC for Dacomitinib Observations after Single Dose and Multiple QD Dose Administration...... 188 Figure 16. Probability of Achieving Objective Response: Dacomitinib Exposure-Response Analysis...... 192 Figure 17. Predicted Probability for max AE Grade ≥3 for RASH/DERMATITIS ACNEIFORM...195 Figure 18. Predicted Probability for max AE Grade ≥3 for OTHER SKIN TOXICITY...... 195 Figure 19. Predicted Probability for max AE Grade ≥3 for Diarrhea...... 195 Figure 20. Predicted Probability for AE Grade _1 for STOMATITIS...... 196

9 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

Reference ID: 4326788 NDA Multi-Disciplinary Review and Evaluation {NDA 211288} VIZIMPRO / dacomitinib

Reviewers of Multi-Disciplinary Review and Evaluation

Regulatory Project Manager Felecia Wilson, M.S. Nonclinical Reviewer Alexander Putman, PhD Nonclinical Team Leader Whitney Helms, PhD Office of Clinical Pharmacology Reviewer(s) Safaa Burns, PhD Xiaofeng Wang, PhD Robert Schuck, PhD Office of Clinical Pharmacology Team Leader(s) Jeanne Zirkelbach Fourie, PhD Jiang Liu, PhD Rosane Charlab Orbach, PhD Clinical Reviewer Barbara Scepura, BSN, MS, CRNP Clinical Team Leader Erin Larkins, MD Safety Analyst Yutao Gong, PhD Statistical Reviewer Weishi (Vivian) Yuan, PhD Statistical Team Leader Kun He, PhD Cross-Disciplinary Team Leader Erin Larkins, MD Division Director (DHOT) John Leighton, PhD Division Director (OCP) Nam Atiqur Rahman, PhD Associate Division Director (OB/DBV) Kun He, PhD Division Director (OHOP) Patricia Keegan, MD Office Director Richard Pazdur, MD

Additional Reviewers of Application (also see the Integrated Quality Assessment Review)

QT/IRT Ferdouse Begum OPDP Nazia Fatima OSI Shital Patel OSE/DEPI Carolyn McCloskey OSE/DMEPA Janine Steward OSE/DRISK Naomi Redd CDRH/OIR Karen Bijwaard QT/IRT=Interdisciplinary Review Team for QT Studies 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 CDRH=Center for Devices and Radiologic Health

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Reference ID: 4326788 NDA Multi-Disciplinary Review and Evaluation {NDA 211288} VIZIMPRO / dacomitinib

Glossary

AC advisory committee ADME absorption, distribution, metabolism, excretion AE adverse event BLA biologics license application BPCA Best Pharmaceuticals for Children Act BRF Benefit Risk Framework CBER Center for Biologics Evaluation and Research CDER Center for Drug Evaluation and Research CDRH Center for Devices and Radiological Health CDTL Cross-Discipline Team Leader CFR Code of Federal Regulations CMC chemistry, manufacturing, and controls COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms CRF case report form CRO contract research organization CRT clinical review template CSR clinical study report CSS Controlled Substance Staff DHOT Division of Hematology Oncology Toxicology DMC data monitoring committee ECG electrocardiogram eCTD electronic common technical document EM Extensive Metabolizers ETASU elements to assure safe use FDA Food and Drug Administration FDAAA Food and Drug Administration Amendments Act of 2007 FDASIA Food and Drug Administration Safety and Innovation Act GCP good clinical practice GRMP good review management practice ICH International Conference on Harmonization IND Investigational New Drug IM Intermediate Metabolizers IR Information Request ISE integrated summary of effectiveness ISS integrated summary of safety ITT intent to treat MedDRA Medical Dictionary for Regulatory Activities mITT modified intent to treat NCI-CTCAE National Cancer Institute-Common Terminology Criteria for Adverse Event

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Reference ID: 4326788 NDA Multi-Disciplinary Review and Evaluation {NDA 211288} VIZIMPRO / dacomitinib

NDA new drug application NME new molecular entity OCS Office of Computational Science OPQ Office of Pharmaceutical Quality OSE Office of Surveillance and Epidemiology OSI Office of Scientific Investigation PBRER Periodic Benefit-Risk Evaluation Report PD pharmacodynamics PI prescribing information PK pharmacokinetics PMC post marketing commitment PMR post marketing requirement PM Poor Metabolizers PP per protocol PPI patient package insert PREA Pediatric Research Equity Act PRO patient reported outcome PSUR Periodic Safety Update report REMS risk evaluation and mitigation strategy SAE serious adverse event SAP statistical analysis plan SGE special government employee SOC standard of care TEAE treatment emergent adverse event UM Ultra-Rapid Metabolizers

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Reference ID: 4326788 NDA Multi-Disciplinary Review and Evaluation {NDA 211288} VIZIMPRO / dacomitinib

1 Executive Summary

1.1 Product Introduction

Dacomitinib is an adenosine triphosphate (ATP)-competitive, irreversible, small molecule inhibitor of the epidermal growth factor receptor (EGFR) receptor tyrosine kinases (RTKs), specifically the wild-type EGFR (HER1), EGFR variants (i.e., EGFR exon 19 deletions or exon 21 L858R mutations), the HER2 receptor (erbB2), and the HER4 receptor (erbB4). In biochemical kinase assays dacomitinib inhibited the activity of HER1, HER2, and HER4. In tumor xenografts expressing RTK targets in vivo dacomitinib demonstrated dose-dependent inhibition of the HER1 and HER2 RTK phosphorylation. In experimental models of cancer, dacomitinib demonstrated inhibition of tumor growth and tumor regression.

Dacomitinib was granted orphan drug designation on March 3, 2015, for the treatment of non- small cell lung cancer (NSCLC) with EGFR, HER2, HER4, or discoidin domain receptor tyrosine kinase 2 (DDR2) mutations.

13 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

Reference ID: 4326788 NDA Multi-Disciplinary Review and Evaluation {NDA 211288} VIZIMPRO / dacomitinib

1.2 Conclusions on the Substantial Evidence of Effectiveness

Pfizer Pharmaceutical Company (Pfizer) has provided substantial evidence of effectiveness supporting the approval of dacomitinib for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test. This application is primarily supported by ARCHER 1050, a randomized, open-label, active controlled trial comparing treatment with dacomitinib to gefitinib in 452 patients with previously untreated metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations. The observed hazard ratio (HR) for progression free survival (PFS) is 0.59 (95% CI: 0.47, 0.74; two-sided p<0.0001), corresponding to a 5.5-month improvement in estimated median PFS favoring the dacomitinib arm. The observed treatment effect on PFS is both statistically significant and clinically meaningful, and there is no suggestion of a detrimental effect of dacomitinib on overall survival.

1.3 Benefit-Risk Assessment

Benefit-Risk Summary and Assessment

Lung cancer is the leading cause of cancer deaths worldwide. Most cases of lung cancer are classified as non-small cell lung cancer (NSCLC). NSCLC is commonly first diagnosed at an advanced stage of disease. Epidermal growth factor receptor (EGFR) activating mutations are present in about 22% of NSCLC in patients in the US. The recommended first-line treatment for patients with EGFR mutation-positive NSCLC is EGFR tyrosine kinase inhibitors (TKIs). Clinical trials have demonstrated that patients with EGFR mutation-positive NSCLC who are treated with first or second-generation EGFR TKIs have a median OS of 23 to 28 months.

This application is primarily supported by the results of ARCHER 1050, a randomized, active-controlled trial comparing dacomitinib to gefitinib for the first-line treatment of metastatic NSCLC with EGFR-activating mutations in 452 patients with previously untreated metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations. The primary endpoint was PFS and secondary endpoints included ORR and OS. The results of the trial demonstrated a statistically significant and clinically improvement in PFS with a HR of 0.59 (95% CI: 0.47, 0.74 and two-sided p<0.0001), corresponding to a 5.5-month improvement in estimated median PFS favoring the dacomitinib arm. Dacomitinib failed to demonstrate statistically significant improvement in ORR. There was no alpha left for comparisons of OS after the hierarchical testing for ORR, which showed no significant difference between arms. In addition, the Kaplan-Meier curves for OS crossed at approximately 12 months, with the curves favoring the dacomitinib arm only after 12 months. Because the OS curves crossed, the hazard ratio may not be an

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Reference ID: 4326788 NDA Multi-Disciplinary Review and Evaluation {NDA 211288} VIZIMPRO / dacomitinib

appropriate summary statistic and the medians are not appropriate to characterize the treatment effects on OS. The KM-curves suggest no meaningful clinical differences in OS between arms.

Adverse reactions observed with dacomitinib are qualitatively similar to those reported for other FDA-approved EGFR TKIs. The most common adverse reactions of dacomitinib are diarrhea (87%), rash (69%), paronychia (64%), stomatitis (45%), decreased appetite (31%), decreased weight (26%), alopecia (23%), cough (21%) and pruritus (21%). Serious adverse reactions observed with dacomitinib across all studies are interstitial lung disease (ILD), diarrhea, and dermatologic adverse reactions. These serious adverse reactions are listed in the Warnings and Precautions section of the product labeling with recommendations for management; safety concerns are adequately mitigated by providing this information in the Warnings and Precautions section and by the recommended dose modifications for adverse reactions included in the product labeling. While a large proportion of patients in ARCHER 1050 required interruption (57%) or dose reduction (66%) of dacomitinib for adverse reactions, only 18% of dacomitinib-treated patients permanently discontinued dacomitinib due to adverse reactions.

In the opinion of the reviewers, the submitted evidence meets the statutory evidentiary standard for regular approval. The magnitude of the treatment effect on PFS in ARCHER 1050 is large and clinically meaningful and is consistent with a significant improvement in the treatment of an advanced NSCLC population with unmet medical need. While findings are not consistent with an improvement in OS for patients treated with dacomitinib compared to gefitinib, there is no suggestion of a detrimental effect of dacomitinib on OS. The overall safety profile of dacomitinib is acceptable relative to its demonstrated clinical benefit in patients with a life-threatening disease. The reviewers recommend granting regular approval of dacomitinib for the following indication: “For the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test”.

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Reference ID: 4326788 NDA Multi-Disciplinary Review and Evaluation {NDA 211288} VIZIMPRO / dacomitinib

Dimension Evidence and Uncertainties Conclusions and Reasons

 Lung cancer is the leading cause of cancer deaths worldwide. Most EGFR mutation-positive metastatic NSCLC is a lung cancer cases are non-small cell lung cancer (NSCLC) and are life-threatening disease. diagnosed when the disease is in an advanced stage.  Epidermal growth factor receptor (EGFR) activating mutations (i.e., exon 19 deletion or exon 21 L858R substitution mutations) are Analysis of present in approximately 22% of patients with metastatic Condition adenocarcinoma NSCLC in the US.  Clinical trials have demonstrated that patients with EGFR mutation- positive NSCLC who are treated with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) have a median OS of 23 to 28 months  There are four EGFR TKIs (erlotinib, gefitinib, afatinib, and There is a significant unmet medical need for osimertinib) that are FDA-approved for the first-line treatment of patients with metastatic EGFR mutation patients with documented EGFR mutation-positive NSCLC. positive NSCLC, as the median OS for patients Current  The median OS for patients treated with first- or second-generation treated with first- or second-generation EGFR Treatment EGFR TKIs in clinical trials is 23 to 28 months. TKIs in clinical trials is 23 to 28 months. Options This unmet need remains as the median OS with dacomitinib is only 34 months.  Dacomitinib was shown to prolong progression-free survival (PFS) There is a statistically significant improvement compared to gefitinib. Median PFS was 14.7 months in the dacomitinib in PFS, with observed median difference of 5.5 arm and 9.2 months in the gefitinib arm (HR 0.59 [95% CI 0.47, 0.74], p- months. value <0.0001). Benefit  There was no difference in overall response rate (ORR) between arms Formal testing of OS could not be performed (75% vs. 72%; p = 0.39) based on the analysis plan.  There was no alpha left for comparisons of OS since testing for ORR showed no significant differences. Additionally, OS curves crossed at Because OS curves crossed, the hazard ratio approximately 12 months; therefore, hazard ratio may not be an and medians may not be appropriate summary

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Dimension Evidence and Uncertainties Conclusions and Reasons appropriate summary statistic and the KM-estimated medians are not statistics to characterize OS results. While appropriate to characterize the treatment effects on OS. These data are findings are not consistent with an provided in the review and product labeling as Kaplan-Meier curves for improvement in OS for patients treated with information only. dacomitinib compared to gefitinib, there is no suggestion of a detrimental effect of dacomitinib on OS.  Dacomitinib’s safety database of 394 patients is adequate in this Overall, the safety profile of dacomitinib is setting and is sufficient in terms of size, exposure, and duration of acceptable relative to the benefit (improved treatment to detect serious adverse reactions occurring at an PFS) in the context of the treatment of this life- incidence of 1%. threatening disease. Adverse reactions  In ARCHER 1050, the most common (≥20% of patients) adverse observed with dacomitinib are qualitatively reactions in the dacomitinib arm were diarrhea (87%), rash (69%), similar to those reported for paronychia (64%), stomatitis (45%), decreased appetite (31%), dry FDA-approved EGFR TKIs. skin (30%), decreased weight (26%), alopecia (23%), cough (21%) and pruritus (21%). While a large proportion of patients in ARCHER  The common adverse reactions observed in the dacomitinib arm in 1050 required interruption (57%) or dose reduction (66%) of dacomitinib for adverse Risk and Risk ARCHER 1050 were similar in incidence and severity to that reactions, only 18% of dacomitinib-treated Management observed in the pooled safety databases for dacomitinib.  Serious adverse reactions (SAEs) occurred in 27% of dacomitinib- patients permanently discontinued treated patients. SAEs occurring in >1% of dacomitinib-treated dacomitinib due to adverse reactions, patients on ARCHER 1050 were diarrhea (2.2%) and ILD (1.3%). suggesting that toxicities can generally be  There were two treatment-related deaths on the dacomitinib arm, managed through dose modification. one due to diarrhea-induced acute renal failure and one due to ILD.  Among patients treated with dacomitinib in ARCHER 1050, 57% Serious adverse reactions, such as ILD and required dose interruption and 66% required dose reduction. Grade 3-4 diarrhea and dermatologic adverse Dacomitinib was permanently discontinued due to adverse reactions, are adequately addressed by reactions in 18% of patients. information in the Warnings and Precautions section and the dose modification recommendations included in the product 17 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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Dimension Evidence and Uncertainties Conclusions and Reasons labeling to allow treating oncologists to effectively manage these toxicities.

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1.4 Patient Experience Data

Patient Experience Data Relevant to this Application (check all that apply) □ The patient experience data that was submitted as part of the application, include: Section where discussed, if applicable x □ Clinical outcome assessment (COA) data, such as [e.g., Section 6.1 Study endpoints]

x □ Patient reported outcome (PRO) Section 8.1 Review of Relevant ndividual Trials Used to Support Efficacy, subsection titled Efficacy Results – Secondary or exploratory COA PRO) endpoints Section 8.2.6 Clinical Outcome Assessment (COA) Analyses nforming Safety/Tolerability □ 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 [e.g., Section 2.1 Analysis of Condition]

□ 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 was not submitted in the application, but was considered in this review.

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Erin Larkins, M.D.

Cross-Disciplinary Team Leader

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2. Therapeutic Context

2.1 Analysis of Condition

Lung cancer is the second most common cancer in the United States (US), but it is responsible for most cancer deaths1. The Surveillance, Epidemiology and End Results Program (SEER) estimates that in 2018, 234,030 new cases of lung cancer will be diagnosed in the US1. Non- small cell lung cancer (NSCLC) is the most common type of lung cancer and the most common histology is adenocarcinoma. Among NSCLC with adenocarcinoma histology, epidermal growth factor receptor (EGFR) mutations have been found in 12% to 47% of tumors depending on the geographic region2. The overall EGFR mutation frequency in the US is 22%2. EGFR mutation- positive NSCLC is more common in Asians, women, and those who have never smoked. EGFR mutation-positive NSCLC tumors are targetable by EGFR tyrosine kinase inhibitors (TKIs) and studies have demonstrated clinically meaningful improvements in progression free survival (PFS) compared to treatment with chemotherapy.

Clinical trials have demonstrated that patients with EGFR mutation-positive NSCLC who are treated with first- or second-generation EGFR TKIs have a median OS of 23 to 28 months3. EGFR mutation-positive lung cancer is a serious a life-threatening disease and more effective treatments are urgently needed.

2.2 Analysis of Current Treatment Options

In May 2013, TARCEVA was approved for the first-line treatment of people with metastatic NSCLC whose tumors have certain EGFR activating mutations as detected by an FDA-approved test based on improved PFS) as compared to chemotherapy. Later that year in July, GILOTRIF was approved for the first-line treatment of EGFR mutation-positive NSCLC, after demonstrating improvement in PFS over standard platinum doublet chemotherapy.

In 2003, IRESSA received accelerated approval for the treatment of NSCLC, regardless of EGFR mutation status, after progression following both platinum-based chemotherapy and docetaxel based on ORR, but this indication was rescinded in 2005 due to the inability to verify clinical benefit in confirmatory trials. A later clinical trial using IRESSA to treat patients with EGFR mutation-positive NSCLC showed ORR and DOR exceeding those expected with platinum-based chemotherapy and, based upon the totality of data in the treatment of patients with EGFR mutation-positive NSCLC, IRESSA was approved in 2015 for the first-line treatment of EGFR mutation-positive NSCLC.

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In April 2018, TAGRISSO received approval for the first-line treatment of EGFR positive NSCLC based on demonstration of a statistically significant and clinically meaningful improvement in median PFS compared to first-generation EGFR TKI (gefitinib or erlotinib).

For further details on the approved drugs for the first-line treatment of metastatic EGFR positive NSCLC at the time of submission of the NDA for dacomitinib, see Table 1. The availability of these targeted treatments is an important improvement over chemotherapy, but the median OS for patients treated with these targeted agents remains low. More effective treatments for patients with EGFR mutation-positive NSCLC are urgently needed.

Table 1: Summary of Treatment Armamentarium Relevant to Proposed Indication

Product (s) Relevant Year of Dosing/ Efficacy Important Safety and Name Indication Approval Administration Information Tolerability Issues and Control TARCEVA First-line 2013 150 mg orally mPFS 10.4 GI perforation, renal erlotinib metastatic daily vs months vs 5.2 failure, hepatic failure NSCLC with platinum- months exon 19 based mOS 22.9 deletions or chemotherapy months vs 19.5 exon 21 (L858R) months substitution mutations GILOTRIF First-line 2013 40 mg orally mPFS 11.1 Diarrhea, skin disorders, afatinib metastatic daily vs months vs 6.9 ILD, hepatic toxicity, NSCLC with pemetrexed months keratitis non-resistant plus cisplatin mOS 28.1 EGFR mutations months vs 28.2 months IRESSA First-line 2015 250 mg orally ORR 50% ILD, hepatotoxicity GI gefitinib metastatic daily DoR 6 months perforation, diarrhea, NSCLC with keratitis, skin disorders. exon 19 deletions or exon 21 (L858R) substitution mutations TAGRISSO First-line 2018 80 mg orally mPFS 18.9 ILD, QTc prolongation, osimertinib metastatic daily vs months vs 10.2 cardiomyopathy, keratitis NSCLC with gefitinib or months exon 19 erlotinib deletions or OS data not exon 21 (L858R) mature substitution mutations (Source: GILOTRIF – afatinib package insert, TARCEVA-erlotinib package insert, IRESSA – gefitinib package insert, TAGRISSO – osimertinib package insert).

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3 Regulatory Background

3.1 U.S. Regulatory Actions and Marketing History

VIZIMPRO (dacomitinib) is a new molecular entity and is not marketed for sale in any country.

3.2 Summary of Pre-submission/Submission Regulatory Activity

Significant regulatory activities relevant to the development program for dacomitinib are summarized in the table below.

July 14, 2005 IND 072775 was submitted for first-in-human study

December 12, 2012 New clinical protocol for ARCHER 1050 was received by FDA

October 23, 2013 Initial Pediatric Study Plan was submitted to the FDA

February 7, 2014 FDA issued letter of agreement to the Agreed Initial Pediatric Study Plan requesting a waiver from all Pediatric Research Equity Act (PREA) for dacomitinib for the treatment of EGFR-mutation positive NSCLC

March 3, 2015 Dacomitinib received orphan drug designation on March 3, 2015, for the indication of non-small cell lung cancer with EGFR, HER2, HER4, or DDR2 mutations

June 13, 2017 Type B Pre-NDA meeting was held at FDA to discuss the overall development program of dacomitinib and to assist in planning the new drug application

January 31, 2018 NDA for dacomitinib for the first-line treatment of patients with EGFR mutation-positive NSCLC was received by FDA. Priority review status was granted for this application.

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CDRH recommends approval of data submitted for P120022/S018 and the associated labeling. For details, see the CDRH review.

APPEARS THIS WAY ON ORIGINAL

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5 Nonclinical Pharmacology/Toxicology

5.1 Executive Summary

Dacomitinib is a small molecule irreversible inhibitor of the human epidermal growth factor receptor (EGFR) family of tyrosine kinases and certain EGFR activating mutations; its established pharmacologic class is kinase inhibitor. Oncogenic activating mutations of EGFR have been shown to cause aberrant signaling for a subpopulation (10-30%) of patients with non-small cell lung cancer (NSCLC) (Ohashi et al., 2013). The most frequent of these mutations consists of deletions in exon 19 (del19) or a point substitution on exon 21 (L858R). A secondary point mutation on exon 20 (T790M) has been found in tumors that were previously responsive to small molecule inhibitors of EGFR but developed resistance.

In vitro, dacomitinib inhibited the kinase activity of EGFR, HER2, and HER4 with IC50 values of 2.8 ng/mL (6.0 nM), 21.5 ng/mL (45.7 nM), and 34.7 ng/mL (73.7 nM), respectively. Dacomitinib also demonstrated activity against wild-type EGFR (Ki = 0.4 nM), the L858R mutant EGFR (Ki = 1 nM), and an EGFR del19 mutant (Ki= 3.8 nM) in a kinetic screening assay. In the same assay, dacomitinib inhibited both the L858R/T790M double mutant EGFR (Ki = 2.2 nM), and, slightly less potently, a del19/T790M double mutant (Ki = 17 nM). The PF-05199265 O- desmethyl metabolite, the most abundant dacomitinib metabolite in humans, had similar in vitro pharmacologic activity against EGFR family members and EGFR activating mutations at similar concentrations.

The Pfizer assessed the off-target pharmacological activity of dacomitinib and its PF-05199265 O-desmethyl active metabolite across various receptors, ion channels, transporters, and enzymes. Dacomitinib showed activity (IC50 ≤ 100 nM) toward DDR1 (Ki = 2 nM), EPHA6 (Ki = 18 nM), LCK (Ki = 29 nM), DDR2 (Ki = 30 nM), and MNK1 (Ki = 45 nM. No biologically relevant off- target pharmacological activity was noted with the PF-05199265 O-desmethyl active metabolite.

Dacomitinib irreversibly inhibited EGFR and HER2 autophosphorylation and demonstrated anti- tumor activity in various human tumor cell lines including those with EGFR mutations or amplifications. In mice bearing subcutaneously implanted human xenografts driven by EGFR family targets including mutated EGFR, dacomitinib demonstrated dose-dependent anti-tumor activity and inhibition of EGFR/HER2 autophosphorylation. Dacomitinib also exhibited anti- tumor activity in orally-dosed mice bearing intracranial human tumor xenografts driven by EGFR amplifications.

Stand-alone GLP-compliant safety pharmacology studies were conducted in rats and dogs to assess the effect of dacomitinib on the central nervous system, pulmonary function, and the cardiovascular system. There were no dacomitinib-related adverse effects on the central nervous system or pulmonary function at doses up to 500 mg/kg. No dacomitinib-related

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adverse effects were noted on the cardiovascular system at doses up to 30 mg/kg. Dacomitinib is a mild hERG blocker (IC50=1.58 μM); however, the IC50 is over 400 times the Cmax in humans at the 45 mg dose. The PF-05199265 O-desmethyl active metabolite of dacomitinib had very low propensity to prolong the QT interval in vivo via hERG inhibition. Consistent with these findings, dacomitinib did not have effects on QT prolongation clinically.

Pfizer evaluated the toxicity of dacomitinib in GLP-compliant repeated-dose toxicity studies in rats and dogs. Rats received up to 2 mg/kg of oral dacomitinib, once per day, for 6-months, resulting in mean exposure levels (AUC) of up to approximately half of those observed clinically at the 45 mg daily dose (2213 ug.h/mL). The highest dose was not tolerated for the entire duration of the study due to skin lesions. Toxicity consisted of epithelial atrophy in various organs (skin, eyes, gastrointestinal tract, and liver), tubular atrophy and necrosis in the kidneys, and generalized inflammation likely secondary to skin lesions. Dermatologic, gastrointestinal, and ocular toxicities are also common clinical findings. Additional changes occurred in the reproductive organs and consisted of reversible epithelial atrophy in the cervix and vagina, and reversible decreased secretion in the prostate; while these findings are included in Section 13.1 of the label, they are unlikely to directly affect fertility and did not result in specific advice on infertility recommendations in Section 8.3.

Dogs received up to 1 mg/kg of dacomitinib orally once daily for 9-months, resulting in mean exposure levels (AUC) up to 0.14 times those in humans at the 45 mg dose. Toxicity consisted of conjunctivitis, erythema, histopathological vacuolation of the adrenal glands, atrophy of the mandibular salivary glands, and generalized inflammation likely secondary to the conjunctivitis. The PF-05199265 O-desmethyl active metabolite was present in rats and dogs with PF- 05199265 to dacomitinib exposure ratios of 0.18 and 1.9, respectively.

Pfizer did not conduct studies investigating the carcinogenic potential of dacomitinib as such studies are not required to support a marketing application for patients with advanced cancer. Dacomitinib was not mutagenic in a bacterial reverse mutation (Ames) assay and did not cause structural or, based on weight of evidence, numerical chromosome aberrations in an in vitro human lymphocyte chromosome aberration assay or in an in vivo rat bone marrow micronucleus assay.

Dedicated fertility and pre- and postnatal development studies were neither conducted nor required to support the development of dacomitinib in patients with advanced cancer. The Pfizer conducted embryo-fetal development studies with dacomitinib in rats and rabbits. Daily oral administration of dacomitinib to pregnant rats resulted in an increased incidence of post- implantation loss and reduced fetal body weight at 5 mg/kg/day (a dose resulting in exposures approximately 1.2 times the exposure based on AUC at the 45 mg human dose). In rabbits, no maternal or fetal toxicity occurred; however, at the highest daily dose administered to pregnant rabbits, dacomitinib exposure levels were only 0.16 times the human exposure at the 45 mg dose. The embryo-fetal toxicity study in rabbits inadequately assessed the embryo-fetal risk to humans. Findings in the rat embryo-fetal development studies were subtle as well, however, 28 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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dacomitinib is an EGFR inhibitor and based on non-product specific reports in the literature, EGFR signaling has a critical role in development. In mice, EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/postnatal survival and development. Reduction or elimination of embryo-fetal or maternal EGFR signaling can prevent implantation, cause embryo-fetal loss during various stages of gestation (through effects on placental development), and cause developmental anomalies and early death in surviving fetuses. In addition, adverse developmental outcomes were observed in multiple organs in embryos/neonates of mice with disrupted EGFR signaling. Based on positive findings in the rats and the available literature on the role of EGFR in development, no additional embryo-fetal toxicity studies will be needed. 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 women to use contraception during treatment with dacomitinib and, based on a half-life of 70 hours, 17 days after the final dose is also included in the label. Similarly, lactating women are advised not to breastfeed during treatment with dacomitinib and for 17 days after the final dose. Based on the weight of evidence approach, dacomitinib does not have genotoxic potential, therefore, no recommendations for contraception are included in the label for males.

There are no outstanding issues from a nonclinical perspective that would prevent the approval of dacomitinib for the treatment of patients with metastatic non-small cell lung cancer with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutation as detected by an FDA-approved test; therefore, the nonclinical team recommends approval.

5.2 Referenced NDAs, BLAs, DMFs

None

5.3 Pharmacology

Primary pharmacology

A. In Vitro Studies

Dacomitinib demonstrated in vitro inhibitory activity against the human catalytic domains of EGFR, HER2, and HER4 with IC50 values of 2.8 ng/mL (6.0 nM), 21.5 ng/mL (45.7 nM), and 34.7 ng/mL (73.7 nM), respectively (Study PF-00299804-Pharm-001). The Pfizer did not assess the inhibitory activity of dacomitinib against HER-3 as HER-3 does not possess intrinsic kinase activity.

Ina kinetic analysis to determine inactivation values, as detailed by Cheng et al., 2016, dacomitinib inhibited wild-type EGFR (Ki = 0.4 nM), the L858R mutant EGFR (Ki = 1 nM), and the EGFR del19 mutant (Ki= 3.8 nM) (Study PF-00299804-063846). Dacomitinib also inhibited the

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L858R/T790M double mutant EGFR (Ki = 2.2 nM). Inhibition of a del19/T790M double mutant EGFR by dacomitinib was less potent (Ki = 17 nM).

In humans, the most abundant metabolite of dacomitinib involves O-desmethylation to PF- 05199265. Utilizing the same kinetic analysis mentioned above, the PF-05199265 O-desmethyl metabolite was shown to be biologically active against EGFR family targets. Specifically, the PF- 05199265 O-desmethyl metabolite inhibited wild-type EGFR (Ki = 4.4 nM), the L858R mutant EGFR (Ki = 1.4 nM), the EGFR del19 mutant (Ki= 0.14 nM), and the del19/T790M double mutant (Ki = 21 nM).

Pfizer also tested dacomitinib’s ability to inhibit epidermal growth factor (EGF) stimulated EGFR and HER2 autophosphorylation in intact cells (Study PF-00299804-Pharm-001). NIH-3T3 fibroblast cells transfected with human EGFR or a chimeric receptor consisting of the extracellular domain of EGFR and the intracellular cytoplasmic domain of HER2 were exposed to increasing concentrations of dacomitinib (up to 500 nM) for 2 hours. During the last 5 minutes of exposure, 20 ng/mL of EGF was added to the culture media to stimulate autophosphorylation of EGFR and HER2. The amount of phosphorylation was quantitated using western blot analysis. Dacomitinib inhibited autophosphorylation of EGFR and HER2 with IC50s of 1.6 ng/mL (3.5 nM) and 19 ng/mL (41 nM), respectively. As shown in Figure 1, dacomitinib also inhibited EGFR autophosphorylation (phosphor-erbB-1) in the EGFR-expressing A431 human squamous cell carcinoma line with an IC50 of 9.9 ng/mL (21 nM).

Figure 1. Dacomitinib (PF-00299804) Inhibition of EGFR Activity in A431 Cells

(Pfizer Figure reproduced from Study PF-00299804-Pharm-001)

Since dacomitinib was designed to covalently react with an unpaired cysteine residue within the ATP binding pocket of the HER family of receptor tyrosine kinases (RTKs), dacomitinib was assessed for its ability to irreversibly inhibit EGFR (Study PF-00299804-Pharm-001). A cell-based EGF-simulated autophosphorylation assay was also used to further support the prolonged interaction and inhibitory activity of dacomitinib against EGFR (Study PF-00299804- Pharm-001). EGFR-expressing A431 cells were incubated with 2 μM of dacomitinib for up to 120 min. Cells were washed for 2 hours before stimulating with EGF. According to Pfizer,

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dacomitinib demonstrated complete inhibition of EGFR phosphorylation within 1 minute of incubation and maintained complete inhibition after washing for 2 hours (data not provided).

Dacomitinib was evaluated for in vitro anti-tumor activity in various human tumor cell lines including those with known EGFR mutations or amplifications, HER-2 amplification, and KRAS or BRAF mutations (Study PF-00299804-Pharm-001). As shown in Table 3, the HCC827 and HCC4006 non-small cell lung cancer (NSCLC) cell lines containing the del19 mutation were the most sensitive to growth inhibition by dacomitinib with IC50 values of 2.2 and 1.4 nM, respectively. The H125 NSCLC line with wild-type EGFR and HER-2 was also sensitive to growth inhibition by dacomitinib, with an IC50 value of 27 nM, and was more potent than gefitinib (IC50 = 202 nM). The BT-474 breast and SKOV3 ovarian cell lines harboring an amplified HER-2 gene locus were also more sensitive to growth inhibition by dacomitinib, compared to gefitinib. In contrast, cell lines harboring K-ras or B-raf mutations (A549, H1666, HT-29, and MDA-MB-231) were resistant to dacomitinib. Collectively, these data demonstrate that NSCLC cells lines with certain EGFR genetic alterations, but not KRAS or BRAF alterations, are sensitive dacomitinib.

Table 3: Tumor Growth Inhibition in Various Human Tumor Cell Lines

(Pfizer Figure reproduced from Study PF-00299804-Pharm-001)

B. In Vivo Studies To assess the in vivo anti-tumor activity of dacomitinib, the Pfizer utilized a mouse model implanted with a human non-small cell lung cancer cell line (Study PF-00299804-Pharm-001). Female athymic mice (n=8/group) were subcutaneously implanted with 5×106 NCI-H1975 non- small cell lung cancer cells that harbor the EGFR L858R/T790M double mutation. Once the mean tumor mass reached 150 mm3 (Day 7), mice received oral dacomitinib or erlotinib once daily for 14 days.

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As shown in Figure 2A, daily oral administration of 7.5 or 15 mg/kg of dacomitinib resulted tumor growth inhibition, whereas 10 or 20 mg/kg of erlotinib had no activity. Two and 26 hours after the last dose of dacomitinib, tumor samples were collected to measure inhibition of EGFR phosphorylation via western blot analysis. As shown in Figure 2B, daily oral administration of 7.5 or 15 mg/kg of dacomitinib resulted in inhibition of EGFR phosphorylation (phosphor-erbB-1) that persisted up to the 26-hour time-point in some tumors, particularly at the high dose of 15 mg/kg. According to Pfizer, inhibition of EGFR phosphorylation did not occur in animals that received erlotinib (data not shown)

Figure 2. Anti-tumor Activity of Dacomitinib (PF-00299804) or Erlotinib in a Mouse Model of NSCLC

Each lane in Figure 2B represents an independent excised tumor (Pfizer Figure reproduced from Study PF-00299804-Pharm-001)

In another mouse model of human NSCLC, nude mice (n=5/group) were subcutaneously implanted with 5 x 106 NSCLC cells that harbor the del19 (HCC827-GFP) or the del19/T790M double mutant EGFR (HCC827-Del/T790M) (Engelman et al., 2007). Once the mean tumor mass reached 400-500 mm3, mice received 10 mg/kg/day of oral dacomitinib or 150 mg/kg/day of gefitinib, once per day. The experiment was terminated when the mean tumor mass reached 2000 mm3. As shown in Figure 3, dacomitinib and gefitinib resulted in similar tumor growth inhibition in NSCLC cells harboring the del 19 mutant (A), while only dacomitinib inhibited tumor growth in NSCLC cells harboring the del19/T790M double mutant EGFR (B).

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Figure 3. In vivo Anti-tumor Activity of Dacomitinib (PF-00299804) or Gefitinib in EGFR Mutation Models of NSCLC

(Figure reproduced from Engelman et al., 2007)

Dacomitinib also demonstrated anti-tumor activity in female severe compromised immunodeficient (SCID) mice subcutaneously implanted with an advanced stage human ovarian carcinoma (SK-OV-3) cells that overexpress HER-2 (Study PF-00299804-Pharm-001). Once the tumors reached 200-250 mm3 in size, mice (n=12/group) received 15 or 30 mg/kg of oral dacomitinib, once per day, for 14 days. As show in Figure 4A, daily administration of dacomitinib resulted in dose-responsive inhibition of tumor growth.

To measure the ability of dacomitinib to inhibit HER2 autophosphorylation in vivo, a separate study was conducted in female SCID mice (n=3/timepoint) that were subcutaneously implanted with SK-OV-3 tumor cells. Once the tumors reach 250 mm3 in size, mice were orally administered vehicle control or 30 mg/kg of dacomitinib, once per day, for 2 days. Tumors were collected at 6, 24, or 48 hours after the second dose and evaluated for phospho-erbB-2 using western blot analysis. As shown in Figure 4B, dacomitinib inhibited HER2 autophosphorylation at all timepoints.

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Figure 4. Anti-tumor Activity of Dacomitinib (PF-00299804) in a Mouse Model of Ovarian Carcinoma A

B

Each lane in Figure 4B represents an independent excised tumor (Pfizer Figure reproduced from Study PF-00299804-Pharm-001)

To investigate the ability of dacomitinib to induce anti-tumor activity in the brain, Zahonero et al., 2015 intracranially injected athymic nude mice with 50,000 glioblastoma tumor cells carrying either amplified EGFR (GBM1) or the EGFR variant III isoform (EGFRvIII) and amplified EGFR (GBM4). EGFRvIII lacks exons 2-7 and has been shown to contribute to resistance to the anti-EGFR antibody, cetuximab. Two to three weeks after tumor cell implantation, mice received intragastric injections of vehicle control or 15 mg/kg of dacomitinib, daily for 5 days/week. As shown in Figure 5, systemic administration of dacomitinib impaired intracranial GBM growth as demonstrated by increased survival (A) and smaller tumors based on contrast enhanced MRI (C).

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Given that the IC50s for both dacomitinib and its metabolite were >10 μM, a concentration much greater the estimated unbound Cmax of 1.72 ng/mL for dacomitinib and 0.07 ng/mL for PF-05199265 in humans at the 45 mg dose, all of these targets are likely pharmacologically irrelevant.

An expanded kinase selectivity analysis (n=274 kinases; Carna Biosciences) was performed to evaluate the selectivity of dacomitinib and the PF-05199265 O-desmethyl active metabolite (Study PF-00299804-063846). Of the 10 other kinases with a reactive cysteine residue homologous to that of EGFR, dacomitinib or PF-05199265 only showed activity (IC50 ≤ 100 nM) toward HER2 and HER4. Of all the kinases without a homologous cysteine to that of EGFR, dacomitinib showed activity (IC50 ≤ 100 nM) toward DDR1 (Ki = 2 nM), EPHA6 (Ki = 18 nM), LCK (Ki = 29 nM), DDR2 (Ki = 30 nM), and MNK1 (Ki = 45 nM), while the PF-05199265 O-desmethyl metabolite did not show any activity.

Safety Pharmacology Stand-alone GLP-compliant safety pharmacology studies were conducted in rats and dogs to assess the effect of dacomitinib on the central nervous system, pulmonary function, and the cardiovascular system.

To evaluate the effect of dacomitinib on the central nervous system, Crl:CD®(SD)IGSBR rats (6/sex/dose) received a single oral dose of 0, 5, 50, or 500 mg/kg of dacomitinib followed by assessment in a functional observational battery (FOB) and evaluation of locomotor activity approximately 4 hours post-dose (Study 04-2730-06). There were no dacomitinib-related effects on FOB parameters, body temperature, or locomotor activity at doses up to 500 mg/kg.

To evaluate the effect of dacomitinib on pulmonary function, male Sprague-Dawley rats (6/group) were administered a single oral dose of 0, 5, 50, or 500 mg/kg of dacomitinib (Study 04-2730-07) and monitored for 120 minutes post-dose using whole body plethysmography. There were no dacomitinib-related effects on tidal volume or respiratory rate at doses up to 500 mg/kg.

To evaluate the effect of dacomitinib on the cardiovascular system, telemetered Beagle dogs (8/sex/dose) were administered a single oral dose of 10 or 30 mg/kg of dacomitinib (Study 04- 2730-04). A parallel group design was used so that each dog was administered control vehicle followed by dacomitinib approximately 48 hours later. Cardiovascular data was obtained from each animal for approximately 24 hours post-dose on Days 1 and 6. Plasma drug concentrations were measured pre-dose and approximately 6 and 144 hours post-dose. Clinical signs, body weights, and food intake were assessed at least daily. Ophthalmic examinations were performed pre-dose and on approximately 7 days post-dose. Adverse clinical signs consisted of dose-responsive emesis and loose stool. Ophthalmic changes were noted in animals at the 30 mg/kg dose level and consisted of reddened conjunctiva and increased fluorescein dye uptake in 6/16 corneas. There were no dacomitinib-related effects on systemic

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arterial (systolic, diastolic, mean) blood pressure and electrocardiogram (ECG) (heart rate, respiration rate [RR], PR, QT, QTc, and QRS intervals) parameters.

To further evaluate the potential effects of dacomitinib on the cardiovascular system, dacomitinib was assessed for its effect on the human ether-à-go-go related gene (hERG) potassium channel stably expressed in HEK293 cells (human embryonic kidney cell type) (Study 04-2730-08). Based on an IC50 of 1.58 μM (743 ng/mL), dacomitinib is considered a mild hERG blocker; however, the IC50 is approximately 432-fold higher than the Cmax in humans at the 45 mg dose (1.72 ng/mL).

The PF-05199265 O-desmethyl active metabolite of dacomitinib was also evaluated for its effect on the hERG potassium channel stably expressed in HEK293 cells (Study 131218.QHJ). Based on an IC50 of 23 μM (10.9 μg/mL), PF-05199265 is considered to have a very low propensity to prolong the QT interval in vivo by this mechanism.

5.4 ADME/PK

Type of study Major findings Absorption Single Dose Pharmacokinetics, Dose Male Spague Dawley rats were administered a single 5- Proportionality, and Oral Bioavailability of minute intravenous infusion of dacomitinib at a dose of 5 or PF-00299804 Following Intravenous or 25 mg/kg. Exposure levels were generally dose-proportional. Oral Administration of PF-00299804-00 to Cmax (ng/mL): 1537 (5 mg/kg; LD); 10120 (25 mg/kg; HD) Male Sprague-Dawley Rats; Study No. 764- AUC (ng.h/mL): 1730 (LD); 11300 (HD) 04427 T1/2 (hours): 10 (LD); 17 (HD)

Male Sprague Dawley rats were also administered a single oral dose of 50 or 750 mg/kg of dacomitinib. Exposure levels were less than dose-proportional. Cmax (ng/mL): 630 (50 mg/kg; LD; 1170 (750 mg/kg; HD) AUC (ng.h/mL): 18800 (LD); 126000 (HD) T1/2 (hours): 19.4 (LD); Not available (HD) Bioavailability: 80% (LD)

Single Dose Pharmacokinetics and Oral Male Beagle dogs were administered a single 5-minute Bioavailability of PF-00299804-00 in Male intravenous infusion of dacomitinib at a dose of 5 mg/kg. Beagle Dogs Following Intravenous and Cmax (ng/mL): Not available Oral Administration of PF-00299804-00; AUC (ng.h/mL): 3040 Study No. 764-04419 T1/2 (hours): 16

Male Beagle dogs were administered a single 50 mg/kg oral dose of dacomitinib. Cmax (ng/mL): 870 AUC (ng.h/mL): 24000 T1/2 (hours): 21 Bioavailability: 74% Distribution In Vitro Protein Binding of PF-00299804-00 The in vitro protein binding of dacomitinib was assessed in to Plasma Proteins of Mouse, Rat, Dog, rat, dog, and human plasma at concentrations of 2.5, 12.5, 37 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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Type of study Major findings Monkey, and Human; Study No. 764- and 50 μg/mL. At the highest concentration, the mean 04410 protein binding was 96.2% in rats, 96.6% in dogs, and 98% in humans. Similar results were noted at lower concentrations (data not shown).

Tissue Distribution of [14C]PF-00299804 in Radiolabeled (14C) dacomitinib was orally administered to Long-Evans Male Rats; Study No. DM2005- male Long-Evans rats at a dose of 5 or 283 mg/kg. 00299804-033  Measurable levels of dacomitinib were noted in the blood from 2 to at least 168 hours post-dose. By 504 hours post-dose dacomitinib levels were below the level or quantitation.  Cmax in hepatic blood was 8 hours; Cmax in myocardial and vena cava blood was 12 hours, Cmax in CNS tissues was 8-12 hours.  CNS tissues (except pituitary and pineal gland), intestinal mucosa, seminal vesicles, and thoracic duct fluid were devoid of dacomitinib at ≥ 96 hours.  Dacomitinib was still present in adrenal gland, bone marrow, brown adipose, kidney, lacrimal glands, liver, lung, meninges, myocardium, parotid gland, testis, uvea, and vitreous body at 504 hours post- dose. Metabolism Identification of In Vitro Metabolites of The primary metabolic pathways for [14C] dacomitinib after PF-00299804 in Liver Microsomes from incubation with human liver microsomes were N-oxidation of Human, Rat, Dog, and Monkey; Study No. the piperidine ring to form dacomitinib N-oxide (M8) and DM2005-00299804-035 deamination of the piperdine ring with subsequent cyclization to form a hydroxy metabolite (M6). These metabolites were also observed in rat, dog, and monkey liver microsomes. In dog and monkey liver microsomes, defluorination and subsequent aromatic hydroxylation to form a hydroxylated metabolite (M3) was also observed.

The major human O-desmethyl metabolite was not identified in vitro but was present in vivo in both rats and dogs Excretion Radiolabeled Mass Balance and Metabolic Based on results from these studies, the primary route of Profiles of [14C] PF-00299804- excretion following oral administration of radiolabeled (14C) 03 in Sprague-Dawley Rats; Study No. dacomitinib was through feces and accounted for up to 97% DM2006-00299804-039 in rats, 89% in dogs, and 79% in humans. Urinary excretion of radioactivity was < 6% in rats, dogs, and humans. Radiolabeled Mass Balance and Metabolic Profiles of [14C] PF-00299804- 03 in Beagle Dogs; Study No. DM2006- 00299804-038 TK data from general toxicology studies Refer to Section 5.5.1 TK data from reproductive toxicology Refer to Section 5.5.4 studies

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5.5 Toxicology

5.5.1 General Toxicology

Study Title / Number: 6-Month Oral Gavage Toxicity and Toxicokinetic Study with PF-00299804 in Rats with 1-Month Recovery/ 6348-474

Key Study Findings:  Eleven HD animals were sacrificed early in moribund condition due to skin lesions as early as on Day 82. All remaining HD males and females were sacrificed early on Days 90 or 131, respectively.  Toxicity was primarily limited to HD animals and consisted of epithelial atrophy, tubular atrophy and necrosis in the kidneys, decreased section in the prostate, and generalized inflammation likely secondary to skin lesions.  Epithelial atrophy was noted in the skin, eye, gastrointestinal tract, liver, cervix, and vagina.

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

Methods Dose and frequency of dosing: 0, 0.2, 0.5, or 2 mg/kg/day Daily for 6 months with 1-month recovery period Route of administration: Oral gavage Formulation/Vehicle: 0.5% (w/v) methylcellulose in reverse osmosis water Species/Strain: Rat / Sprague-Dawley (Crl:CD®[SD]) Number/Sex/Group: 20 (5 continued through recovery period) Age: 48-54 days Satellite groups/ unique design: For toxicokinetics - 3 animals/sex for control and 6 animals/sex for dacomitinib dose groups / No unique study design Dose justification: Based on results from a previously conducted 1- month repeated-dose toxicity study in rats; ≥ 5 mg/kg/day resulted in moribundity and morbidity (refer to additional studies). Deviations from study protocol affecting interpretation of results: No

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Observations and Results: Parameters Major findings Mortality Six HD males (Days 82-90) and 5 HD females (Days 96-127) were sacrificed in moribund condition due to skin lesions. All remaining HD males and females were sacrificed early on Day 90 or Day 131, respectively. HD recovery animals survived through a recovery period of 98 days in males and 85 days in females. Clinical Signs Beginning on Week 4, skin lesions were noted in HD animals. Multiple animals required treatment with triple antibiotic ointment and hydrocortisone. Refer to histopathology results for more detail. Body Weights On Day 85, HD males had a 10% reduction in body weight. On Day 127, HD females had a 5% reduction in body weight. Ophthalmoscopy Unremarkable Electrocardiography Unremarkable Hematology Percent Differences in Mean Values vs. Concurrent Controls

Clinical Chemistry Percent Differences in Mean Values vs. Concurrent Controls

Urinalysis Urine occult blood was present in HD animals. Gross Pathology Skin lesions and large mandibular lymph nodes were noted in HD animals. Refer to histopathology results for more detail. Organ Weights Unremarkable

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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 All dacomitinib-related findings were reversible or on a trend of reversibility by the end of the recovery period.

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Toxicokinetics Dose proportionality: Generally, dose proportional. Accumulation: Yes Gender differences: No significant differences were noted.

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

Study Title / Number: 9-Month Oral Toxicity and Toxicokinetic Study of PF-00299804 in Dogs with 3-Month Recovery / 6348-475

Key Study Findings:  No mortalities occurred.  Toxicity was primarily limited to HD animals and consisted of conjunctivitis, erythema, histopathological vacuolation of the adrenal glands, atrophy of the mandibular salivary glands, and generalized inflammation likely secondary to the conjunctivitis.

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

Methods Dose and frequency of dosing: 0, 0.03, 0.1, or 1 mg/kg/day Daily for 9 months with 3-month recovery period Route of administration: Oral gavage Formulation/Vehicle: 0.5% (w/v) methylcellulose in reverse osmosis water Species/Strain: Dog / Beagle Number/Sex/Group: 6 (2 continued through recovery period) Age: 8-9 months Satellite groups/ unique design: None / No Dose justification: Based on results from a previously conducted 1- month repeated-dose toxicity study in dogs; doses up to 3 mg/kg/day did not result in moribundity or mortality (refer to additional studies).

Deviations from study protocol No affecting interpretation of results:

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Observations and Results: Parameters Major findings Mortality None Clinical Signs Beginning on Week 1, conjunctivitis and other adverse findings in the eye (clear or cloudy discharge and squinting) were noted in numerous HD animals. Multiple animals required treatment with triple antibiotic ointment and nonsteroidal anti-inflammatory drugs. Dose-dependent erythema of the gums, muzzle, ears, and/or paws occurred. Body Weights Unremarkable Ophthalmoscopy No adverse findings except for the conjunctivitis described in clinical signs. Electrocardiography Unremarkable Hematology A 40% increase in neutrophils, 17% increase in white blood cells, and 32% increase in fibrinogen was noted in HD females. Clinical Chemistry A 13% decrease in albumin was noted in HD animals. Urinalysis Unremarkable Gross Pathology Unremarkable Organ Weights A 28% increase in adrenal weight in HD females. 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 Reversibility All dacomitinib-related findings were reversible or on a trend of reversibility by the end of the recovery period. Toxicokinetics Dose proportionality: Generally dose proportional. Accumulation: No significant accumulation was noted. Gender differences: No significant differences were noted.

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

General toxicology; additional studies

Pfizer conducted a GLP-compliant repeated-dose toxicology study in Sprague-Dawley rats (10- 15/sex/group) administered dacomitinib daily at doses of 0, 0.5, 5, or 20 mg/kg for 30 days (Study 04-2730-11). The HD was intolerable and following cessation of dosing on Days 6/7, 43 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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animals were either euthanized or retained to assess reversibility. Two MD animals were sacrificed in moribund condition on Day 22 due to decreased food consumption and body weight. Adverse findings were generally consistent with results from the 6-month toxicity study in rats (Study 6348-474) and consisted of dose-responsive epithelial atrophy of multiple organs (skin, eye, GI tract, cervix, and vagina), renal necrosis, and generalized inflammation.

Pfizer conducted a GLP-compliant repeated-dose toxicology study in Beagle dogs (3- 5/sex/group) administered dacomitinib once daily at doses of 0, 0.3, 1, or 3 mg/kg for 30 days (Study 04-2730-05). No mortality occurred. Adverse findings were generally consistent with results from the 9-month toxicity study in dogs (Study 6348-475) and consisted of dose- responsive conjunctivitis, erythema, and generalized inflammation.

To confirm that each species used in non-clinical studies was exposed to the PF-05199265 O- desmethyl active metabolite, Pfizer conducted non-GLP 3-day repeated-dose pharmacokinetic studies in rats, rabbits, and dogs, and compared the systemic level of PF-05199265 to dacomitinib. Male Sprague-Dawley rats were administered 1 mg/kg of oral dacomitinib, once per day, for 3 days (Study PF-00299804-140632). Female NZW rabbits were administered 4 mg/kg of oral dacomitinib, once per day, for 3 days (Study PF-002990804-095344). Male Beagle dogs were administered 0.1 mg/kg of oral dacomitinib, once per day, for 3 days (Study PF- 002990804-141511). As shown in the table below, on Day 3, the PF-05199265 to dacomitinib AUC ratio was 0.18 in rats and 1.9 in dogs. Rabbits were not exposed to the PF-05199265 O- desmethyl active metabolite.

Table 4: Plasma Levels of Dacomitinib and PF-05199265 in Rats, Rabbits, and Dogs

(Pfizer Figure reproduced from Studies PF-00299804-140632, -095344, and -141511).

Daily oral administration of the 45 mg human dose of dacomitinib results in PF-05199265 O- desmethyl active metabolite mean exposure levels (AUC) of approximately 509 ng.h/mL in humans. In dogs, the highest dose in the 6-month repeated-dose toxicity study was 1 mg/kg/day, resulting in a dacomitinib exposure level (AUC) of 308 ng.h/mL. Based on a PF- 05199265 to dacomitinib AUC ratio of 1.9 in dogs, the estimated exposure to PF-05199265 in 44 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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dogs at this dose level is 585 ng.h/mL, equal to or exceeding the PF-05199265 exposure level in humans. Given these findings, no additional toxicology studies to assess the safety of the PF- 05199265 O-desmethyl metabolite are needed.

5.5.2 Genetic Toxicology

In Vitro Reverse Mutation Assay in Bacterial Cells (Ames) Study Title / Number: Bacterial Mutagenicity Assay / 04-2730-10

Key Study Findings:  Dacomitinib did not show genotoxic activity in the presence or absence of S9 activation  Cytotoxicity noted ≥ 1000 μg/plate  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 WP2 uvrA pKM101; ≤ 5000 ug/plate of Dacomitinib; +/- S9 Study is valid: Yes

In Vitro Assays in Mammalian Cells Study Title / Number: Human Lymphocyte Assay / 04-2730-09

Key Study Findings:  Dacomitinib did not induce structural chromosome aberrations in the absence or presence of S9 activation.  A significant increase in the frequency of polyploid cells at 0.8 ug/mL (the highest dose examined for polyploidy) occurred in the 24-hour test without metabolic activation. Lower concentrations tested (≤ 0.64 μg/mL) were within the range of negative historical controls. In the 3-hour test with or without metabolic activation, concentrations ≥ 0.8 μg/mL had no effect on the frequency of polypoid cells.  Positive controls caused substantial increases in the proportion of chromosomal aberrations confirming the sensitivity and validity of the study.

GLP compliance: Yes Test system: human peripheral blood lymphocytes; ≤ 4 mg/mL of dacomitinib in the 3 hour test and ≤ 1 μg/mL in the 24 hour test; +/- S9 Study is valid: Yes

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Table 5: Human Lymphocyte Assay: 24-Hour Treatment without Metabolic Activation

(Pfizer Figure reproduced from Study 04-2730-09)

In Vivo Clastogenicity Assay in Rodent (Micronucleus Assay) Study Title / Number: In Vivo Bone Marrow Micronucleus Assay of PF-00299804 / 06GR304

Key Study Findings:  Oral administration of dacomitinib up to 2000 mg/kg/day for 2 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: rat, bone marrow micronuclei; 5, 250, or 2000 mg/kg/day of oral dacomitinib once per day for 2 consecutive days Positive control: 10 mg/kg cyclophosphamide

5.5.3 Carcinogenicity

Not conducted per ICH S9.

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5.5.4 Reproductive and Developmental Toxicology

Based on its mechanism of action, dacomitinib can cause fetal harm or developmental anomalies. EGFR is critically important in reproductive and developmental processes in mice including blastocyst implantation, placental development, and embryo-fetal/postnatal survival and development. For example, maternal levels of circulating EGF correlate with fetal growth in mice (Kamei et al., 1999). In various EGFR knock-out models, mice showed retardation of fetal growth, mid-gestational death, early post-natal death, or developmental defects in multiple organs (Sibilia and Wagner, 1995; Miettinen et al., 1995; Threadgill et al., 1995).

Embryo-Fetal Development Study Title / Number: Oral Dose Range-Finding Study of PF-00299804 in Pregnant Rats / 08GR122

Key Study Findings:  Maternal toxicity was limited to HD animals and consisted of chromodacryorrhea, chromorhinorrhea, skin lesions, alopecia, and an 8% reduction in body weight.  Fetal toxicity consisted of an 7% decrease in mean fetal body weight in LD and HD females.  Cesarean section data showed a non-dose responsive increase in post-implantation loss and a 17% decrease in gravid uterine weight in all dacomitinib dose groups.

Conducting laboratory and location: Pfizer Global Research and Development, Groton, CT GLP compliance: No

Methods Dose and frequency of dosing: 0.5, 2, and 5 mg/kg/day Daily from Days 6 to 17 post coitum Route of administration: Oral gavage Formulation/Vehicle: 0.5% methylcellulose Species/Strain: Rat / Sprague-Dawley (Crl:CD®[SD]) Number/Sex/Group: 6/group Satellite groups: Yes; 3 control and 5 treated animals 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 1- month repeated-dose toxicity study in rats; ≥ 5 mg/kg/day resulted in moribundity and morbidity (refer to general toxicology; additional studies).

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Deviation from study protocol No affecting interpretation of results:

Observations and Results: Parameters Major findings Mortality No test article related deaths Clinical Signs Chromodacryorrhea and chromorhinorrhea were noted in 5/6 and 6/6 HD rats, respectively. Skin lesions and alopecia were noted in 1/20 and 2/6 HD rats, respectively. Body Weights An 8% decrease in mean body weight was noted in HD animals at the end of the dosing period. Cesarean Cesarean section data: As detailed in the following table, post-implantation Section loss was increased in all dacomitinib dose groups. A 17% decrease in gravid uterine weight was also noted in all dacomitinib dose groups.

Fetal body weight: An 7% decrease in mean fetal body weight was noted in LD and HD animals. Offspring Fetal external exam: Unremarkable Necropsy Toxicokinetics Not conducted LD: low dose; MD: mid dose; HD: high dose.

Study Title / Number: Oral Embryo-fetal Development Study of PF-00299804 in Rats / 08GR326

Key Study Findings:  Maternal toxicity was limited to HD animals and consisted of chromodacryorrhea, chromorhinorrhea, skin lesions, and a 10% reduction in body weight.  Fetal toxicity consisted of an 8% decrease in mean fetal body weight in HD females and unossified metatarsals in approximately 8% of all PF-00299804 treated rat pups.  Cesarean section data showed an increase in post-implantation loss in HD females. Based on the steady state AUC in patients (2213 ng.hr/mL), dacomitinib exposures in pregnant rats were up to 1.2 times those in humans at the 45 mg dose.

Conducting laboratory and location: Pfizer Global Research and Development, Groton, CT GLP compliance: Yes

Methods Dose and frequency of dosing: 0.2, 1, and 5 mg/kg/day Daily from Days 6 to 17 post coitum 48 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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Route of administration: Oral gavage Formulation/Vehicle: 0.5% methylcellulose Species/Strain: Rat / Sprague-Dawley (Crl:CD®[SD]) Number/Sex/Group: 20/group Satellite groups: Yes; 3 control and 5 treated animals 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 the previously conducted dose-range finding embryo-fetal toxicity study in rats (reviewed above); 5 mg/kg/day resulted an 8% decrease in maternal body weight. Deviation from study protocol affecting interpretation of results: No

Observations and Results: Parameters Major findings Mortality No test article related deaths Clinical Signs Chromodacryorrhea and chromorhinorrhea were noted in 7/20 and 14/20 HD rats, respectively. Skin lesions were noted in 5/20 HD rats. Body Weights A 10% decrease in mean body weight was noted in HD animals at the end of the dosing period. Cesarean Cesarean section data: As detailed in the following table, post-implantation Section loss was increased in HD animals.

Fetal body weight: An 8% decrease in mean fetal body weight was noted in HD animals. Offspring Fetal external exam: Unremarkable Necropsy Fetal visceral exam: Unremarkable Fetal skeletal exam:

Toxicokinetics Dose proportionality: Generally greater than dose proportional Maternal Exposure on Day 17:

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

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Study Title / Number: Oral Embryo-fetal Development Study of PF-00299804 in Rabbits / 08GR498

Key Study Findings:  No maternal or fetal toxicity occurred.  Based on the steady state AUC in patients (2213 ng.hr/mL), PF-00299804 exposures in pregnant rabbits at the high dose of 4 mg/kg were approximately 0.16 times the clinical exposure at the 45-mg human dose.

Conducting laboratory and location: Pfizer Global Research and Development, Groton, CT GLP compliance: Yes

Methods Dose and frequency of dosing: 0.5, 1.5, and 4 mg/kg/day Daily from Days 7 to 19 post coitum Route of administration: Oral gavage Formulation/Vehicle: 0.5% methylcellulose Species/Strain: Rabbit / New Zealand White Number/Sex/Group: 20/group Satellite groups: Yes; 3 control and 5 treated animals Study design: Time-mated rabbits were treated once daily via oral gavage from Days 7 to 19 post coitum. Cesarean section occurred on Day 29. Dose justification: Based on results from the previously conducted dose-range finding embryo-fetal toxicity study in rabbits; 5 mg/kg/day resulted an 8% decrease in maternal body weight. Deviation from study protocol No affecting interpretation of results:

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Observations and Results: Parameters Major findings Mortality No test article related deaths Clinical Signs Unremarkable Body Weights Unremarkable Cesarean Cesarean section data: Unremarkable Section Fetal body weight: Unremarkable Offspring Fetal external exam: Unremarkable Necropsy Fetal visceral exam: Unremarkable Fetal skeletal exam: Unremarkable Toxicokinetics Dose proportionality: Generally, dose proportional Maternal Exposure on Day 19:

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

5.5.5 Other Toxicology Studies

Dacomitinib was evaluated for potential phototoxicity in vivo when administered as a single oral (gavage) dose to Long-Evans pigmented female rats, before exposure to ultraviolet radiation (UVR) from a xenon lamp to simulate sunlight (Study 20025592). In this GLP-compliant study, four groups of female rats (5/group) were administered dacomitinib at doses of 0, 10, 30, or 100 mg/kg. The positive control was 50 mg/kg of 8-methoxypsoralen (8-MOP). Vehicle and dacomitinib-treated rats were exposed to UVR (0.5 minimal erythema dose [MED]) approximately 4 hours post-dose, and 8-MOP-treated rats were exposed to UVR approximately 1 hour post-dose. An additional group of 5 rats were administered 100 mg/kg dacomitinib without UVR exposure. All main study animals were euthanized on Day 4 (3 days post-dose). A satellite group of animals (3/dose) was utilized for toxicokinetic evaluation. The results showed no evidence of cutaneous or ocular phototoxicity after a single oral gavage administration of dacomitinib at doses up to 100 mg/kg followed by a single exposure of simulated sunlight.

Primary Reviewer Team Leader

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APPEARS THIS WAY ON ORIGINAL

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6. Clinical Pharmacology

6.1 Executive Summary

Pfizer seeks approval of VIZIMPRO (dacomitinib) for the first-line treatment of patients with (b) (4) metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)(b) (4) mutations as detected by an FDA-approved test. The proposed dosing regimen is 45 mg orally once daily with or without food. The primary evidence of efficacy is based on the demonstrated increase in PFS in Study 1050, a randomized two-arm trial in previously untreated patients with advanced stage or metastatic NSCLC. The exposure- response (ER) relationship between dacomitinib exposure and PFS was not well established due to confounding caused by a high rate of dose reduction or interruption in the clinical studies. The exposure-safety analysis suggested that higher dacomitinib exposures, across the range of exposures with the recommended dose of 45 mg daily, correlate with an increased probability of Grade ≥3 adverse events, specifically dermatological toxicities and diarrhea. The Clinical Pharmacology Review evaluated the acceptability of the proposed dosing regimen and adjustment of the starting dose for drug interactions and patients with organ impairment. 6.2 Recommendations The Office of Clinical Pharmacology has reviewed the information contained in NDA 211288 and found that this NDA is approvable from a Clinical Pharmacology perspective. The key review issues with specific recommendations and comments are summarized below:

Review Issues Recommendations and Comments Supportive evidence of The primary evidence of effectiveness comes from trial 1050 in the effectiveness target population. Refer to section 7 for further details. General dosing The proposed dosage regimen of 45 mg once daily with or without instructions food is acceptable. No clinically relevant food effect was observed on exposure of dacomitinib when it is administered with a high-fat, high-calorie meal. The exposure-response relationships for efficacy and safety support selection of the proposed 45 mg once daily regimen. Dosing in patient . Specific Populations: Subjects with mild and moderate renal subgroups (intrinsic impairment had comparable dacomitinib exposure to those with and extrinsic factors) normal renal function. Subjects with mild and moderate hepatic impairment had comparable dacomitinib exposure to those with normal hepatic function. No dose adjustments are needed in patients with mild or moderate renal impairment or in patients with mild or moderate hepatic impairment. Patients with severe renal or hepatic impairment have not been studied.

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. PPIs: Rabeprazole, a PPI, decreased mean Cmax and AUC0-inf of dacomitinib by 50% and 30%, respectively. Concomitant use of PPIs with dacomitinib are to be avoided.

. Antacids: Maalox® did not significantly influence the mean Cmax or AUC0-inf of dacomitinib. There is no need to delay dacomitinib dosing when it must be coadministered with antacids. . H2-receptor antagonists: The effect of these agents on dacomitinib exposure has not been studied. VIZIMPRO is to be administered at least 6 hours before or 10 hours after taking an H2-receptor antagonist. . Strong CYP2D6 inhibitors/CYP2D6 poor metabolizer (PM) phenotype: Paroxetine, a strong CYP2D6 inhibitor, increased geometric mean AUC0-inf of dacomitinib by 37% and by only 5.7% based on total drug moiety (parent + metabolite). Therefore, no starting dose adjustment is needed for patients taking a strong CYP2D6 inhibitor (Response to IR dated 6/13/2018, SDN 36). In addition, there was no clinically relevant change in the geometric mean steady state AUC0-24h for the total drug moiety (parent + metabolite) in patients who are CYP2D6 PMs versus patients who are CYP2D6 extensive metabolizers (EMs). No starting dose adjustment is needed for patients who are CYP2D6 PMs as the incidence of Grade ≥3 AEs was comparable across the three CYP2D6 phenotypes (EM, intermediate metabolizer (IM) and PM) (Response to IR dated 6/14/2018, SDN 37). . Sensitive CYP2D6 substrates: Dacomitinib, a strong CYP2D6 inhibitor, increased geometric mean AUC0-inf and Cmax of dextro- methorphan, a CYP2D6 substrate, by 362% and 973%, respectively. Dose reduction or substitution may be needed. Avoid the concomitant use of CYP2D6 substrates with a narrow therapeutic index with dacomitinib. Labeling Labeling recommendations were communicated to Pfizer. Refer to Section 10 for details. Bridge between the The proposed to-be-marketed debossed blue film-coated tablet to-be marketed and formulation was used in trial 1050, which was designed to clinical trial demonstrate the efficacy and safety of dacomitinib for the formulations proposed indication.

6.3 Post-marketing Requirements and Commitments A post-marketing requirement (PMR) study is requested in patients with severe hepatic impairment.

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6.4 Summary of Clinical Pharmacology Assessment

6.5 Pharmacology and Clinical Pharmacokinetics

Dacomitinib (PF-00299804) is an irreversible, pan-human epidermal growth factor receptor (HER) (EGFR/HER-1, HER-2, and HER-4) inhibitor with a clinical activity against the mutated EGFR with deletions in exon 19 or the L858R substitution in exon 21. The clinical pharmacokinetics (PK) of dacomitinib is summarized below:  Absorption: Following oral administration, the mean absolute bioavailability of dacomitinib is 80%. Median time to peak plasma concentration of dacomitinib (Tmax) is 6 hours. A high-fat/high calorie meal did not significantly affect dacomitinib exposure. However, rabeprazole, a PPI, significantly increased dacomitinib exposure.

 Distribution: Mean (%CV) apparent volume of distribution (Vz/F) is 1889 L (18%) following a single intravenous (IV) dose of 20 mg administered as a 1-hour infusion in healthy subjects. The protein binding of dacomitinib in human plasma averaged 98% at both in vitro concentrations of 250 ng/mL and 1000 ng/mL. Dacomitinib distributes equally between red blood cells and plasma with a mean Cblood/Cplasma ratio of 1.08 in humans.  Metabolism: Dacomitinib is primarily metabolized in the liver by CYP2D6 enzyme to form the major circulating active O-desmethyl metabolite, PF-05199265. PF-05199265 has the same pharmacological activity to inhibit the HER kinase family as the parent compound. Mean metabolite-to-parent AUC0-inf ratio is 0.23 after a single 45 mg oral dose in healthy subjects.  Elimination: Following a single 45 mg oral dose of dacomitinib, the mean terminal elimination half-life (t1/2) of dacomitinib is 70.3 hours and that of PF-05199265 is 72.8 hours. The mean apparent oral clearance (CL/F) of dacomitinib is 26.9 L/h. The PK of dacomitinib appears to be similar between patients and healthy subjects. Dacomitinib accumulates upon once daily dosing with a mean accumulation ratio (Rac) of 5.7. In the mass balance study, 78.8 % of the radiolabeled material is excreted in feces and 3.2 % was recovered in urine. Unchanged dacomitinib accounted for approximately 20% in feces and <1% in urine.

6.6 General Dosing and Therapeutic Individualization

6.6.1 General Dosing

The proposed recommended dose is 45 mg given orally once daily with or without food for the first-line treatment of patients with (b) (4) metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)(b) (4) mutations as detected by an FDA-approved test.

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6.6.2 Therapeutic Individualization

Specific Populations Renal Impairment: The PopPK analysis of pooled data from clinical trials indicates that subjects with mild (creatinine clearance [CLcr]=60-89 mL/min, n=590), moderate (CLcr=30-59 mL/min, n=218) and sever (CLcr <30mL/min, n=4) renal impairment had comparable dacomitinib exposure to patients with normal renal function (CLcr ≥ 90 mL/min, n=567). Creatinine clearance (CLcr was estimated using the Kidney Disease Outcome Quality Initiative [KDOQI] staging method. No dosage adjustment is needed in patients with mild or moderate renal impairment. Renal elimination is a minor route of dacomitinib clearance; <1% of administered dose was excreted unchanged in urine. Therefore, there is no need to request a post-marketing requirement (PMR) for patient with severe renal impairment. Hepatic Impairment: The PopPK analysis of pooled data from clinical trials indicates that patients with mild (n=158), moderate (n=5) and severe (n=1) hepatic impairment had comparable dacomitinib exposure to patients with normal hepatic function (n=1202) based on NCI Criteria. In a formal PK study in 25 healthy subjects, it is found that the geometric mean unbound dacomitinib Cmax,u and AUC0-inf,u values were comparable for subjects with mild (Child- Pugh class A:, n=8) to moderate hepatic impairment (Child-Pugh class B:, n=9) versus those with normal hepatic function (n=8). The same trend was noted for the major active metabolite, PF- 05199265. No dosage adjustment is needed in patients with mild or moderate hepatic impairment. DDIs

PPIs: Rabeprazole, a PPI, decreased the geometric mean Cmax and AUC0-inf of dacomitinib by 50% and 30%, respectively, following a single 45 mg oral dose in healthy male subjects. Concomitant use of PPIs with VIZIMPRO is to be avoided.

Antacids: Maalox® did not significantly influence the mean Cmax or AUC0-inf of dacomitinib following a single 45 mg dose in patients with advanced solid tumors. There is no need to stagger VIZIMPRO dosing when antacids are coadministered. H2-receptor antagonists: The effect of these agents on dacomitinib exposure has not been studied. VIZIMPRO is to be administered at least 6 hours before or 10 hours after taking an H2- receptor antagonist. Strong CYP2D6 inhibitors/CYP2D6 poor metabolizer (PM) phenotype: Paroxetine, a strong CYP2D6 inhibitor, increased the geometric mean AUC0-inf for total drug moiety (parent + metabolite) by 6%, which is not considered to be clinically relevant (Pfizer’s response to the FDA’s Information Request [IR] dated 6/13/2018, SDN 36). Therefore, based on the total drug moiety exposure, no starting dose adjustment for VISIMPRO is when strong CYP2D6 inhibitors must be coadministered. The incidence of ≥ Grade 3 AEs was comparable across the three CYP2D6 phenotypes: EMs, intermediate metabolizers (IMs) and PMs (Pfizer’s response to the FDA’s Information Request [IR] dated 6/14/2018, SDN 37).

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Sensitive CYP2D6 substrates: Dacomitinib, a strong CYP2D6 inhibitor, increased the geometric mean AUC0-inf and Cmax of dextromethorphan, a CYP2D6 substrate, by 362% and 973%, respectively, in healthy male subjects. The concomitant use of CYP2D6 substrates with a narrow therapeutic index with dacomitinib is to be avoided. If these cannot be avoided, a dose reduction or substitution of the CYP2D6 substrate may be needed.

6.6.3 Outstanding Issues

One PMR to assess the effect of severe hepatic impairment on dacomitinib exposure has been issued. There are no other outstanding issues.

6.6.4 Summary of Labeling Recommendations . Specific Populations: No dosing adjustments are needed in patients with mild to moderate renal impairment or in patients with mild to moderate hepatic impairment. Patients with severe renal or hepatic impairment have not been studied. . PPIs: Concomitant use of PPIs with VIZIMPRO are to be avoided. . Antacids: These agents have no effect on dacomitinib absorption. . H2-receptor antagonists: The effect of H2-receptor antagonists on dacomitinib exposure has not been studied. Administer VIZIMPRO at least 6 hours before or 10 hours after taking an H2-receptor antagonist. . Strong CYP2D6 inhibitors/CYP2D6 PM phenotype: No starting dose adjustment of VIZIMPRO is needed for patients taking a strong CYP2D6 inhibitor or for patients who are CYP2D6 PMs. . Sensitive CYP2D6 substrates: The concomitant use of CYP2D6 substrates with a narrow therapeutic index with dacomitinib is to be avoided. If these agents cannot be avoided a dose reduction or substitution of the CYP2D6 substrate may be needed.

6.7 Comprehensive Clinical Pharmacology Review

6.7.1 General Pharmacology and Pharmacokinetic Characteristics

PHYSICOCHEMICAL PROPERTIES Chemical structure Dacomitinib PF-05199265 and molecular formula & weight

Molecular formula: C24H25ClFN5O2.H2O Molecular formula: C23H22ClFN5O2.H2O Molecular weight: 488 Daltons Molecular weight: 456 Daltons

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Aqueous solubility Dacomitinib exhibits a pH-dependent solubility (BCS Class II compound).

PHARMACOLOGY Mechanism of Dacomitinib is a pan-human epidermal growth factor receptor (HER) action (EGFR/HER1, HER2, and HER4) inhibitor with a clinical activity against the mutated EGFR with deletions in exon 19 or the L858R substitution in exon 21. Dacomitinib irreversibly binds to HER1, HER2 and HER4 with IC50 values of 2.8 ng/mL (6.0 nM), 21.5 ng/mL (45.7 nM), and 34.7 ng/mL (73.7 nM), respectively [mean Cmax,u of dacomitinib is 1.71 ng/ mL (3.6 nM) at the 45 mg once daily doses]. Active moiety Dacomitinib and its major circulating active O-desmethyl metabolite, PF-05199265 QT/QTc The effect of dacomitinib on the QT interval was evaluated in STUDY prolongation 1047. QT prolongation was corrected for heart rate (QTcF) using time- matched ECGs baseline and corresponding PK data in 32 patients with advanced NSCLC. As per the FDA’s IRT-QT review, dacomitinib did not prolong QTc to any clinically relevant extent (90% CIs of mean ΔQTcF <20 ms) at therapeutic maximum concentrations expected following 45 mg once daily. GENERAL INFORMATION Bioanalytical assay A validated high-performance liquid chromatography (HPLC) with atomic pressure ionization tandem mass spectrometry detection (LC- API/MS/MS) assay was used to measure the concentrations of dacomitinib and PF-05199265 in human plasma, urine, plasma dialysate samples in clinical pharmacology studies of the NDA (See Appendix 19.4). Patient PK vs. Appears to be similar for both dacomitinib and PF-05199265 healthy subject PK Steady-state Following once daily 45 mg doses of dacomitinib in patients with exposure at the advanced solid tumors, mean dacomitinib Cmax.ss and AUC0-24h values proposed dosing are 108 ng/mL and 2342 ng·h/mL, respectively (Study 1001). Mean Cmin regimen is 73.1 ng/mL.

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Minimal effective Exposure-Response (E-R) analyses indicate that dacomitinib exposure dose or exposure was not a significant predictor of PFS, whereas patients who presented with certain dermatologic AEs were more likely to have a longer PFS. The incidence of dermatologic AEs increased with dacomitinib exposure. In Study 1050, the dose of dacomitinib was reduced from 45 mg to 30 mg and to 15 mg once daily based on individual tolerance. Maximum tolerated Based on the dose-limited toxicity data from Study 1001, the MTD dose or exposure assessed in patients with solid tumors is 45 mg once daily (doses tested in the study ranged from 0.5 mg to 60 mg once daily). Dose Dacomitinib PK is dose-proportional at doses ranging from 2 to 45 mg proportionality following once daily dosing (Study 1001). Accumulation Dacomitinib accumulates upon once daily 45 mg doses for 14 days [mean (%CV) Rac= 5.7 (28%)] Variability Inter-patient variability (CV%) is 35% for both Cmax,ss and AUC0-24h and 45% for Cmin following once daily 45 doses for 14 days (Study 1001). ABSORPTION Absolute GM AUC0-inf (Oral) GM AUC0-inf (IV) GM Ratio 90% CI bioavailability (ng.h/mL/dose (ng.h/mL/dose) (Oral/IV) 33.05 41.31 80.01% (75%, 85%) Absolute bioavailability (Fab)of dacomitinib is 80% following a single 45 mg oral dose and a single 20 mg IV dose in 14 healthy male subjects (Study 1046). Tmax Median (range) Tmax is 6 (2-24) hours after a single 45 mg dose (Study 1001). Effect of food GM Ratio Cmax (90% CI) GM Ratio AUC0-inf (90% CI) Median TMAX 123.7 [105%, 145%] 114.2 [105%, 125%] 8 h (Fed) 8 h (Fasted) A high-fat/high calorie meal increased mean Cmax and AUC0-inf of dacomitinib by 24% and 14%, respectively, following a single 45 mg oral dose in healthy male subjects (Study 1015). Effect of GM Ratio Cmax (90% CI) GM Ratio AUC0-inf (90% CI) Median TMAX rabeprazole, PPI 49.5 [41%, 60%] 71.1 [62%, 82%] 11.9 h (+rabeprazole 8 h (alone) Rabeprazole decreased mean Cmax and AUC0-inf of dacomitinib by 50% and 30%, respectively, following a single 45 mg oral dose in healthy male subjects (Study 1015). The exposure response analysis for PFS is difficult to interpret due to confounding caused by a high rate of dose reductions in the clinical trials. Exploratory tumor growth inhibition modeling indicated a positive relationship between dacomitinib exposure and tumor shrinkage. Therefore, a 30% reduction in AUC may result in less tumor shrinkage.

GM Ratio Cmax (90% CI) GM Ratio AUC0-inf (90% CI) Median TMAX

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Effect of Maalox®, 88 [62%, 124%] 105 [81%, 136%] 8 h (+ Maalox®) antacid 5 h (alone) Maalox® did not significantly influence the mean Cmax or AUC0-inf of dacomitinib following a single 45 mg dose in 8 patients with advanced solid tumors (Study 1001). DISTRIBUTION Steady state Mean (%CV) Vz/F is 1889 L (18%) following a single intravenous (IV) volume of dose of 20 mg administered as a 1-hour infusion in healthy subjects distribution (Study 1046). Protein binding of dacomitinib to human plasma averaged 98.04±0.30% and 98.18±0.26% at in vitro concentrations of 250 ng/mL and 1000 ng/mL, respectively. Dacomitinib distributes equally between red blood cells and plasma; blood-to-plasma ratio averaged 1.08±0.086 in humans. Substrate of CYP/ . CYP450/UGT Enzymes transporter systems – Dacomitinib is a substrate for CYP2D6 forming a major circulating active O-desmethyl metabolite, PF-05199265. – Dacomitinib is a strong Inhibitor of CYP2D6 and an Inhibitor of UGT1A1. Dacomitinib did not an inducer of any CYP. . Transporters – Dacomitinib is a substrate for both P-gp and BCRP transporters. – Dacomitinib is not an inhibitor of P-gp (systemically), OATP1B1, OATP1B3, OAT1, OAT3, OCT2 or BSEP but it is an inhibitor of P-gp (in GI tract), BCRP (systemically and in GI tract) and OCT1. ELIMINATION Terminal Mean (%CV) t1/2 is 70.3 hours (21%) and CL/F is 24.9 L/h (36%) for elimination half-life dacomitinib following a single 45 mg oral dose (Study 1001). Mean and apparent (%CV) t1/2 for PF-05199265 is 72.8 hours (19%) following a single 45 mg clearance dose of dacomitinib (Study 1020). Metabolism Dacomitinib undergoes extensive metabolism in the liver through oxidation and glutathione conjugation. Cytochrome P-450 2D6 (CYP2D6) is the primary CYP enzyme involving in the oxidative metabolism of dacomitinib to form the O-desmethyl metabolite, PF- 05199265. Mean metabolite-to-parent AUC0-inf ratio is 0.23 (75%) after a single 45 mg oral dose in 10 healthy subjects (Study 1046). The CYP3A4 enzyme is involved in the formation of other minor oxidative metabolites. The conjugation pathway includes glutathione conjugation of the α,β-unsaturated amide moiety with subsequent cleavage to the cysteine conjugate of parent.

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Excretion Following a single 45 mg (100 µCi) oral dose of [14C]-dacomitinib in 6 male healthy subjects, the overall mean±SD total recovery of radioactivity is 81.9±7.55% of which 78.8±7.6% excreted in feces and 3.17±0.74% in urine over 552 hours after dosing (Study 1020). Unchanged dacomitinib accounted for approximately 20% in feces and <1% in urine. Drug interactions Effect of Strong CYP2D6 inhibitors on Dacomitinib: Paroxetine, a (DDI) liability strong CYP2D6 inhibitor, increased the geometric mean AUC0-inf by 6% based on total drug moiety (parent + metabolite), which is not considered clinically relevant (Study 1021). Effect of Dacomitinib on CYP2D6 substrates: Dacomitinib, a strong CYP2D6 inhibitor, increased geometric mean AUC0-inf and Cmax of dextromethorphan, a CYP2D6 substrate, by 362% and 973%, respectively, in healthy male subjects (Study 1039).

6.7.2 Clinical Pharmacology Questions

Does the clinical pharmacology program provide supportive evidence of effectiveness?

The clinical pharmacology information along with the efficacy results from the pivotal phase 3 Study 1050 provided adequate support for evidence of effectiveness of dacomitinib (b) (4) as detailed in the sections below. The single-dose and multiple-dose PKs of dacomitinib were determined in Study 1001 in which patients with advanced solid tumors received escalating dacomitinib doses ranging from 0.5 mg to 60 mg (Tables 6 and 7). Dacomitinib plasma concentrations were below the limit of quantification at the 0.5 mg and 1 mg single dose levels. The PK of the major active metabolite, PF-05199265, was determined in this study. At the proposed 45 mg once daily dose, mean Cmax of 108 ng/mL reached in a median Tmax of 6 hours. Mean terminal elimination t1/2 is 70.3 hour after a single 45 mg dose. Dacomitinib accumulates upon multiple dosing with a mean accumulation ratio (Rac) of 5.7 (28%). Dacomitinib exhibits linear kinetics over the dosing range of 2 to 45 mg once daily.

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Table 6: Geometric Mean (%CV) PK Parameters of Dacomitinib on Day 1 After Single-Dose Administration (Study 1001)

+ + Dose N Cmax Tmax AUC0-72h AUC0-inf t1/2 CL/F Vz/F (mg) (ng/mL) (h) (ng·h/mL) (ng·h/mL) (h) (L/h) (L) 2 1 2.1 2 9.5 NC NC NC NC 4 1 2.7 4 21.6 NC NC NC NC 8 3 2.8 (44%) 4 (4 - 6) 64.7 NC NC NC NC 16 4 9.7 (65%) 7 (4 - 8) 328 (38%) NC NC NC NC 30 13 15.1 (35%) 6 (4 - 24) 531 (41%) 905 (59) 59.0 (28%) 33.2 (47%) 2641 (12%) 45 45 23.2 (51%) 6 (2 - 24) 950 (36%) 1810 (35%) 70.3 (21%) 24.9 (36) 2424 (31%) *60 5 NC 6 (1 - 8) 1241 (53%) NC NC NC NC **60 10 34.1 (37%) 8 (4 – 8) 1641 (78%) 3296 (64%) 81 (28%) 18.2 (17%) 2033 (54%) +Median (range) NC = Not calculated *Once daily dosing **Once daily dosing for 14 days followed by 7 days off Table 7: Geometric Mean (%CV) PK Parameters of Dacomitinib on Day 14 After Once Daily Dosing (Study 1001)

+ Dose N Cmax,ss Cmin Tmax AUC0-24h CL/F Rac (mg) (ng/mL) (ng/mL) (h) (ng·h/mL) (L/h) 1 2 1.2, 2.2 NC 6, 6 13.9, 41.6 24.0, 71.8 NC 2 3 3.9 (20%) 2.5 (19%) 4 (4 – 6) 71.8 (18%) 27.8 (18%) 6.34 (n=1) 4 3 5.5 (7%) 3.3 (21%) 4 (4 – 6) 102 (11%) 39.4 (11%) 4.37 (n=1) 8 3 9.8 (51%) 6.1 (52%) 6 (4 - 8) 186 (46%) 42.9 (38%) 4.7 (26%) 16 4 27.4 (26%) 24.7 (64%) 6 (4 - 6) 569 (28%) 28.1 (27%) 4.5 (34%) 30 9 50.9 (38%) 29.3 (50%) 4 (4 - 24) 1061 (37%) 28.3 (34%) 4.6 (19%) 45 21 108 (35%) 73.1 (45%) 6 (0 - 24) 2213 (35%) 20.4 (33) 5.7 (28%) *60 2 89, 116 58.4, 82.0 8, 24 1800, 2570 23.4, 33.4 3.6, 6.3

**60 4 105 (57%) 46.7 (74%) 5 (4 – 6) 1720 (70%) 34.9 (143%) 3.6 (5%)

+Median (range) NC=Not calculated *Once daily dosing **Once daily dosing for 14 days followed by 7 days off

Mean trough concentrations (Ctrough) were measured on Day 1 of each treatment cycle for both dacomitinib and its major active metabolite, PF-05199265, in Study 1050 in NSCLC patients who received 45 mg once daily doses of dacomitinib without interruptions or dose reductions. The data are summarized in Table 8 by treatment cycle. The geometric mean Ctrough values were similar across the cycles in each study indicating that steady-state has been reached after 10 to 14 days of dosing. Mean metabolite/parent Ctrough ratio is 20%.

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Table 8: Geometric (%CV) Trough Plasma Concentrations (Ctrough, ng/mL) for Dacomitinib and PF-05199265 following Once Daily 45 mg Oral Doses of Dacomitinib

Cycle N Dacomitinib PF-05199265 PF-05199265/PF- 05199265 Ratio (%) Cycle 2 176 70.2 (39%) 13.2 (65%) 18.8% Cycle 3 143 68.3 (38%) 14.4 (63%) 21% Cycle 4 112 68.2 (37%) 13.7 (61%) 20% Cycle 5 85 64.5 (39%) 12.5 (54%) 19% Cycle 6 74 61.7 (37%) 13.0 (50%) 21%

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

Yes, the proposed dosing regimen is acceptable for the proposed patient population.

The proposed doing regimen of dacomitinib is a starting dose of 45 mg QD with dose reductions by 15 mg decrements as needed based on individual patient tolerability to dacomitinib. The 45 mg QD dose was determined as the MTD based on phase 1 dose escalation studies and was selected for evaluation in the pivotal Phase 3 Study 1050. Study 1050 met its primary objective by demonstrating that dacomitinib was superior to gefitinib in prolonging PFS in the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR-activating mutations with a 41.4% reduction in risk of disease progression for death. The safety profile of in patients treated with dacomitinib in Study 1050 was considered manageable with an option for dose interruption/reduction based on tolerability.

Given the fact that only a single dose level was evaluated in the pivotal Study 1050 and the incidence of dose interruption/reduction was high (>60%), E-R analysis, especially for efficacy, is challenging, and therefore is unlikely to convincingly justify an alternative dose or regimen.

Significant relationships between dacomitinib exposure and safety endpoints including Grade ≥ 3 Rash/Dermatitis Acneiform, Grade ≥ 3 Other Skin Toxicities, Grade ≥ 3 diarrhea, and Grade ≥ 1 Stomatitis were observed, and suggest a higher risk of these adverse events with higher dacomitinib dose/exposure.

The exposure-response analysis for PFS based on steady-steady dacomitinib exposure or overall average dacomitinib exposure showed inverse relationships. The FDA reviewers conclude that the inverse ER relationship for PFS is biased and highly likely due to the high dose interruption/ reduction rate in the clinical studies. The exploratory E-R analysis for PFS based on dacomitinib exposure after the first dose was conducted by the FDA reviewer and the results showed a flat/slightly positive E-R relationship. Furthermore, E-R modeling for the time course of tumor size change incorporating longitudinal drug exposure based on actual doses suggested a

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positive E-R relationship between dacomitinib exposure and tumor shrinkage, and suggests a greater tumor shrinkage with higher dacomitinib dose/exposure.

In conclusion, given the significant survival benefit, it is acceptable to start treatment at 45 mg QD and adjust the dose based on individual patient tolerability as needed.

Exposure-Response (E-R) Relationships for Efficacy, Safety and QTc  E-R Relationships for Efficacy No dacomitinib exposure metrics were found to be statistically significant predictors of achieving an objective response.  E-R Relationships for Safety A significant E-R relationship between the occurrence of a Grade ≥3 AE for rash/dermatitis, acneiform, other Skin toxicity and diarrhea with Cavg of dacomitinib up to the day of the event. Refer to APPENDEX 19.4 for more detailed information of E-R relationships for efficacy and safety. QT/QTc Prolongation A summary of QTcF changes from baseline is presented in Table 9 (from the FDA IRT-QT Review). The results of the study indicate that all upper limits of the 90% CIs for the least square (LS) mean change from baseline in QTcF were <20 ms at all time points after drug administration. Thus, dacomitinib is not to prolong QTcF interval at any clinically relevant extent at therapeutic maximum concentrations expected following 45 mg once daily. Table 9: Point Estimates and 90% CIs Corresponding to the Largest Upper Bounds for Dacomitinib in ΔQTcF (FDA Analysis)

[Source: FDA’s IRT-QT review in DARRTS, Page 2]

Is an alternative dosing regimen or management strategy required for subpopulations based on intrinsic patient factors?  No dose adjustments are needed for age, race, sex, body weight, EGFR mutation status, AST and albumin concentrations.  No dose adjustments are needed for patients with mild to moderate renal impairment. Patients with severe renal impairment have not been adequately studied.  No dose adjustment is needed for patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment have not been adequately studied. 64 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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Effect of Various Covariates PopPK analyses were performed on the pooled data from clinical trials from 1381 subjects (10% healthy subjects and 90% patients with solid tumors) to evaluate the effect of various covariates on the plasma clearance (CL) of dacomitinib. . Age and Body Weight: Based on the results of these analyses, age (median [range]= 61 [20-92] years) and body weight (median [range]= 67 [30-158] kg) had no clinically relevant effects on dacomitinib CL. . Sex: Dacomitinib CL was 11.5% lower in females (n=609) than in males (n=772); this effect is not clinically relevant to warrant dosage adjustments. . Race: Dacomitinib CL was 8.5% higher in Asians (n=425) than non-Asians (n=956); this not clinically relevant to warrant dosage adjustments. . EGFR Mutation Status: EGFR mutants have 9% faster CL relative to unknown EGFR population status. EGFR wild-type exhibited a 5% slower CL relative to subjects with unknown EGFR status.; however, this effect is not clinically relevant to warrant dosing adjustments. [In the dataset contains: 31% subjects were not tested for EGFR mutation (10% of subjects were healthy subjects), 31% were EGFR-positive, 28% were EGFR wild- type and 9% were unknown] . Albumin: Baseline albumin concentrations [median (range)=4.0 (1.8-15.7) g/dL] was a significant covariate affecting dacomitinib CL; CL increased by 8% and decreased by 10% at baseline albumin concentrations of 4.6 g/dL and 3.3 g/dL, respectively. Although the effect of albumin on CL was significant, this effect is not clinically relevant to warrant dosing adjustments. . AST: Baseline AST levels (median (range)= 22 (7-195) Unit/L] was a significant factor affecting dacomitinib CL (CL increased by 3% at baseline AST levels values of 38 Unit/L). This effect is not clinically relevant to warrant dosing adjustments. . CYP2D6 Inhibitors: Fourteen subjects (1%) who are taking paroxetine had a 33% lower dacomitinib CL than those subjects who are not taking paroxetine, a strong CYP2D6 inhibitor. The formation of major active metabolite, PF-05199265, is reduced by 84% In the presence of paroxetine. Although, the concomitant use of CYP2D6 inhibitors on CL was statistically significant, the effect on CL was not considered clinically relevant to warrant dose adjustments. These results agree with those obtained from Study 1021. (Note: these 14 subjects were the same ones who were enrolled in Study 1021 to assess the effect of paroxetine on dacomitinib exposure, no other subject in the dataset was taking a CYP2D6 inhibitor). . CYP2D6 Metabolizers: In a PopPK analysis, CYP2D6 genotype-inferred phenotype was not a significant covariate affecting dacomitinib CL. Pfizer also assessed the impact of CYP2D6 genotype-inferred phenotypes on dacomitinib PK at steady state in dose- compliant patients in a combined analysis of Studies 1042 and 1050 (N=77). Blood samples for genotyping were collected from all patients enrolled in Study A7471042 or

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in the Chinese PK subgroup in Study 1050, and on an optional basis from the additional patients enrolled in in Study A7471050. CYP2D6 was genotyped for 15 alleles (*2, *3, *4, *5, *6, *7, *8. *9, *10, *14, *17, *18, *21, *36, *41) and gene duplication. According to Pfizer’s response to an Information Request (IR) sent on April 9, 2018, inference of CYP2D6 metabolizer phenotypes from genotypes was based on the Dutch Pharmacogenetics Working Group Guideline (Clin Pharmacol Ther. 2011; 89(5):662-73). CYP2D6 inferred phenotype was available from 168 patients out of 231 As-Treated patients in Study A7471042 and 20 patients in Study A7471050. Of these 168 patients, 77 had PK data. The observed distribution of CYP2D6 phenotypes in the combined analysis of Studies A7471042 and A7471050 was as follows: 6 poor metabolizers (PMs), 33 intermediate metabolizers (IMs), 35 normal (or extensive) metabolizers (NMs) and 3 ultra-rapid metabolizers (UMs.) Analysis of exposure data from Studies 1042 and 1050 in patients with NSCLC by CYP2D6 phenotype indicate that geometric mean dacomitinib

steady state AUC0-24h and Cmax,ss values were 52% and 37% higher, respectively, in patients who are CYP2D6 PMs versus patients who are CYP2D6 EMs (see Table 10 below).

Table 10: Summary of Steady State Exposure Data after 45 mg Once Daily doses of dacomitinib by CYP2D6 phenotype Groups (Studies 1042 and 1050)

*Parameter PMs IMs NMs UM (N=6) (N=33) (N=35) (N=3) Dacomitinib

Cmax,ss (ng/mL) 117 (24%) 88.9 (36%) 85.2 (52%) 62.8 (23%)

AUC0-24h (ng·h/mL) 2598 (27%) 1800 (32%) 1708 (52%) 1320 (22%) PF-05199265

Cmax,ss (ng/mL) 1.1 (58%) 7.3 (72%) 10.5 (74%) 7.5 (160%)

AUC0-24h (ng·h/mL) 24.5 (58%) 166 (73%) 222 (80%) 157 (154%) *Geometric mean (%CV)

Steady state AUC0-24h was 52% for dacomitinib and 39% higher for total drug moiety (dacomitinib + PF-05199265) in patients who are CYP2D6 PMs versus patients who are CYP2D6 NMs. No patients with PM or UM phenotypes were identified in study A7471050. As the frequency of all Grades adverse events (AEs) in study A7471042 was comparable across the of the three CYP2D6 phenotypes: NMs, IMs and PMs, no starting dose adjustment for VISIMPRO is needed for CYP2D6 PMs (Refer to Pfizer’s responses to the FDA’s Information Request [IR] dated 6/14/2018, SDN 37 in DARRTS). As per Pfizer, there was a trend toward more events for rash/dermatitis acneiform, other skin toxicity, and stomatitis in patients who were IMs and PMs compared to patients who were NMs, however the frequencies were similar across the 3 phenotypes for diarrhea. Only 3 patients identified as UMs were enrolled in Study 1042.

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clearance in the PopPK analysis, CYP2D6 phenotypes appear to have a moderate impact on dacomitinib PK, with CYP2D6 PMs having higher exposures compared to CYP2D6 NMs. Given the moderate change in PK, the similar activity of dacomitinib and the CYP2D6-derived metabolite PF-05199265, and that management of skin toxicities with dose modifications and supportive care is described in labeling, a different starting dose is not recommended for CYP2D6 PMs or for patients taking CYP2D6 strong inhibitors in labeling.

 Effect of Renal Impairment: PopPK analyses were performed on the pooled data from clinical trials to determine the effect of renal function on dacomitinib exposure. Renal function is categorized as normal (CLcr ≥ 90 mL/min, n=567), mild (CLcr=60-89 mL/min, n=590), moderate (CLcr=30-59 mL/min, n=218) and severe (CLcr < 30 mL/min, n=4)] based on creatinine clearance (CLcr) values estimated using the Kidney Disease Outcome Quality Initiative [KDOQI] staging method. The results of these analyses indicate that the renal function was not a significant covariate affecting dacomitinib CL. The renal elimination is a minor route of dacomitinib clearance; <1% of administered dose was excreted unchanged in urine.

 Effect of Hepatic Impairment: PopPK analyses were performed on the pooled data from clinical trials to determine the effect of hepatic function on dacomitinib exposure. Hepatic function is categorized as normal (N=1202), mild (N=158), moderate (N=5) and severe (N=1) based on NCI Criteria (see Pfizer’s Tables 11 and 12 below). The results of these analyses indicate that hepatic function was not a significant covariate affecting dacomitinib CL. A limited number of patients with moderate and severe hepatic impairment were enrolled in clinical trials.

Table 11: NCI Criteria of Hepatic Function

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Table 12: Dacomitinib Individual CLs in the Dataset by Hepatic Function (NCI Criteria)

Additionally, Study 1018 evaluated the effect of hepatic impairment on the exposure of dacomitinib and its major circulating O-desmethyl metabolite, PF-05199265. This was a phase 1, parallel-group, single-dose study in 25 healthy male subjects with varying degrees of hepatic function as determined by Child-Pugh classification into normal (n=8), mild (Child-Pugh class A: Score 5 – 6, n=8) and moderate (Child-Pugh class B: Score 7 – 9, n=9). The study did not enroll subjects with severe hepatic impairment (Child-Pugh class C, Score 10 -15). All subjects received a single 30 mg oral dose of dacomitinib and the PK of dacomitinib and its metabolite, PF- 05199265 was determined. A summary of PK parameters for both total and unbound dacomitinib and PF-05199265 by hepatic group is presented in Tables 13 and 14, respectively. Results of the statistical analysis of group comparisons is presented for total and unbound dacomitinib in Table 15. Table 13: Geometric Mean (%CV) PK Parameters for Total and Unbound Dacomitinib after a Single 30 mg Oral Dose Parameter Normal Hepatic Mild Hepatic Moderate Function Impairment Hepatic Impairment N 8 8 9

Cmax (ng/mL) 12.68 (33%) 13.12 (50%) 10.15 (32%)

Cmax,u (ng/mL) 0.200 (36%) 0.253 (52%) 0.185 (26%)

+ Tmax (h) 8 (6 – 24) 8 (6 – 12) 6 (1 – 12)

AUC0-last (ng·h/mL) 688 (38%) 684 (30%) 500 (36%)

AUC0-last,u (ng·h/mL) 10.87 (36%) 13.16 (41%) 9.12 (46%)

AUC0-inf (ng·h/mL) 805 (40%) 811 (29%) 682 (33%)

AUC0-inf,u (ng·h/mL) 12.71 (37%) 15.64 (41%) 12.46 (37%) ++ t1/2 (h) 59.5 (42%) 72.9 (58%) 92.2 (46%) CL/F (L/h) 37.3 (41%) 37.0 (34%) 43.9 (39%)

Vz/F (L) 2943 (48%) 3413 (45%) 5291 (35%)

fu (%) 1.59 (16%) 1.96 (21%) 1.87 (22%) +Median (range) ++ Arithmetic mean

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Table 14: Geometric Mean (%CV) PK Parameters for Total and Unbound PF-05199265 after a Single 30 mg Oral Dose of Dacomitinib

Parameter Normal Hepatic Mild Hepatic Moderate Function Impairment Hepatic Impairment N 8 8 9

Cmax (ng/mL) 1.02 (84%) 3.53 (107%) 1.59 (66%)

Cmax,u (ng/mL) 0.00034 (85%) 0.00050 (196%) 0.00035 (61%)

+ Tmax (h) 4 (4 – 6) 6 (3 – 8) 12 (6 – 72)

AUC0-last (ng·h/mL) 252 (95%) 199.9 (113%) 145 (58%)

AUC0-last,u (ng·h/mL) 0.0085 (100%) 0.028 (204%) 0.032 (56%)

AUC0-inf (ng·h/mL) 349 (64%) 216 (110%) 198 (54%)

AUC0-inf,u (ng·h/mL) 0.038 (70%) 0.031 (202%) 0.037 (69%) ++ t1/2 (h) 60.9 (21%) 65.8 (21%) 90.0 (16%)

fu (%) 0.0107 (28%) 0.0161 (69%) 0.0249 (62%) +Median (range) ++ Arithmetic mean

Table 15: Statistical Summary of Hepatic Group Comparison for Total and Unbound Dacomitinib

Parameter Mild hepatic Normal hepatic *Ratio 90% CI Impairment Function (Mild/Normal)

Cmax (ng/mL) 13.12 12.68 103% (69%, 153%)

Cmax,u (ng/mL) 0.253 0.200 126% (83%, 192%)

AUC0-inf (ng·h/mL) 811 805 100% (73%, 138%)

AUC0-inf,u (ng·h/mL) 15.64 12.71 123 (86%, 175%) Parameter Moderate hepatic Normal hepatic *Ratio 90% CI impairment Function (Moderate/Normal)

Cmax (ng/mL) 10.15 12.68 80% (54%, 117%)

Cmax,u (ng/mL) 0.185 0.200 92% (61%, 139%)

AUC0-inf (ng·h/mL) 682 805 85% (62%, 115%)

AUC0-inf,u (ng·h/mL) 12.46 12.71 98% (69%, 138%) *Ratio of adjusted geometric means (test/reference)

Geometric mean AUC0-inf and Cmax values for total dacomitinib were comparable between the subjects with mild hepatic impairment and those with normal hepatic function; however, these parameters were about 15% and 20% lower, respectively, in subjects with moderate hepatic impairment than in subjects with normal hepatic function. Approximately 1.6–2.0% of

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dacomitinib was unbound in plasma of subjects across all hepatic groups. The geometric mean unbound dacomitinib Cmax,u and AUC0-inf,u values were comparable between subjects with mild to moderate hepatic impairment and those with normal hepatic function. The same trend was noted for PF-05199265. Subjects in the normal hepatic function group or the mild hepatic impairment group did not experience any adverse events (AEs). One subject in the moderate hepatic impairment group died due to a road traffic accident. This death was classified as an SAE and considered to be severe but was not treatment-related (see Pfizer’s table below).

Based on these results, no dosage adjustment is recommended in patients with mild to moderate hepatic impairment. A PMR was issued to assess the effect on severe hepatic impairment on dacomitinib exposure, as dacomitinib is extensively metabolized by the liver (79% excreted in feces).

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

Food did not significantly affect dacomitinib exposure. Dacomitinib is recommended to be taken with or without food. Effect of food Study 1015 assessed the effect of food on dacomitinib exposure. This was a phase 1, open- label, randomized, single dose, 2-sequence, and 3-period crossover study in 24 healthy male subjects. Subjects received a single 45 mg dose of dacomitinib under the following conditions: overnight fast, high-fat/high-calorie breakfast and with a protein pump inhibitor (PPI), rabeprazole, with a washout period of 2 weeks between treatments as shown in Pfizer’s table below.

A high-fat (approximately 50% of total caloric content of the meal)/high-calorie (approximately 800-1000 Calories with 150, 250, and 500-600 Calories from protein, carbohydrate and fat, respectively) breakfast was taken 30 minutes prior to administration of dacomitinib. The high- fat/high-calorie breakfast consisted of fried eggs, bacon strip, slice bread, butter pat, hash 70 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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browned potatoes, and whole milk. Serial blood samples were collected up to 264 hours after dosing on Day 1 of each treatment period to determine the plasma PK of dacomitinib and its metabolite, PF-05199265. A summary of PK parameters for dacomitinib and PF-05199265 is presented in Tables 16 and 17, respectively. Results of the statistical analysis of group comparisons are presented for dacomitinib in Table 18. Table 16: Geometric Mean (%CV) PK Parameters for Dacomitinib after a Single 45 mg Oral Dose to Healthy Subjects (Study 1015) Parameter High-fat/High-calorie Overnight Fast Breakfast N, n 24, 21 24, 22

Cmax (ng/mL) 21.97 (30%) 17.77 (50%) + Tmax (h) 8 (6 – 24) 8 (6 – 24)

AUC0-inf (ng·h/mL) 1405 (35%) 1234 (36%) ++ t1/2 (h) 67.2 (16%) 67.2 (24%) CL/F (L/h) 32.0 (34%) 36.5 (36%)

Vz/F (L) 3058 (29%) 3432 (30%) +Median (range) ++ Arithmetic mean

Table 17: Geometric Mean (%CV) PK Parameters for PF-05199265 after a Single 30 mg Oral Dose of Dacomitinib in Healthy Subjects (Study 1015)

Parameter High-fat/High-calorie Overnight Fast Breakfast N, n 24, 21 24, 22

Cmax (ng/mL) 8.6 (71%) 9.5 (76%) + Tmax (h) 6 (4 – 24) 4 (3.9 – 24)

AUC0-inf (ng·h/mL) 613 (57%) 577 (59%) +Median (range)

Table 18: Statistical Summary of Treatment Comparison for Food Effect (Study 1015)

Parameter Fed Fasted *Ratio (Fed/Fasted) 90% CI

Cmax (ng/mL) 21.97 17.77 124% (104%, 145%)

AUC0-inf (ng·h/mL) 1405 1234 114% (105%, 124%) *Ratio of adjusted geometric means (test/reference)

Geometric mean AUC0-inf and Cmax values for dacomitinib increased by about 14% and 24%, respectively, when dacomitinib is administered with a high-fat/high calorie breakfast compared 71 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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to the fasted condition. The adjusted geometric mean ratios (90% CIs) for dacomitinib AUC0-inf and Cmax in the fed state compared to the fasted state were 114% (104%, 124%) and 124% (105%, 145%), respectively. Inter-subject variability (%CV) in AUC0-inf was about 35%, whereas for Cmax, it ranged from 30-50% with or without food. Mean AUC0-inf and Cmax values for PF- 05199265 are comparable whether dacomitinib was taken with or without food.

In summary, the increase in dacomitinib exposure (AUC0-inf and Cmax) with high-fat/high calorie breakfast is not considered clinically relevant and dacomitinib can be administered with or without food. Regarding the use of PPIs, antacids and H2-receptor antagonists the following dose modifications are recommended:

 PPIs: Rabeprazole, a PPI, decreased the geometric mean Cmax and AUC0-inf of dacomitinib by 50% and 30%, respectively, following a single 45 mg oral dose in healthy male subjects. Concomitant use of PPIs with dacomitinib is to be avoided.

 Antacids: Maalox® did not significantly influence the mean Cmax or AUC0-inf of dacomitinib following a single 45 mg dose in patients with advanced solid tumors. There is no need to delay dacomitinib dosing when it must be co-administered with antacids. . H2-receptor antagonists: No study has been conducted with H2-receptor antagonists. VIZIMPRO is to be administered at least 6 hours before or 10 hours after taking an H2- receptor antagonist. Effect PPIs The solubility of dacomitinib is pH-dependent being highly water soluble at low pH (>80% dissolved within 15 minutes at pH ranging between 2.1 and 4.5) and demonstrates a marked decrease in its aqueous solubility as pH goes above 4.5. As per the Biopharmaceutics Classification System (BCS), dacomitinib is a class II compound, which is highly permeable but poorly water soluble. For Class II compounds, where solubility is pH-dependent, the administration of gastric pH elevating agents may affect drug absorption. The effect of rabeprazole (a PPI) on dacomitinib exposure was evaluated in 24 healthy male subjects as described above (Study 1015 above). Subjects were administered dacomitinib single 45 mg dose in the fasted state on Day 1 with rabeprazole 40 mg orally once daily on Days -5 to Day 1 (7 days). As per the product’s label, rabeprazole at the 40 mg once daily doses for 7 days significantly decreased intra-gastric acidity with a maximum acid suppression occurring around 12 hours after dosing on Day 1 of each period. A summary of PK parameters for dacomitinib and PF-05199265 is presented in Tables 19 and 20, respectively. Results of the statistical analysis of group comparisons are presented for dacomitinib in Table 21.

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Table 19: Geometric Mean (%CV) PK Parameters for Dacomitinib after a Single 45 mg Oral Dose With or Without Rabeprazole 40 mg Once Daily for 7 Days to Healthy Subjects (Study 1015) Parameter Dacomitinib + Rabeprazole Dacomitinib Alone

N, n 24, 14 24, 22

Cmax (ng/mL) 8.79 (54%) 17.77 (50%) + Tmax (h) 12 (8 – 48) 8 (6 – 24)

AUC0-inf (ng·h/mL) 877 (37%) 1234 (36%) ++ t1/2 (h) 62.5 (42%) 67.2 (24%) CL/F (L/h) 49.2 (37%) 36.5 (36%)

Vz/F (L) 4151 (26%) 3432 (30%) +Median (range) ++ Arithmetic mean

Table 20: Geometric Mean (%CV) PK Parameters for PF-05199265 after a Single 45 mg Oral Dose of Dacomitinib in Healthy Subjects With or Without Rabeprazole 40 mg Once Daily for 7 Days to Healthy Subjects (Study 1015)

Parameter Dacomitinib + Rabeprazole Dacomitinib Alone

N, n 24, 14 24, 22

Cmax (ng/mL) 5.82 (92%) 9.48 (76%) + Tmax (h) 8 (4 – 24) 4 (3.9 – 24)

AUC0-inf (ng·h/mL) 422 (41%) 577 (59%) +Median (range)

Table 21: Statistical Summary of Treatment Comparison for Rabeprazole Effect (Study 1015)

Parameter Dacomitinib + Dacomitinib Alone *Ratio 90% CI Rabeprazole (Reference) (Test/Reference) (Test)

Cmax (ng/mL) 8.79 17.77 49.5% (40%, 60%)

AUC0-inf (ng·h/mL) 877 1234 71% (62%, 82%) *Ratio of adjusted geometric means (test/reference)

Geometric mean AUC0-inf and Cmax values for dacomitinib decreased by about 29% and 50%, respectively, when dacomitinib is administered with rabeprazole compared to dacomitinib alone. The adjusted geometric mean ratios (90% CIs) for dacomitinib AUC0-inf and Cmax when given with rabeprazole compared to dacomitinib alone were 71% (62%, 82%) and 49.5% (40%, 73 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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60%), respectively. Inter-subject variability (%CV) in AUC0-inf and Cmax was about 37% and 54%, respectively, when dacomitinib is administered alone or with rabeprazole.

Geometric mean AUC0-inf and Cmax values for PF-05199265 decreased by about 27% and 38%, respectively, when dacomitinib is administered with rabeprazole compared to dacomitinib alone. In summary, the concomitant administration of rabeprazole (40 mg once daily for 7 days), a PPI, with dacomitinib decreased the geometric mean AUC0-inf and Cmax of dacomitinib by about 29% and 50%, respectively; therefore, administration PPIs with dacomitinib are to be avoided. Effect of Antacids In Study 1001, eight patients with advanced solid tumors were administered a single 20 mL dose of magnesium oxide liquid (400 mg/5 mL, Maalox® Maximum Strength) on the fasted state. A summary of PK parameters for dacomitinib is presented in Table 22. Results of the statistical analysis of group comparisons are presented for dacomitinib in Table 23. PF- 05199265 plasma concentrations were not measured in Study 1001. Table 22: Geometric Mean (%CV) PK Parameters for Dacomitinib after a Single 45 mg Oral Dose With or Without 20 mL of Maalox® (400 mg/5 mL) to Patients with Solid Tumors (Study 1001) Parameter Dacomitinib + Maalox® Dacomitinib Alone

N 8 8

Cmax (ng/mL) 19.24 (42%) 21.97 (52%) + Tmax (h) 8 (4 – 24) 5 (4 – 8)

AUC0-inf (ng·h/mL) 1653 (34%) 1576 (42%) ++ t1/2 (h) 68.7 (27%) 59.4 (26%) CL/F (L/h) 29.8 (53%) 31.1 (45%)

Vz/F (L) 2868 (50%) 2511 (34%) +Median (range) ++ Arithmetic mean

Table 23: Statistical Summary of Treatment Comparison for Maalox® Effect (Study 1001) Parameter Dacomitinib With Dacomitinib Alone *Ratio 90% CI Maalox® (Reference) (Test/Reference) (Test)

Cmax (ng/mL) 19.24 21.97 88% (62%, 124%)

AUC0-inf (ng·h/mL) 1653 1576 105% (81%, 136%) *Ratio of adjusted geometric means (test/reference)

The geometric mean Cmax for dacomitinib decreased by about 12% when dacomitinib was administered with Maalox® compared to dacomitinib alone while the AUC0-inf was comparable 74 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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for both treatments. Inter-subject variability (%CV) in AUC0-inf and Cmax ranged from 34-42% and 42-52%, respectively, when dacomitinib is administered with or without Maalox®. PF-05199265 plasma concentrations were not measured in Study 1001. In summary, the concomitant administration of antacid (Maalox® Maximum Strength) had no clinically relevant effect of dacomitinib exposure, and dacomitinib can be administered with or without antacids. The effect of H2-receptor antagonists (e.g., cimetidine, ranitidine, famotidine and nizatidine) on dacomitinib exposure has not been studied. VIZIMPRO is to be administered at least 6 hours before or 10 hours after taking an H2-receptor antagonist.

Regarding DDI potential, the following dose modifications are recommended:  Strong CYP2D6 inhibitors: Paroxetine, a strong CYP2D6 inhibitor, increased the geometric mean AUC0-inf of total active moiety (dacomitinib + PF-05199265) by 6%, which is not considered clinically relevant. Therefore, no adjustment in the VISIMPRO starting dose when a strong CYP2D6 inhibitor is administered concomitantly.  Sensitive CYP2D6 substrates: Dacomitinib, a strong CYP2D6 inhibitor, increased geometric mean AUC0-inf of dextromethorphan, a CYP2D6 substrate, by 362% and its Cmax by 973 in healthy male subjects. The concomitant use of CYP2D6 substrates with a narrow therapeutic index with dacomitinib is to be avoided. If these agents cannot be avoided, a dose reduction or substitution of the CYP2D6 substrate may be needed. Effect of CYP2D6 Inhibitors on Dacomitinib Study 1021 evaluated the effect of paroxetine, a strong CYP2D6 inhibitor, on dacomitinib exposure. This was a phase 1, single-sequence, two-period, single-dose study in 14 healthy male subjects. Only extensive male metabolizers were enrolled in the study. Subsects received a single 45 mg dose of dacomitinib on Day 1 of Period 1. During Period 2, subjects received a single 30 mg dose of paroxetine once daily for 3 days in the fasted state. On Day 4, subjects were coadministered a single 45 mg dose of dacomitinib plus a single 30 mg dose of paroxetine in the fasted state. There was a 21-day washout period between dose administration in Periods 1 and 2. Paroxetine 30 mg was administered once daily for the next 6 days (a total of 10 days). As per paroxetine labeling, a dose of 20 mg to 60 mg is considered safe and efficacious. The 30-mg paroxetine dose was selected to be used in this study because it falls with the range shown to be clinically active for the treatment of major depressive disorder and at which also the CYP2D6 activity appears to be saturated. Serial plasma samples to determine plasma concentrations of dacomitinib and its metabolite, PF-05199265, were collected up to 240 hours after dosing on Day 1 of Period 1 and on Day 4 of Period 2. A summary of PK parameters for dacomitinib and PF-05199265 is presented in Tables 24 and 25, respectively. Results of the statistical analysis of group comparisons are presented for dacomitinib in Table 26.

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Table 24: Geometric Mean (%CV) PK Parameters for Dacomitinib after a Single 45 mg Oral Dose in the Presence or Absence of Paroxetine 30 mg Once Daily for 10 Days to Healthy Subjects (Study 1021) Parameter Dacomitinib + Paroxetine Dacomitinib Alone

N, n 14, 11 14, 14

Cmax (ng/mL) 18.42 (47%) 16.79 (42%) + Tmax (h) 8 (6 – 24) 10 (6 – 24)

AUC0-inf (ng·h/mL) 1943 (25%) 1415 (26%) ++ t1/2 (h) 96.2 (20%) 90.1 (27%) CL/F (L/h) 23.2 (37%) 31.8 (50%)

Vz/F (L) 3167 (36%) 4005 (33%) +Median (range) ++ Arithmetic mean

Table 25: Geometric Mean (%CV) PK Parameters for PF-05199265 after a Single 45 mg Oral Dose of Dacomitinib in Healthy Subjects With or Without Paroxetine 30 mg Once Daily for 10 Days to Healthy Subjects (Study 1021)

Parameter Dacomitinib + Paroxetine Dacomitinib Alone

N, n 14, 2 14, 14

+ Cmax (ng/mL) 0.74 (0.20 – 1.84) 5.05 (48%) +5.14 (2.2 – 9.65) + Tmax (h) 3.5 (3 – 8) 4 (4 – 12)

AUC0-inf (ng·h/mL) 359 (40%) +38.45 (36.1 – 40.8) +360.5 (189 – 629) +Median (range)

Table 26: Statistical Summary of Treatment Comparison for Paroxetine Effect (Study 1021)

Parameter Dacomitinib + Dacomitinib Alone *Ratio 90% CI Paroxetine (Reference) (Test/Reference) (Test)

Cmax (ng/mL) 18.42 16.79 110% (83%, 145%)

AUC0-inf (ng·h/mL) 1943 1415 137% (109%, 172%) *Ratio of adjusted geometric means (test/reference)

Geometric mean AUC0-inf and Cmax values for dacomitinib increased by about 37% and 10%, respectively, when dacomitinib is administered with paroxetine compared to dacomitinib alone. The adjusted geometric mean ratios (90% CIs) for dacomitinib AUC0-inf with paroxetine 76 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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compared to dacomitinib alone was 137% (109%, 172%). The adjusted geometric mean ratio (90% CI) for Cmax for dacomitinib with paroxetine compared to dacomitinib alone was 110% (83%, 145%). Inter-subject variability (%CV) in AUC0-inf and Cmax was about 26% and 47%, respectively, when dacomitinib is administered with or without paroxetine.

The median AUC0-inf and Cmax values for PF-05199265 were reduced by about 90% and 85%, respectively, when dacomitinib is administered with paroxetine compared to dacomitinib alone. Although paroxetine significantly inhibited CYP2D6-mediated metabolism of dacomitinib, this metabolic pathway is not the primary route of elimination of dacomitinib. In addition to CYP2D6 metabolism, dacomitinib undergoes glutathione conjugation and CYP3A4 metabolism to form other minor inactive metabolites. As indicated in Pfizer’s response to the FDA’s IR dated 6/13/2018 (SDN 36), CYP2D6 mediated metabolism of dacomitinib [fm(2D6)] is estimated to be less than 20% of the overall metabolism of dacomitinib following multiple dosing. In addition, the results from Study 1021 showed only a 6% increase in AUC0-last of total drug moiety (dacomitinib + PF-05199265) for dacomitinib in combination with paroxetine compared to dacomitinib alone, which was considerably less than the observed impact on parent drug (dacomitinib) alone (i.e., 37%). Pfizer re-analyzed the PK data from Study 1021 to include the effect of paroxetine on the exposure to the total drug moiety (parent + metabolite) (Table 27 below). Table 27: Summary of Statistical Treatment Comparisons of Total Drug Moiety (Dacomitinib + PF-05199265)

Therefore, based on the small contribution of CYP2D6 to the overall dacomitinib metabolism and the results from the drug interaction study showing no clinically relevant effect of paroxetine on total active moiety exposure, a dose adjustment is not needed when VISIMPRO is coadministered with a strong CYP2D6 inhibitor. Paroxetine plasma samples were also collected during Study 1021 prior to dosing on Day 4 and up to 24 hours after dosing to determine the effect of dacomitinib, a strong CYP2D6 inhibitor, on paroxetine exposure, a CYP2D6 substrate as per FDA’s request during the EOP2 meeting on 6/30/2009 (IND 72,775). The metabolism of paroxetine is partially mediated through CYP2D6 and through glucuronide and sulfate conjugations (as per approved Paxil® package insert).

The mean AUC0-24h and Cmax,ss values of 884 ng·h/mL and 50.4 ng/mL, respectively, determined for paroxetine in Study 1021 were comparable to those reported in literature following once

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daily 30 mg oral doses for 10 days (Table 28). This indicate that dacomitinib single 45 mg dose has no effect on paroxetine exposure. Table 28: Geometric Mean (%CV) PK Parameters for Paroxetine 30 mg Once Daily Oral Doses (Study 1021) Compared to Historical Data Parameter Paroxetine + Dacomitinib *Historical Data (Study 1021)

Cmax (ng/mL) 50.4 (39%) 61.7 (42%) + Tmax (h) 6 (4 – 8) 5 (2 – 6)

AUC0-24h (ng·h/mL) 884 (39%) 1020 (26%) CL/F (L/h) 33.9 (61%) 31.8 (50%) *[Heydorn, WE, Exp. Opin. Invest. Drugs (1999) 8(4):417-441] & Paxil® Label, GlaxoSmithKline +Median (range) In summary, the concomitant administration of paroxetine (30 mg once daily for 10 days), a strong CYP2D6 inhibitor, increased mean AUC0-inf of the total active moiety (dacomitinib + PF- 05199265) by 6% which is not clinically relevant. Therefore, no dose adjustment is needed when VISIMPRO is coadministered with a strong CYP2D6 inhibitor. Effect of Dacomitinib on CYP2D6 Substrates Study 1039 evaluated the effect of dacomitinib, a strong CYP2D6 inhibitor, on dextromethorphan (a CYP2D6 probe substrate) exposure. This was a randomized, 2-period, 2- treatment, 2-sequence, single-dose cross-over study in 14 healthy male subjects. Only extensive male metabolizers were enrolled in the study. Subjects were randomized to receive either of the following two treatments with at least 14-day washout period:  Treatment A: A single 30 mg oral dose of dextromethorphan  Treatment B: A single 45 mg oral dose of dacomitinib followed 4 hours later by a single 30 mg oral dose of dextromethorphan. Plasma samples for PK analysis of dextromethorphan and its metabolite, dextrorphan, were collected at pre-dose and up to 48 hours after dosing on Day 1 of Treatment A and at pre-dose and up to 52 hours after dosing on Day 1 of Treatment B. A summary of PK parameters for dextromethorphan and dextrorphan is presented in Tables 29 and 30, respectively. Results of the statistical analysis of group comparisons are presented in Table 31 for dextromethorphan.

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Table 29: Geometric Mean (%CV) PK Parameters for Dextromethorphan after a Single 30 mg Oral Dose With or Without Dacomitinib 45 mg Single Dose in Healthy Subjects (Study 1039) Parameter Dextromethorphan + Dextromethorphan Dacomitinib Alone N, n 14, 9 14, 3

Cmax (ng/mL) 6.62 (109%) 0.68 (190%) + Tmax (h) 3 (2 – 4) 5.9 (2 – 6)

AUC0-tlast (ng·h/mL) 52.6 (148%) 5.51 (420%)

AUC0-inf (ng·h/mL) 87.27 (72%) 24.13 (118%) ++ t1/2 (h) 8.4 (20%) 9.8 (30%) CL/F (L/min) 5.85 (72%) 15.9 (118%)

Vz/F (L) 4206 (54%) 13110 (90%) +Median (range) ++ Arithmetic mean

Table 30: Geometric Mean (%CV) PK Parameters for Dextrorphan after a Single 45 mg Oral Dose of Dacomitinib in Healthy Subjects With or Without Dacomitinib 45 mg Single Dose in Healthy Subjects (Study 1039) Parameter Dextromethorphan + Dextromethorphan Dacomitinib Alone N, n 14, 14 14, 10

Cmax (ng/mL) 223.6 (39%) 273.4 (20%) + Tmax (h) 3 (2 – 6) 3 (2 – 4)

AUC0-inf (ng·h/mL) 1935 (29%) 2239 (20%)

++ t1/2 (h) 6.90 (23%) 5.51 (23%) +Median (range) ++Arithmetic mean

Table 31: Statistical Summary of Treatment Comparison for Effect of Dacomitinib on Dextromethorphan (Study 1039)

†Ratio of adjusted geometric means * Adjusted geometric mean values

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Geometric mean AUC0-inf and Cmax values for dextromethorphan increased by about 362% and 973%, respectively, when dextromethorphan was administered with dacomitinib compared to dextromethorphan alone. Inter-subject variability (%CV) in AUC0-inf and Cmax ranged from 148- 420% and 109-190%, respectively, and were similar across treatments.

The geometric mean Cmax for dextrorphan decreased by about 18% whereas, the geometric mean AUC0-inf was comparable when dextromethorphan is administered with dacomitinib compared to dextromethorphan alone. To determine the potential inhibitory effect of an investigational drug on CYP450 enzymes, the FDA drug-interaction guidance recommends that multiple doses of study drug be used in DDI studies to fully inhibit or induce a certain enzyme. However, in Study 1039, a single 45 mg dose of dacomitinib was used because administration of multiple doses of dacomitinib to healthy subjects is not recommended. While Study 1039 did not explore the effects of dacomitinib in subjects within the other CYP2D6 metabolizer categories (ultra-rapid, intermediate or poor), the results from this study would indicate the worst-case scenario, as the inhibitory effect of dacomitinib on poor or intermediate metabolizers would be expected to be less than the effect on extensive metabolizers. In summary, the concomitant administration of dacomitinib (single 45 mg oral dose), a strong CYP2D6 inhibitor, with dextromethorphan (single 30 mg oral dose), a probe CYP2D6 substrate, increased the geometric mean AUC0-inf and Cmax of dextromethorphan by about 362% and 973%, respectively; therefore, administration sensitive CYP2D6 substrates and those with narrow therapeutic index with dacomitinib are to be avoided.

Safaa Burns Jeanne Fourie Zirkelbach Primary Reviewer Team Leader

Robert Schuck Rosane Charlab Orbach Genomics Reviewer Genomics Team Leader

Xiaofeng Wang______Jiang Liu______Pharmacometrics Reviewer Pharmacometrics Team Leader

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7 Sources of Clinical Data and Review Strategy

APPEARS THIS WAY ON ORIGINAL

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7.1 Table of Clinical Studies

Table 32 lists the clinical studies included in the NDA submission. The primary evidence to substantiate the claims of safety and efficacy of dacomitinib is from the randomized trial entitled ARCHER 1050: A Randomized, Open-Label, Phase 3, Efficacy and Safety Study of Dacomitinib (PF-00299804) Versus Gefitinib for the First Line Treatment of Locally Advanced or Metastatic Non-Small Cell Lung Cancer in Subjects with Epidermal Growth Factor Receptor (EGFR) Activating Mutation(s)”, hereafter referred to as ARCHER 1050.

The results of ARCHER 1050 are supported by subgroup analyses of patients with EGFR mutation-positive NSCLC enrolled in Studies A7471017, A7471009, and A7471011 (see Table 32 for details).

The submission includes an assessment of safety from pooled analyses of patients with any line of treatment EGFR mutation- positive NSCLC treated at the recommended 45 mg dose of dacomitinib enrolled in five studies (Pool A, n=394) and of patients with NSCLC unselected for EGFR-activating mutations treated at the 45 mg dose enrolled in ten studies (Pool B, n=1473).

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Table 32: Listing of Clinical Trials Relevant to this NDA

Trial NCT no. Trial Design Regimen/ Study Endpoints Treatment No. of patients Study No. of Centers and Identity schedule/ route Duration/ enrolled Population Countries Follow Up Controlled Studies to Support Efficacy and Safety A7471050 01774721 Multinational, Dacomitinib 45 PFS by BIRC Treatment Dacomitinib Adult 90 study centers randomized mg orally daily ORR until un- N=227 patients worldwide: (1:1), versus OS by acceptable with China (21 sites), controlled trial Gefitinib 250 mg toxicity, Gefitinib newly Hong Kong (2 sites), orally daily tumor N=225 diagnosed Italy (13 sites), progression, stage Japan (10 sites), or death IIIB/IV or Poland (3 sites), recurrent Rep. of Korea (5 NSCLC + for sites), EGFR- Spain (17 sites). activating mutation exon 19 deletion or the L858R mutation in exon 21 A7471017 00818441 Multi-center, Dacomitinib 30- PFS at 4months Treatment Dacomitinib Adult 25 centers in Hong open-label, mg or 45-mg BOR, DOR, PFS, until un- N=89 patients Kong, Japan, single-arm orally daily and PS acceptable with Korea, Taiwan, and study toxicity, advanced United States tumor NSCLC progression, (Stage IIIB- or death IV), adenocarcin oma subtype 83 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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A7471009 02382796 Multicenter, Dacomitinib 45- PFS, OS, ORR, Treatment Dacomitinib Patients 134 centers in the randomized mg orally daily and DOR until un- N=439 with following countries: controlled, Erlotinib 150 mg acceptable Erlotinib advanced Austria, Belgium, double blinded orally daily toxicity, N=439 NSCLC China, Denmark, trial of tumor Finland, France, dacomitinib progression, Germany, Greece, versus or death Hungary, India, erlotinib Ireland, Japan, Republic of Korea, Mexico, Poland, Russia Federation, Slovakia, South Africa, Spain, Sweden, Switzerland, the United Kingdom, and the United States A7471011 01000025 Double-blind, Dacomitinib 45- OS, PFS, and ORR Treatment Dacomitinib Advanced 91 centers in randomized mg orally daily until un- N=477 NSCLC Argentina, Australia, placebo- Placebo control acceptable Placebo Brazil, controlled trial toxicity, N=239 Canada, Italy, the of dacomitinib tumor Republic of Korea, progression, New Zealand, Peru, or death the Philippines, Taiwan, Thailand, and the United States (US)

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Studies to Support Safety Pool A 1050 01774721 See above 1009 02382796 See above 1011 01000025 See above 1017 00818441 See above 1028 00769067 Open-label RCT Dacomitinib 45- PFS, ORR, OS Treatment Dacomitinib Advanced 47 centers in of dacomitinib mg orally daily until un- N=93 NSCLC Australia; Brazil; versus acceptable Erlotinib previously Canada; Hong Kong; erlotinib Erlotinib 150-mg toxicity, N=94 treated with Korea, Republic of; orally daily tumor at least 1 Poland; Puerto Rico; progression, but no more Singapore; Spain; or death than 2 Taiwan; United regimen(s) Kingdom; United of systemic States chemo- therapy. Pool B 1050 01774721 See above 1009 02382796 See above 1011 01000025 See above 1017 00818441 See above 1028 00769067 See above 1001 00225121 Multi-center, Dose escalation To determine the Treatment Dacomitinib Patients 3 centers in the open-label of dacomitinib MTD of a until un- N=121 with United States and 1 dose continuous acceptable advanced in the Netherlands escalation dosing schedule toxicity, malignant study of tumor solid dacomitinib Arm A: ORR in progression, tumors. patients with or death adenocarcinoma Arm B: ORR in

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patients with non- adenocarcinoma

1002 00548093 Multi-center, Dacomitinib 45 Phase 1: To Treatment Arm A N=50 Patients 6 United States open-label mg orally daily define the until un- Arm B N=16 with centers study in RP2D dose. acceptable advanced patients with toxicity, adenocarcin KRAS wild-type Phase 2: PFS at 4 tumor oma and NSCLC who months. progression, non- had failed at or death adenocarcin least 1 oma who chemo-therapy had failed regimen and chemothera erlotinib. py and erlotinib

1003 00553254 Multi-center, Phase 1 30- To evaluate the Treatment N=55 KRAS 3 centers: Korea open-label, 45 mg QD and safety and until un- wild-type single-arm, Phase 2: 45 mg tolerability of acceptable Stage IIIb/IV Phase 1/2 QD dacomitinib toxicity, NSCLC study of when tumor refractory to single-agent administered in progression, at least 1 dacomitinib combination or death chemothera with py regimen figitumumab. and gefitinib or erlotinib.

1004 00728390 Multicenter, Dacomitinib: To evaluate the Treatment N=71 Patients 4 centers: US (2), open-label, (Route: oral; safety and until un- with France, Spain

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Phase 1 Dose Regimen: tolerability of acceptable advanced study 10, 15, 20, or dacomitinib in toxicity, malignant evaluating 30 mg QD) Japanese tumor solid escalating Figitumumab: patients at doses progression, tumors doses (Route: IV; used or death of dacomitinib Dose Regimen: non-Japanese in combination 10 or 20 mg/kg studies with every 3 weeks) figitumumab.

1005 00783328 Single-center, Dacomitinib - Treatment N=13 Japanese 1 center: Japan open-label, 15 mg QD, until un- patients dose 30 mg QD, and acceptable with escalation 45 mg QD) toxicity, advanced Phase 1 clinical tumor malignant study. progression, solid tumors or death

First Line Pool 1050 See above 1009 See above 1011 See above 1017 See above 1028 See above

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7.2 Review Strategy

The review of efficacy focused on a detailed review and analysis of data for the following:  ARCHER 1050 (n=452),  Cohort A of Study 1017 (n=45),  EGFR-positive subset of Study 1009 (n=76), and  EDGR-positive subset of Study 1011 (n=135).

The review of safety focused on ARCHER 1050 (n=227), Pool A (n=394) and Pool B (n=1473). Cohort A of Study 1017 is included in Pool B.

The statistical and clinical reviews of safety and efficacy included the following:  Review of current literature in NSCLC and treatment of NSCLC  Review of the ARCHER study, including CSR, case report forms (CRFs), protocol, protocol amendments, statistical analysis plan (SAP), and SAP amendments  Review and assessment of Pfizer analyses of dacomitinib safety and efficacy in the CSR  Review of datasets submitted as SAS transport files and SAS programs  Review of patient narratives of serious adverse events and deaths  Review of minutes of key meetings conducted during dacomitinib development for NSCLC  Review and assessment of the Module 2 and Module 5 summaries, including the Summary of Clinical Efficacy, Summary of Clinical Safety, Integrated Summary of Efficacy, and Integrated Summary of Safety Requests of additional information from Pfizer and review of Pfizer responses  Formulation of the benefit-risk analysis and recommendations  Review and editorial changes and comments to the proposed labeling

8 Statistical and Clinical Evaluation

8.1 Review of Relevant Individual Trials Used to Support Efficacy

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8.1.1 ARCHER 1050: A randomized, open label, phase 3, efficacy and safety study of dacomitinib (PF-00299804) versus gefitinib for the first line treatment of locally advanced non-small cell lung cancer in subjects with epidermal growth factor receptor activating mutations

Trial Design

ARCHER 1050 is a randomized, open-label, multinational active-controlled trial comparing dacomitinib to gefitinib for the treatment of patients with EGFR mutation-positive (exon 19 deletion or exon 21 L858R mutation) newly diagnosed stage IIIB/IV (based on Union for International Cancer Control (UICC) staging system version 7) or recurrent NSCLC. Patients with recurrent NSCLC must have only completed neoadjuvant/adjuvant therapy previously and have had a minimum 12-month disease-free interval between completion of prior systemic therapy (adjuvant or neoadjuvant or therapy for earlier stages of NSCLC) and recurrence of NSCLC. Approximately 450 patients were randomized (in a 1:1 ratio) to 1 of 2 treatment arms: dacomitinib (n=227) (45 mg orally once daily) or gefitinib (n=225) (250 mg orally once daily). Randomization was stratified by two factors: race (Japanese vs mainland Chinese vs other East Asian vs non-Asian) and EGFR mutation status (exon 19 deletion vs exon 21 L858R mutation). Treatment was on both arms was with continuous daily dosing on a 28-day cycle until disease progression or intolerable toxicity.

Reviewer’s Comment: The criteria used by the Union for International Cancer Control staging system v7 is similar to the staging criteria used by the American Joint Committee on Cancer (AJCC).

Study Endpoints

The primary endpoint is PFS as determined by blinded independent radiology committee (BIRC).

Major secondary endpoints included:  OS, defined as the time from randomization to the date of death for any cause.  Objective response rate (ORR), defined as the proportion of subjects with a best overall response (BOR) of either complete response (CR) or partial response (PR) per RECIST v1.1 guidelines.  Duration of response (DOR), defined as the time from first documentation of objective response (CR or PR, whichever occurs first) to the date of disease progression or to death due to any cause, whichever occurs first.

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 PRO assessments were health-related quality of life (HRQoL), disease and treatment- related symptoms and general health status.

Sample Size

The sample size was determined based on the following design aspects and assumptions:

 The primary endpoint PFS follows an exponential distribution. The estimated median PFS was assumed to be 9.5 months in the gefitinib arm and 14.3 months in the dacomitinib arm, with a corresponding HR of 0.67.  Randomization to treatment arms in a 1:1 ratio.  The type I error rate is 0.05, two-sided.  The power to declare superiority of dacomitinib to gefitinib is approximately 90%.

Approximately 256 PFS events in the intent-to-treat (ITT) population were required for the primary analysis from 440 patients planned for enrollment.

Statistical Analysis Plan

The ITT population was used for the efficacy analysis. The ITT population comprises all randomized patients regardless of whether treatment was administered.

Time-to-event endpoints were summarized using Kaplan-Meier estimates and the difference between treatment arms was tested using a stratified log-rank test, stratifying for the pre- specified stratification factors used for randomization. The hazard ratio and corresponding 95% CI were calculated using the Cox proportional hazards model.

The ORR and corresponding 95% confidence intervals (CIs) were estimated using the Clopper- Pearson method. The difference in the response rates for each treatment comparison is also presented along with its 95% exact confidence intervals. Comparisons of ORRs were conducted based on the Cochran-Mantel Haenszel (CMH) test stratified by the pre-specified stratification factors. DOR was analyzed using Kaplan-Meier estimates.

There is no interim analysis for PFS. An interim analysis of OS, to assess for futility only, was performed at the time of the final analysis of PFS; no alpha was spent for this OS analysis.

At the time of final analysis of the primary endpoint of PFS, a gate-keeping procedure was used for hypothesis testing in a hierarchical approach in the order of PFS, ORR per BIRC, and OS.

The PRO analyses assessed pain, dyspnea, fatigue, and cough from the EORTC QLQ-C30 and the QLQ- LC13 instruments.

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Protocol Amendments

Protocol amendment 2 allowed for continuation of dacomitinib until the patient is no longer receiving clinical benefit, even if the re-staging scan showed progressive disease per RECIST. The prohibited drug list was updated to include CYP2D6 substrates (procainamide, pimozide, and thioridazine etc.)

Protocol amendment 3 broadened the inclusion criteria to allow patients with recurrent (minimum of 12 months disease-free interval between completion of systemic therapy and recurrence required) NSCLC to participate. Inclusion criteria was also broadened to allow patients with completed neoadjuvant/adjuvant chemo-therapy and/or combined modality chemo-therapy/radiation therapy permitted only in cases in which there is a minimum of 12 months disease-free interval between completion of systemic therapy and recurrence of NSCLC to enroll.

Protocol amendment 4 consisted of administrative changes only.

Protocol amendment 5 states that loperamide should be started at the first evidence of increased frequency of bowel movements, paronychia guidelines were updated to include a dermatology consultation.

Protocol amendment 6 removed a previously planned interim analysis of PFS at approximately 50% of information. The number of events for PFS final analysis was changed from 275 to 256. Per FDA’s request, an interim analysis of OS was added, to be conducted at the time of the final PFS analysis.

Protocol amendment 7 consisted of administrative changes only.

8.1.2 Study Results of ARCHER 1050 Compliance with Good Clinical Practices

All study reports contained in the NDA included a statement that the trials were conducted in accordance with Good Clinical Practices.

Financial Disclosure

In accordance with 21 CFR 54, the Pfizer submitted a financial disclosure certification document in module 1.3.4. The Pfizer provided a listing of all investigators who participated in the 17 studies included in the NDA submission indicating whether the investigators have provided a Certification (Form 3454), a Disclosure statement (Form 3455) or if the financial disclosure information is missing. For investigators with missing financial disclosures, the Pfizer stated that “due diligence was performed to obtain disclosures from these investigators”.

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Patient Disposition

The study was initiated on May 9, 2013, and trial enrollment completed on March 25, 2015, with a total of 452 patients randomized, 227 to dacomitinib and 224 to gefitinib. Patient (b) (6) was inadvertently randomized to the gefitinib arm but was not treated due to known brain metastases on baseline scan. The Pfizer provided reasons for disposition for the entire ITT patient population. Table 33 summarizes the patient disposition for ARCHER 1050. At the data cutoff date of July 29, 2016, most of the patients in each treatment arm had permanently discontinued treatment (70.9% in the dacomitinib arm and 82.7% in the gefitinib arm); 60% of dacomitinib-treated patients and 53% of gefitinib-treated patients remained on study / were ongoing on study.

Table 33. ARCHER 1050 Patient Disposition

Number (%) of Patients Dacomitinib Gefitinib Randomized 227 (100) 225 (100) Treated 227 (100) 224 (99.6) Discontinued from treatment 161 (70.9) 186 (82.7) Ongoing on treatment 66 (29.1) 38 (16.9) Discontinued from study 91 (40.1) 105 (46.7) Ongoing on study 136 (59.9) 120 (53.3)

Protocol Violations/Deviations

There were protocol violations on both arms of ARCHER 1050. The incidence of protocol violations was 3% or less and was balanced between the study arms.

Table 34: ACRCHER 1050: Protocol Deviations

Protocol Deviations Dacomitinib Gefitinib Total N=227 (%) N=225 (%) N=452 (%) Patients with any protocol 120 (53) 102 (45) 222 (49) deviation Inclusion / exclusion 49 (22) 43 (19) 92 (20) Informed consent deviations 21 (9) 24 (11) 45 (10) Study treatment 39 (17) 32 (14) 71 (16) Labs / procedures / tests 10 (4) 10 (4) 20 (4) Study procedure criteria 50 (22) 43(19) 93(21)

Baseline Demographic and Disease Characteristics

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The following two tables summarize the demographic and baseline characteristics of the patient population in ARCHER 1050.

Table 35. ARCHER 1050: Demographic Characteristics

Dacomitinib Gefitinib N (%) N (%) Randomized 227 225 Age Median 63 62 Age <65 133 (58.6) 140 (62.2) Age ≥65 94 (41.4) 85 (37.8) Gender Male 81 (35.7) 100 (44.4) Female 146 (64.3) 125 (55.6) Race Asian 170 (74.9) 176 (78.2) White 56 (24.7) 49 (21.8) African American / Black 1 (0.4) 0 Region Japanese 40 (17.6) 41 (18.2) Mainland Chinese 115 (50.7) 119 (52.9) Non-East Asian 57 (25.1) 48 (21.3) Other East Asian 15 (6.6) 17 (7.6)

Reviewer’s Comment: The distribution of demographic characteristics is generally balanced between the two treatment arms. Most patients are Asians, half of the patients in ARCHER 1050 were enrolled in mainland China. There were more female patients in the dacomitinib arm than in the gefitinib arm.

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Table 36. ARCHER 1050: Baseline characteristics

Dacomitinib Gefitinib N (%) N (%) Randomized 227 225 ECOG performance 0 75 (33.0) 62 (27.6) 1 152 (67.0) 163 (72.4) Histology Adenocarcinoma 227 (100) 225 (100) Smoking Status Never Smoker 147 (64.8) 144 (64.0) Current Smoker 15 (6.6) 19 (8.4) Former Smoker 65 (28.6) 62 (27.6) Prior Therapy Surgery 21 (9.3) 19 (8.4) Radiation 7 (3.1) 6 (2.7) Systemic chemotherapy* 2 (0.9) 2 (0.9) Current Disease Stage Stage IIIB 18 (7.9) 16 (7.1) Stage IV 184 (81.1) 183 (81.3) Unknown 25 (11.0) 26 (11.6) EGFR status Exon 19 del 134 (59.0) 133 (59.1) Exon 21 L858R 93 (41.0) 92 (40.9) *Two patients in each arm received prior adjuvant or neoadjuvant platinum-based chemotherapy

Reviewer’s Comment: The distribution of baseline characteristics is generally balanced between the two treatment arms. The majority of patients were never smokers. The majority of patients had Stage IV disease at study entry. More patients had tumors harboring the exon 19 deletion.

Treatment Compliance, Concomitant Medications, and Rescue Medication Use

•Treatment Compliance: Patients were required to maintain a dosing diary to record treatment compliance. Dosing diaries were reviewed at specified visits and dosing non-compliance was documented as a protocol deviation; see Section 8.1.2 Protocol Deviations.

•Concomitant Medications: Concomitant medications and treatments received by patients from the time they signed the informed consent document (ICD) until the posttreatment

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follow-up visit or until they initiated a new anti-cancer therapy (whichever occurred first) were recorded on the eCRF.

•Rescue Medication: The use of rescue medication is not applicable to the study treatment mechanism of action.

Efficacy Results – Primary Endpoint

There were 452 patients in the ITT population, with 227 in the dacomitinib arm and 225 in the gefitinib arm. A total of 315 patients had progressed or died at time of the primary analysis, of which 136 were in the dacomitinib arm and 179 in the gefitinib arm.

The following table summarizes the results of the primary analysis of PFS. Dacomitinib was shown to be prolong median PFS by 5.5 months compared to gefitinib based on a stratified log-rank test stratified by the pre-specified stratification factors.

Table 37. ARCHER 1050: PFS Primary Analysis

Dacomitinib Gefitinib N (%) N (%) Randomized 227 225 Number of Events (%) 136 (59.9) 179 (79.6) Median PFS (95%CI) 14.7 (11.1, 16.6) 9.2 (9.1, 11.1) HR (95% CI) 0.59 (0.47, 0.74) p-value <0.0001

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The following figure displays the Kaplan-Meier curves for PFS.

Figure 6. ARCHER 1050: Kaplan Meier Curves for PFS

Data Quality and Integrity

Data and reports of this submission were submitted electronically. The Pfizer submitted data as well as the related SAS programs for analysis. The reviewer was able to perform the analyses required for a thorough and substantive review of the NDA using the submitted data.

Efficacy Results – Secondary and other relevant endpoints

The secondary endpoints were ORR and OS. According to the protocol, if PFS was statistically significant, then the testing order would be ORR followed by OS.

The analysis results of ORR and DOR are summarized in the following table. The ORRs were similar in the two arms. The CMH test failed to show a statistically significant difference for the dacomitinib arm compared with the gefitinib arm.

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Table 38. ARCHER 1050: ORR and DoR Analyses

Dacomitinib Gefitinib N (%) N (%) Randomized 227 225 Number of responders (%) 170 161 CR 12 4 PR 158 157 ORR (95%CI) 74.9 (68.7, 80.4) 71.6 (65.2, 77.4) p-value (2-sided) 0.3884 Median DOR (95% CI) 14.8 (12.0, 17.4) 8.3 (7.4, 9.2)

Reviewer’s Comment: While there was no statistically significant or clinically meaningful difference in ORR between arms, the median DOR was longer for the dacomitinib arm vs the gefitinib arm.

Among the 452 patients in the ITT population, a total of 220 patients had died by the time of the primary analysis, 103 in the dacomitinib arm and 117 in the gefitinib arm.

The following table summarizes the results of the analysis of OS. Since the test for ORR was not statistically significant there is no alpha left to test for OS.

Table 39. ARCHER 1050: OS Analysis

Dacomitinib Gefitinib N (%) N (%) Number of Events (%) 103 (45.4) 117 (52.0) Median Survival (95% CI) 34.1 (29.5, 37.7) 26.8 (23.7, 32.1) HR (95% CI) 0.76 (0.58, 0.99)

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The following are the Kaplan-Meier curves for OS.

Figure 7. ARCHER 1050: Kaplan Meier Curves of OS

Reviewer’s Comment: Note that the OS curves cross at approximately 12 months. The assumption of proportional hazards is violated. Therefore, hazard ratio may not be appropriate to summarize the results and the KM-estimated medians are not appropriate summary statistics to characterize OS. Kaplan-Meier Curves are provided for information only to summarize OS results.

Various subgroup analyses were also conducted to investigate differential effects on OS that may have caused the curves to cross.

Table 40. Subgroup Analysis of OS by OS Time <12 Months vs ≥12 Months

OS Events / N Medians HR (95% CI) DACOM GEF DACOM GEF OS final 103/227 117/225 34.1 26.8 0.76 (0.58, 0.99) OS < 12 mos 32/39 31/39 7.6 9.8 1.24 (0.68, 2.25) OS ≥12 mos 71/188 86/186 36.7 32.1 0.67 (0.49, 0.92)

The number of deaths that occurred before 12 months are approximately the same in the two arms; however, the patients in the gefitinib arm with OS <12 months had a higher median survival than those in the dacomitinib arm. Deaths prior to 12 months accounted for 98 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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approximately one-third of the death events on the dacomitinib arm. More patients died in the gefitinib arm after 12 months.

Further investigations into the OS outcome were conducted. There were no outliers among the demographic and baseline characteristics. Most of the OS subgroups analyses based on these characteristics also resulted in crossing Kaplan-Meier survival curves. The analyses conducted did not indicate a reason for the crossing of the OS curves.

Table 41. ARCHER 1050: Baseline Characteristics by OS Time <12 Months vs ≥12 Months

OS <12 OS >=12 DACOM GEF DACOM GEF Age <65 21 (53.8%) 25 (64.1%) 112 (59.6%) 115 (61.8%) Age >=65 18 (46.2%) 14 (35.9%) 76 (40.4%) 71 (38.2%) Female 20 (51.3%) 22 (56.4%) 126 (67.0%) 103 (55.4%) Male 19 (48.7%) 17 (43.6%) 62 (33.0%) 83 (44.6%) ASIAN 23 (59.0%) 31 (79.5%) 147 (78.2%) 145 (78.0%) WHITE 15 (38.5%) 8 (20.5%) 41 (21.8%) 41 (22.0%) Japanese 3 (7.7%) 4 (10.3%) 37 (19.7%) 37 (19.9%) Mainland Chinese 19 (48.7%) 24 (61.5%) 96 (51.1%) 95 (51.1%) Non-East Asian 16 (41.0%) 8 (20.5%) 41 (21.8%) 40 (21.5%) Other East Asian 1 (2.6%) 3 (7.7%) 14 (7.4%) 14 (7.5%) Ever-smoker 18 (46.2%) 10 (25.6%) 62 (33.0%) 71 (38.2%) Never-smoker 21 (53.8%) 29 (74.4%) 126 (67.0%) 115 (61.8%) ECOG = 0 10 (25.6%) 6 (15.4%) 65 (34.6%) 56 (30.1%) ECOG = 1 29 (74.4%) 33 (84.6%) 123 (65.4%) 130 (69.9%) Exon 19 deletion 23 (59.0%) 19 (48.7%) 111 (59.0%) 114 (61.3%) L858R mutation in exon 21 16 (41.0%) 20 (51.3%) 77 (41.0%) 72 (38.7%)

Persistence of Effect

See discussion of DOR above.

Efficacy Results – Secondary or exploratory COA (PRO) endpoints

PROs were listed as one of the secondary endpoints in the protocol; however, there was no formal statistical analysis testing specified.

PROs of health-related quality of life (HRQOL), disease/treatment-related symptoms, and health status were assessed using the EORTC QLQ-C30 and QLQ-LC13 tools. Patients completed the self-administered questionnaires pre-dose at Day 1 of Cycle 1, Day 8 and Day 15 of Cycle 1; Day 1 of each subsequent cycle; at the end of treatment visit; and at the post-treatment follow up visit. Patients must complete these questionnaires prior to the patient having any tests, and 99 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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prior to any discussion of the patient’s progress with their physician or any other healthcare personnel at the site.

The EORTC QLQ-C30 (Version 3.0) is comprised of 30 questions in total. Within the 30 questions are nine multi-item scales and six single-item measures. There are five functional scales; physical, role, cognitive, emotional and social, three symptom scales; fatigue, pain, nausea and vomiting, and a global health status/QOL scale. There are five single item measures assessing additional symptoms commonly reported by cancer subjects (dyspnea, loss of appetite, insomnia, constipation, and diarrhea) and a single item concerning perceived financial impact of the disease.

The QLQ-LC13 consists of 13 questions relating to disease symptoms specific to lung cancer and treatment side effects typical of treatment with chemotherapy and radiotherapy. The 13 questions comprise one multi-item scale for dyspnea and 10 single-item measures assessing symptoms and side effects (e.g., coughing, hemoptysis, sore mouth, dysphagia, peripheral neuropathy, alopecia, pain in the chest, pain in the arm, other pain, and medicine for pain).

The PRO evaluable population was the primary population for PRO analyses and included patients who received at least one dose of study treatment, completed a baseline PRO assessment, and completed at least one post-baseline PRO assessment after the first dose. There were 448 patients included in the PRO analysis set, with 226 in the dacomitinib arm and 222 in the gefitinib arm.

The following table summarizes the completion rate of the EORTC QLQ-C30 and QLQ-LC13 tools. The completion rate is defined as the proportion of patients who answered all questions for EORTC QLQ-C30 and QLQ-LC13.

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Table 42. ARCHER 1050: PRO Completion Rates

Dacomitinib Gefitinib BASELINE* 212/226 (93.8) 211/222 (95.0) CYCLE 1/DAY8 210/217 (96.8) 202/210 (96.2) CYCLE 1/DAY15 193/201 (96.0) 194/202 (96.0) CYCLE 2/DAY1 203/217 (93.5) 207/212 (97.6) CYCLE 3/DAY1 195/202 (96.5) 198/204 (97.1) CYCLE 4/DAY1 187/195 (95.9) 194/201 (96.5) CYCLE 5/DAY1 182/190 (95.8) 186/195 (95.4) CYCLE 6/DAY1 174/182 (95.6) 181/189 (95.8) CYCLE 7/DAY1 171/178 (96.1) 174/179 (97.2) CYCLE 8/DAY1 166/171 (97.1) 163/168 (97.0) CYCLE 9/DAY1 156/164 (95.1) 157/160 (98.1) CYCLE 10/DAY1 147/155 (94.8) 146/152 (96.1) CYCLE 11/DAY1 139/148 (93.9) 135/140 (96.4) CYCLE 12/DAY1 138/141 (97.9) 122/127 (96.1) CYCLE 13/DAY1 130/134 (97.0) 111/113 (98.2) CYCLE 14/DAY1 128/130 (98.5) 101/104 (97.1) CYCLE 15/DAY1 121/124 (97.6) 93/96 (96.9) CYCLE 16/DAY1 118/119 (99.2) 81/85 (95.3) CYCLE 17/DAY1 110/112 (98.2) 78/78 (100) CYCLE 18/DAY1 107/108 (99.1) 68/72 (94.4) CYCLE 19/DAY1 100/101 (99.0) 61/64 (95.3) CYCLE 20/DAY1 95/97 (97.9) 55/58 (94.8) *Baseline: Cycle 1/Day1

Across most domains, there were no clear sustained differences between the dacomitinib and gefitinib treatment arms in PRO endpoints. Figures, abstracted from the CSR, are provided below for symptoms considered of interest in patients with NSCLC (i.e., chest pain, shortness of breath, and cough).

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Figure 8. ARCHER 1050: PRO Chest Pain

(Source: ARCHER 1050 CSR)

Figure 9. ARCHER 1050: PRO Shortness of Breath

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(Source: ARCHER 1050 CSR)

Figure 10. ARCHER 1050: Cough

(Source: ARCHER 1050 CSR)

Reviewer’s Comment: All PRO analyses are considered exploratory since they do not have a pre- specified multiplicity adjustment.

Additional Analyses Conducted on the Individual Trial

The following table summarizes subgroup analyses of PFS based on age, gender, race and region. Since these analyses were not pre-specified in the protocol, the results are considered exploratory. There are no outliers in these analyses.

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Table 43. ARCHER 1050: PFS Subgroup Analyses

PFS Events / N Medians HR (95% CI) DACOM GEF DACOM GEF PFS, ITT 136/227 179/225 14.7 9.2 0.58 (0.46, 0.73) Age < 65 83/133 114/140 16.0 9.2 0.55 (0.41, 0.74) Age >= 65 53/94 65/85 11.3 9.2 0.60 (0.40, 0.89) Male 54/81 77/100 12.3 9.2 0.70 (0.49, 1.01) Female 82/146 102/125 14.8 9.2 0.50 (0.37, 0.68) Asian 97/170 140/176 16.5 9.3 0.51 (0.39, 0.67) White 38/56 39/49 10.8 9.2 0.80 (0.51, 1.26) Chinese 67/115 95/119 16.0 9.2 0.50 (0.36, 0.68) Japanese 22/40 31/41 18.2 9.3 0.54 (0.30, 0.95) Other East Asian 8/15 14/17 16.5 12.7 0.67 (0.27, 1.67) Non-East Asian 39/57 39/48 9.3 9.2 0.83 (0.53, 1.30) ECOG 0 40/75 46/62 14.6 11.1 0.64 (0.41, 1.00) ECOG 1 96/152 133/163 14.7 9.2 0.58 (0.44, 0.76) Never-smoker 87/147 117/144 14.7 9.2 0.52 (0.39, 0.69) Ever-smoker 49/80 62/81 14.7 9.4 0.74 (0.50, 1.09) Exon 19 deletion 75/134 103/133 16.5 9.2 0.55 (0.40, 0.74) L858R mutation in exon 21 61/93 76/92 12.3 9.8 0.63 (0.45, 0.90)

The following table summarizes subgroup analyses of OS based on age, gender, race and region. Since these analyses were not pre-specified in the protocol, the results are considered exploratory. There are no outliers in these analyses.

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Table 44. ARCHER 1050: OS Subgroup Analyses

OS Events / N Medians HR (95% CI) DACOM GEF DACOM GEF OS 103/227 117/225 34.1 26.8 0.76 (0.58, 0.99) Age < 65 59/133 75/140 34.2 26.7 0.69 (0.49, 0.98) Age >= 65 44/94 42/85 32.6 27.1 0.91 (0.59, 1.42) Male 42/81 55/100 29.5 26.7 0.84 (0.56, 1.28) Female 61/146 62/125 34.2 27.0 0.68 (0.48, 0.97) Asian 74/170 86/176 34.2 29.1 0.79 (0.58, 1.09) White 28/56 31/49 29.5 20.6 0.63 (0.37, 1.06) Chinese 58/115 69/119 31.0 24.9 0.77 (0.54, 1.09) Japanese 13/40 13/41 NE NE 0.96 (0.44, 2.07) Other East Asian 3/15 4/17 NE NE 0.85 (0.19, 3.90) Non-East Asian 29/57 31/48 29.5 20.6 0.65 (0.39, 1.09) ECOG 0 31/75 23/62 34.7 NE 0.95 (0.54, 1.66) ECOG 1 72/152 94/163 31.0 24.9 0.69 (0.51, 0.94) Never-smoker 65/147 74/144 34.1 26.4 0.69 (0.49, 0.96) Ever-smoker 38/80 43/81 30.1 28.6 0.96 (0.62, 1.49) Exon 19 deletion 57/134 61/133 34.1 NE 0.82 (0.57, 1.18) L858R mutation in exon 21 46/93 56/92 32.5 23.2 0.69 (0.46, 1.02)

8.1.2 Study A741017 (Study 1017): A PHASE 2, OPEN LABEL, TRIAL OF DACOMITINIB (PF-00299804) IN SELECTED PATIENTS WITH ADVANCED ADENOCARCINOMA OF THE LUNG

Trial Design

This is a multicenter, open label, two cohort study of dacomitinib 30 mg or 45 mg daily administered as a single agent on a continuous oral schedule to patients with advanced NSCLC enrolled in one of the following cohorts:

 Cohort A: patients with adenocarcinoma of the lung who have not received prior systemic therapy and are either:

o Non-smokers or former light smokers, or

o Patients, regardless of smoking status, who are known to have an EGFR activating mutation.

 Cohort B: NSCLC of any histology demonstrated to have either HER2 gene amplification or HER2 mutation. Patients in this cohort could have received any number of prior

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chemotherapies and prior EGFR targeted therapy. Patients with HER2 gene amplification cannot have received prior HER2 targeted therapy.

Study Endpoints

The primary endpoint was PFS at 4 months in Cohort A, defined as the proportion of patients who are alive without progression at 4 months relative to all patients enrolled in Cohort A.

Secondary endpoints included PFS at 4 months in Cohort B; BOR per RECIST in each cohort, defined as the best response per RECIST from the start of treatment until disease progression; DOR), OS and PFS.

Reviewer’s Comment: All results related to PFS and OS are not interpretable in single arm trials. Only the results of the subgroup of patients who had tumor harboring an EGFR exon 19 deletion or exon 21 L858R substitution mutation in Cohort A are considered as supportive evidence to this application. All results in this section only pertain to Cohort A.

Statistical Analysis Plan

The BOR and its 95% CI were calculated using the exact method.

Study Results of Study 1017

Compliance with Good Clinical Practices

Study 1017 was conducted in compliance with Good Clinical Practice (GCP) guidelines and local country regulations relevant to the use of new therapeutic agents in the country/countries of conduct, including the archiving of essential documents.

Protocol Violations/Deviations

Protocol deviations for Stud 1017 were: 2 reports of protocol deviations related to inclusion / exclusion error, 24 reports of investigational product error (includes patient missed dose, patient took dose before PK draw, patient took incorrect dose, and pharmacy dispensing error), 2 reports of concomitant medication errors, 139 reports of laboratory error, 28 reports of visit schedule error, 87 reports of procedure or test error, 2 reports of missed SAE reporting, 3 reports of protocol specific discontinuation criteria, 18 reports of informed consent deviations.

Reviewer’s Comment: Most protocol deviations were related to laboratory deviations and were unlikely to alter the results of the study.

Efficacy Results - Primary Endpoint

A total of 89 patients were enrolled in the study. Among these patients, 25 (28.1%) had tumor harboring an EGFR exon 19 deletion and 20 (22.5%) had tumor harboring EGFR exon 21 L858R 106 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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substitution mutation. Among these 45 patients, no patient had a CR, while 34 patients (75.6%) had a PR for a BOR of 75.6% with 95% CI (60.5, 87.1).

Reviewer’s Comment: These results are considered exploratory. The observed ORR in this subgroup appear to be consistent with the results observed in ARCHER 1050.

Data Quality and Integrity - Reviewers' Assessment

Data and reports of this submission were submitted electronically. The Pfizer submitted data as well as the related SAS programs for analysis. The reviewer was able to perform the analyses required for a thorough and substantive review of the NDA using the submitted data.

81.3 ARCHER 1009: A Randomized Double Blind Phase 3 Efficacy and Safety Study of PF-00299804 (Dacomitinib) vs Erlotinib for the Treatment of Advanced Non-Small Cell Lung Cancer Following Progression After, or Intolerance to, at Least One Prior Chemotherapy

Trial Design

ARCHER 1009 was a multicenter, randomized, double-blinded, clinical trial comparing the efficacy and safety of dacomitinib compared to erlotinib in patients with locally advanced or metastatic NSCLC who have previously had at least one (no more than two) prior chemotherapy regimen within the following two co-primary populations:

 all patients with advanced NSCLC (ITT population) and

 patients with confirmed KRAS wild-type NSCLC (KRAS-WT).

Patients were stratified by histology (adenocarcinoma versus non-adenocarcinoma), race (Asian versus non-Asian and Indian subcontinent race), ECOG performance status (PS) (0-1 versus 2) and smoking status (never smoker, defined as ≤100 cigarettes, cigar or pipe lifetime vs. ever smoker). Eligible patients were randomized in 1:1 ratio to receive:

 Treatment: dacomitinib 45 mg daily

 Control: erlotinib 150 mg daily

Study Endpoints

The primary endpoint was PFS, defined as the time from randomization to the date of disease progression per RECIST v1.1 as assessed by IRC or death due to any cause, whichever occurred first.

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Secondary endpoints are listed and were tested in the following order after the test of the primary endpoint:

 OS, defined as the time from randomization to the date of death for any cause. In the absence of confirmation of death, survival time will be censored at the last date the patient is known to be alive.  PFS per investigator’s assessment.  BOR, defined as the best response recorded from the start of treatment until disease progression. ORR is defined as the proportion of patients with a BOR characterized as either a CR or PR (defined according to RECIST version 1.1) relative to the total number of patients.  DOR, defined as the time from first documentation of response (CR or PR whichever occurs first) to the date of disease progression or to death due to any cause, whichever occurs first.

Reviewer’s Comment: DOR should not be included in the testing procedure because it is not evaluated in a randomized patient population.

Only the results for the subgroup of patients who had tumor harboring an EGFR exon 19 deletion or exon 21 L858R substitution mutation are considered as supportive evidence to this application. All results in this section pertain only to this subgroup.

Sample Size

The type-I error rate of 0.025 (one-sided) was split between the primary analysis populations (ITT or confirmed KRAS wild-type subpopulation). It was estimated that at least 50% of enrolled patients will have adequate tissue for analysis and be determined to be KRAS wild type. The study planned to enroll a total of approximately 800 patients with at least 400 patients confirmed as KRAS-WT in about 20 months.

The following statements describe the statistical power available to detect a specified hazard ratio for PFS in the ITT population and in the KRAS-WT subpopulation:  Assuming the median PFS was 2.26 months in the control arm, a minimum of 617 PFS events were required to have 90% power to detect a hazard ratio of 0.75 in the ITT population receiving dacomitinib versus erlotinib at a significance level of 1.5%.  Assuming the median PFS was 3 months in the control arm, a minimum of 313 PFS events were required to have 80% power to detect a hazard ratio of 0.69 in KRAS-WT subpopulation receiving dacomitinib versus erlotinib at a significance level of 1%.

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The study was also powered for OS. The following statements describe the statistical power available to detect a specified hazard ratio for OS in the ITT population and in the KRAS-WT subpopulation:  Assuming the median OS was 6.7 months in the control arm, a minimum of 610 OS events were required to have 85% power to detect a hazard ratio of 0.77 in the ITT population receiving dacomitinib versus erlotinib at a significance level of 1.5%.  Assuming the median OS was 7.5 months in the control arm, a minimum of 309 OS events were required to have 80% power to detect a hazard ratio of 0.69 in KRAS-WT subpopulation receiving dacomitinib versus erlotinib at a significance level of 1%.

Statistical Analysis Plan

All analyses will be conducted in both of the co-primary populations (ITT population and KRAS- WT subpopulation).

Difference in PFS between the two arms were tested using a stratified log-rank test (one-sided, α = 0.015 for the ITT population and α = 0.01 for KRAS-WT subpopulation). Cox regression models were used to estimate the hazard ratio and its 95% CI. Kaplan-Meier methods were used to estimate the median event time and corresponding 2-sided 95% CI. OS was analyzed using the same methods as PFS.

BOR was summarized by arm with corresponding two-sided 95% CI and tested by the Pearson test (unstratified) and Cochran-Mantel-Hansel (CMH) test stratified by baseline stratification factors will be used to compare ORR between two arms. DOR were summarized using Kaplan- Meier methods.

The study had two interim analyses. The first interim analysis for futility was conducted in the co-primary populations using PFS per investigator’s assessment, which would occur at about 104 (33%) of PFS events for KRAS-WT subpopulation, and about 245 (40%) PFS events for the ITT population. The second interim analysis for efficacy was conducted for OS in the co-primary populations at the same time as final analyses of PFS. Approximately 565 deaths from the ITT population and 260 deaths from KRAS-WT subpopulation were anticipated at the time of interim OS analysis.

Study Results ARCHER 1009

Since the patient population related to this NDA is patients with EGFR mutation-positive NSCLC, only the results from this patient subgroup are presented in this review.

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Compliance with Good Clinical Practices

Study 1009 was conducted in compliance with Good Clinical Practice (GCP) guidelines and local country regulations relevant to the use of new therapeutic agents in the country/countries of conduct, including the archiving of essential documents.

Patient Disposition

A total of 878 patients were randomized into the study, with 439 in each arm. Among these patients, there were 76 (17%) patients with tumors harboring EGFR exon 19 deletion or exon 21 L858R substitution mutation, of which 37 were in the dacomitinib arm and 39 were in the erlotinib arm.

Protocol Violations/Deviations

Protocol deviations for Study 1009 from both study arms (dacomitinib and erlotinib) were: 5 reports of concomitant medication deviations, 94 informed consent deviations, 44 inclusion /exclusion deviations, 14 laboratory deviations, 22 deviations categorized as “other” (unreported SAE, safety reporting deviations, and protocol specific discontinuation criteria deviations), 152 procedure deviations, 28 study drug deviations, 2 visit schedule deviations.

Reviewer’s Comment: Most of the protocol deviations were related to missed procedures and were unlikely to affect the results of the study.

Efficacy Results The following table summarizes the PFS results per IRC in patients with NSCLC harboring EGFR exon 19 deletion or exon 21 L858R.

Table 45. ARCHER 1009: PFS results in Patients with EGFR Exon 19 Deletion or Exon 21 L858R

Dacomitinib Erlotinib Randomized 37 39 Number of Events (%) 18 (48.6) 23 (59.0) Median PFS (95%CI) 14.6 (7.4, NE) 9.6 (7.3, 16.6) HR (95% CI) 0.71 (0.38, 1.32)

The following tables summarized the results of OS and ORR per IRC.

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Table 46. ARCHER 1009: OS and ORR results in Patients with EGFR Exon 19 Deletion or Exon 21 L858R

Dacomitinib Erlotinib Randomized 37 39 OS Number of Events (%) 15 (40.5) 20 (51.3) Median Survival (95%CI) 26.6 (21.6,NE) 23.2 (16.0, NE) HR (95% CI) 0.80 (0.41, 1.57) ORR Number of responders (%) 25 26 CR 2 6 PR 23 20 ORR (95%CI) 67.6 (50.2, 82.0) 66.7 (49.8, 80.9) Median DoR (95% CI) 9.2 (5.6, NE) 7.6 (5.6, 14.8)

Reviewer’s Comment: These results are considered exploratory. While the results from the ITT population failed to show improvement in PFS, the observed PFS, OS and ORR results in the EGFR mutation-positive subgroup appear consistent with the results in ARCHER 1050.

8.1.4 Study A7471011 (Study 1011): A Double-Blind Placebo Controlled Randomized Trial of PF-804 In Patients With Incurable Stage IIIb/IV Non- Small Cell Lung Cancer After Failure Of Standard Therapy For Advanced Or Metastatic Disease

Trial Design

This is a double blind, randomized trial of dacomitinib versus matched placebo in patients with incurable, stage IIIB/IV NSCLC for which they have failed standard therapy for advanced or metastatic disease.

Patients were stratified by: • center • performance status (0 or 1 vs. 2 or 3) • tobacco use (never vs. past or present) • best response to prior EGFR TKI (PD vs. other) • weight loss (< 5% vs. > 5% or unknown) • ethnicity (east Asian vs. other)

Patients were randomized 2:1 to receive treatment with dacomitinib 45 mg daily or placebo until unmanageable toxicity or progression.

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An interim analysis was to be performed for futility when around 300 events (disease progression or death) had occurred.

Study Endpoints

The primary endpoint is overall survival (OS).

The secondary endpoints include:  overall survival (OS) in KRAS-WT patients  overall survival (OS) in EGFR mutant patients  progression-free survival (PFS)  objective response rates (RR) and duration of response (DoR)

Reviewer’s Comment: Only the results for the subgroup patients whose tumors had an EGFR exon 19 deletion or exon 21 L858R substitution mutation are considered as supportive evidence to this application and are presented in this section.

Sample Size

In order to have 90% power to detect a 33% improvement with dacomitinib (i.e. from 4 months to 5.3 months) using a one-sided 2.5% level significance test, a minimum of 581 deaths from 720 patients were required.

Statistical Analysis Plan

Time-to-event endpoints were summarized using Kaplan-Meier estimates and the difference between treatment arms was tested using a stratified log-rank test, stratifying for the pre- specified stratification factors used for randomization. The hazard ratio and corresponding 95% CI were calculated using the Cox proportional hazards model.

The ORR and corresponding 95% confidence intervals (CIs) were estimated using the Clopper- Pearson method. DOR was analyzed using Kaplan-Meier estimates.

Study Results

Compliance with Good Clinical Practices

Study 1011 was conducted in compliance with Good Clinical Practice (GCP) guidelines and, where applicable, local country regulations relevant to the use of new therapeutic agents in the country/countries of conduct, including the archiving of essential documents.

Protocol Violations/Deviations

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Protocol deviations for Study 1011 from both study arms (dacomitinib and placebo) were in the categories of investigations (459 reports), patient eligibility (55 reports), “other” (47 reports), adverse events (25 reports), and patient confidentiality (2 reports).

Reviewer’s Comment: Most of the protocol deviations were related to investigations and were not likely to affect the overall results of the study.

Efficacy Results

The following table summarizes the OS results in the subgroup of patients with EGFR mutation- positive NSCLC.

Table 47. Study 1011: OS Analysis in Patients with EGFR Exon 19 Deletion or Exon 21 L858R

Dacomitinib Placebo Randomized 83 52 Number of Events (%) 68 (81.9) 44 (84.6) Median Survival (95%CI) 7.5 (5.5, 9.1) 8.1 (5.1, 9.5) HR (95% CI) 0.91 (0.62, 1.33)

Table 48. Study 1011: PFS and OS Results in Patients with EGFR Exon 19 Deletion or Exon 21 L858R

Dacomitinib Placebo Randomized 83 52 PFS Number of Events (%) 78 (94.0) 51 (98.1) Median PFS (95%CI) 3.3 (1.8, 3.7) 1.0 (0.9, 1.7) HR (95% CI) 0.54 (0.37, 0.77) ORR Number of responders (%) 10 (12.0) 1 (1.9) CR 0 0 PR 10 1 ORR (95%CI) 12.0 (5.9, 21.0) 1.9 (0.0, 10.3)

Reviewer’s comment: These results are considered exploratory. While the results in the ITT population failed to show an improvement in OS, the observed OS, PFS and ORR in this EGFR mutation-positive subgroup appear to be consistent with the results observed in ARCHER 1050.

8.1.5 Integrated Assessment of Effectiveness

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ARCHER 1050 met its primary objective by demonstrating a statistically significant improvement in PFS as assessed by BIRC for dacomitinib compared to gefitinib in the first-line treatment of patients with metastatic EGFR mutation-positive (exon 19 deletion or exon 21 L858R substitution) NSCLC with a HR of 0.59 (95% CI: 0.47, 0.74; two-sided stratified log-rank p- value<0.0001), corresponding to a 5.5-month improvement in estimated median PFS favoring the dacomitinib arm. There was no difference in ORR between arms. Since the pre-specified hierarchical testing order was PFS, ORR and OS, there was no alpha left to test for OS. The Kaplan-Meier curves for OS crossed at approximately 12 months, which indicates that the proportional hazards assumption was violated. Therefore, the HR may not be an appropriate summary statistic to characterize the treatment effects on OS and the KM-estimated medians are not appropriate summary statistics to characterize the treatment effect on OS.

Subgroup analyses of EGFR-mutation positive patients treated on one single-arm study (Study 1017, Cohort A) and three randomized studies (Study 1009, Study 1011, and Study 1028) provide supportive evidence of the efficacy of dacomitinib in the population of patients with metastatic NSCLC harboring EGFR exon 19 deletion or exon 21 L858R substitution mutations.

The observed treatment effect on PFS is both statistically significant and clinically meaningful, and there is no suggestion of a detrimental effect of dacomitinib on overall survival. The results of ARCHER 1050 demonstrate substantial evidence of effectiveness on PFS that is statistically robust and clinically meaningful supporting the approval of dacomitinib for the first-line treatment of patients with NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test.

8.2 Review of Safety

8.2.1 Safety Review Approach

The safety evaluation of dacomitinib for the first-line treatment of patients with metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test is based on ARCHER 1050, which included 227 patients who received at least one dose of dacomitinib, and pooled safety sets, described below.

• Pool A contains 394 dacomitinib-treated patients with EGFR mutation-positive NSCLC (previously treated or first-line) from five studies who received single-agent dacomitinib 45 mg orally daily. • Pool B contains 1473 dacomitinib-treated patients with NSCLC (not selected for EGFR, previously treated or first-line) from 10 studies who received single-agent dacomitinib at 45 mg orally daily. • First-line Pool contains 255 dacomitinib-treated patients with EGFR mutation-positive NSCLC from two studies (227 from ARCHER 1050 and 28 from Study 1017). Patients in Study

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1017 received either 45 mg or 30 mg per day starting dose, depending on which amendment was active at the time of their enrollment.

Safety data from ARCHER 1050 is compared to the incidence of adverse events observed in the Pools A and B.

To assess the reliability and quality of the data in the submission, the clinical safety reviewer conducted random cross-validation of datasets with case report forms (CRF) from ARCHER 1050. The review and analysis of data includes the datasets, clinical study report (CSR), case narratives, and integrated summary of safety.

8.2.2 Review of the Safety Database

Overall Exposure

In ARCHER 1050, all 227 patients randomized to the dacomitinib arm received at least one dose of dacomitinib. Of the 225 patients randomized to gefitinib, 224 patients received at least one dose of gefitinib. One patient in the gefitinib arm was not treated because it was determined after randomization that study eligibility criteria were not met. Dacomitinib-treated patients had a median treatment duration of 66 weeks (15 months) and gefitinib-treated patients had a median treatment duration of 52 weeks (12 months). Only 30% of dacomitinib-treated patients received a 90-100% relative dose intensity (RDI) while 90% of gefitinib treated patients received 90-100% of the RDI. More than half of dacomitinib-treated patients received RDI of less than 75% due to toxicity-induced dose reductions.

Table 49. ARCHER 1050 Exposure Summary

Treatment Duration and Dose Intensity ARCHER 1050 ARCHER 1050 Safety Safety Dacomitinib Gefitinib Pool A Pool B N=227 N=224 N= 394 N=1473 Median Treatment Duration (wks) Range 66 52 47 12 (0.3 – 163) (0.3-148.3) (0.3-296.3) (0.1-296.3) Relative Dose Intensity (RDI) Mean (SD) Median (range) 73 (21.5) 96 (9.5) 78 (21.4) 86 (18.8) 72.5 (10 -100) 99.8 (55-100) 79 (21.7-100.0) 98 (21.7-133.3) RDI 90 – 100% 67 (30) 201 (90) 160 (41) 8601 (58) 75-90% 38 (17) 8 (4) 60 (15) 191 (13) <75% 122 (54) 15 (7) 174 (44) 422 (29) (Source: NDA 211288, ARCHER Interim CSR, ISS) Note: Pool B treated 20 patients at RDI of 100-125%.

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sufficient in duration to characterize the safety of dacomitinib. The treatment duration for Pool A and Pool B are notably shorter than that in ARCHER 1050. This discrepancy is likely due to the lack of adequate patient selection in these pools. In Pool A and Pool B some patients were heavily pre-treated. In addition, many of the patients in Pool B were not selected for EGFR mutations.

Relevant characteristics of the safety population:

The safety population from ARCHER 1050 is comprised of patients with newly diagnosed Stage IIIB/IV or recurrent (minimum 12-month disease-free interval between completion of systemic therapy) NSCLC of adenocarcinoma histology harboring an EGFR exon 19 deletion or exon 21 L858R mutation. Refer to Table 50 in Section 8.1 of this review for baseline disease characteristics. In line with the epidemiology and natural history of patients with EGFR mutation-positive NSCLC across ARCHER 1050 and safety pools A and B, more than half of the patients were female, median age was approximately 62 years, and most of the patients were of Asian race.

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sample size of 1473 dacomitinib-treated patients is sufficient to identify adverse events that occur at an incidence of 1% or higher.

ARCHER 1050 was conducted outside of the United States. The indication statement for dacomitinib is specific to the disease type and mutation status; therefore, the results of the efficacy and safety studies are considered applicable to all patients meeting these specifications, regardless of their nation of origin.

8.2.3 Adequacy of Pfizer’s Clinical Safety Assessments

Issues Regarding Data Integrity and Submission Quality

The NDA submission contains all the required components of the electronic Common Technical Document (eCTD). The overall integrity and quality of the submission is acceptable to allow for substantive review of the contents.

Categorization of Adverse Events

Adverse Event Coding Adverse event coding for ARCHER 1050 is based on Medical Dictionary for Regulatory Activities (MedDRA) v20.0 and graded for severity per the National Cancer Institute Common Terminology Criteria for Adverse Events NCI CTCAE v4.0.

Reviewer’s Comment: Adverse events for studies other than ARCHER 1050 in this submission are coded based on MedDRA v19.1.

Treatment-related adverse events (TEAEs) were defined as events with a cause possibly, probably, or related to treatment as judged by the investigator.

AEs meeting any of the following criteria are classified as treatment emergent adverse events (TEAE):

• The event occurred after the start of study treatment and before 28 days after final dose of study treatment and was not seen prior to the start of treatment. • The event was seen prior to the start of treatment but increased in CTCAE v4.0 grade after the start of treatment but before 28 days after final dose of study treatment. • Disease progression was not considered a TEAE unless the patient died of disease prior to 28 days after discontinuation of treatment. • AEs reported beyond 28 days and recorded in the database were included in the data listings and corresponding summary tables.

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28 days after the last dose of study treatment.

Protocol specified SAEs are:  Deep vein thrombosis  Dyspnea (except due to ILD)  Pulmonary embolism  Respiratory distress or failure

Reviewer’s Comment: Pfizer classified AEs using a 3-tiered approach to aggregate individual preferred terms as clustered terms. Tier 1 terms were prespecified and clustered / grouped to ensure that cases with similar toxicities were captured. For example, the toxicity “rash” is a compilation of 16 terms (acne, acne, cosmetic, acne cystic, acne fulminans, acne infantile, acne occupational, acne pustular, acne varioliformis, drug eruptions, mechanical acne, oil acne, rash, rash erythematous, rash generalized, rash maculopapular, rash pruritic) to ensure that the incidence of rash is adequately represented. The Pfizer’s list of clustered terms is provided in Appendix 1.

Pfizer’s use of a 3-tiered approach to aggregate preferred terms to capture all events related to a central concept term, like rash, is useful. However, the usefulness of some of the terms included in the list of terms is limited (e.g. acne infantile, acne occupational, acute fatty liver of pregnancy, white nipple sign). Additionally, there are limitations of the Pfizer’s system. The list of terms included under the large clustered term “rash” does not include general terms like “rash popular” and “rash pustular”. The omission of these preferred terms provoked an analysis by the DOP2 Safety Analysis Team examining the inclusion of all MEDdra preferred terms related to rash, rhinitis, pain and pruritus to ensure accurate representation of these toxicities in the product label. This analysis revealed the incidence of rash to be 87% and highlighted two adverse event terms that were not proposed by the Pfizer for inclusion in the label, specifically “rhinitis” and “pruritus”. The additional terms, rhinitis and pruritus, have been included in the safety section of patient labeling and the incidence of adverse events has been verified and applied to the product label.

Routine Clinical Tests

In ARCHER 1050, routine safety assessments included the collection of AEs, concomitant medications, vital signs, and body weight. Routine laboratory tests included hematology, blood chemistry, serum chemistry, urinalysis, and coagulation parameters performed within 28 days of the start of treatment, on day 1 of each cycle and when medically necessary. Vital signs were taken at screening, baseline, study day 1, day 8 and 15 for cycle 1. For all subsequent cycles, vital signs were taken on day 1. For cycle 1, electrocardiograms were taken at screening, baseline, study day 1, 8 and 15. Contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) was used for tumor assessment at screening, at the end of Cycles 1 and 2, and then every other cycle (within 7 days of the start of subsequent cycle including Day 1

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of subsequent cycle).

8. 2.4 Safety Results

Table 51 provides an overview of the incidence of TEAEs, AEs leading to dose reduction, AEs leading to dose discontinuation, and AEs leading to death. The total number of TEAEs, AEs leading to dose reduction, and AEs leading to discontinuation were higher on the dacomitinib arm. The incidence of death attributed to an AE was not significantly different between the two study arms.

Table 51. ARCHER 1050 Overview of Safety

Dacomitinib Gefitinib N=227 (%) N=224 (%) TEAE 226 (99.6) 220 (98.2) AE leading to dose reduction 150 (66) 18 (8) AE leading to discontinuation 41 (18) 38 (17) Death due to AE 22 (10) 20 (9) (Source: Adapted from Pfizer’s Table, NDA 211288, ARCHER Interim CSR, page 189)

Reviewer’s comment: There were approximately eight times more dose reductions for toxicities on the dacomitinib arm compared to the gefitinib arm.

Deaths

In ARCHER 1050, at the time of data cut-off (July 29, 2016), 76 (34%) of dacomitinib-treated patients died and 91 (41%) of gefitinib-treated patients died. Most deaths on both study arms were due to disease progression. Both study arms had patients with death due to treatment toxicity, unknown cause of death and “other” causes of death; please see Table 52 for details.

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Table 52. All Deaths ARCHER 1050 Study

Deaths Dacomitinib Gefitinib N=227 (%) N=224 (%) Deaths from all causes 76 (34) 91 (41) Death due to disease 68 (30) 85 (38) progression Death due to TEAE1 22 (10) 20 (9) Unknown cause of death2 2 (0.9) 4 (1.8) “Other” cause of death3 4 (1.8) 1 (0.4) (Source: Adapted from Pfizer’s Table, NDA 211288, ARCHER Interim CSR, ISS Table 14.3.2.1.2) 1 Death due to TEAE: See Table 53 for summary of patient narratives. 2 Unknown cause of death: patients died at home and no autopsy was performed. 3 Other causes of death: dacomitinib arm: bronchopulmonary aspergillosis, pneumonia, diazepam overdose, gefitinib arm malnutrition.

The case narratives and CRFs of patients who experienced a TEAE leading to death on the dacomitinib arm were reviewed and are summarized in Table 53 below.

Table 53. Adverse Events Leading to Death on the Dacomitinib Arm of ARCHER 1050

Case Patient ID AE Summary Reported leading Cause of to death Death 1 (b) (6) Diarrhea 87 yof treated with dacomitinib 45 mg, on study Death due day 16 developed intermittent diarrhea, to diarrhea supportive care was not started, and dose not induced changed. On study day 83, she was diagnosed acute with grade 3 decreased ejection fraction kidney determined to be abnormal, but not clinically injury, significant and requiring no treatment, assessed as dacomitinib was held. On study day 89, the treatment- ejection fraction improved and study medication related. was re-started at 30 mg dose. On study day 310, the patient’s creatinine was noted to be WNL. On (b) (6) she was hospitalized with grade 3 diarrhea, elevated creatinine (1.2 mg/dL) (ref 0.5-1.1 mg/dL), urea 91 (mg/dL) (ref 19-50 mg/dL) and BUN 43 (no ref. provided) and diagnosed with grade 4 kidney injury. Dacomitinib was held. She remained hospitalized and experienced clinical deterioration and dacomitinib was discontinued. She died 7 days

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after he last dose of dacomitinib, on (b) (6) . 21 (b) (6) Drug 66 yof treated with dacomitinib 45 mg, on study Cause of induced day 29 she had asymptomatic grade 1 increase death DILI, liver alkaline phosphatase (ALP), no action was taken. assessed as injury On study day 57, grade 1 ALP persisted, and she treatment- (DILI) developed grade 1 increased LDH. On study day related. 87 the LDH was normal, the ALP increased to grade 2, and the patient had grade 1 eye inflammation. The dacomitinib dose was reduced to 30 mg for eye inflammation. On study day 226, the ALP was resolved, but she developed grade 1 LDH elevation. On study day 367, she had grade 3 ALP and grade 2 increased ALT. Dacomitinib was held. Five days later she was admitted to the hospital with grade 3 liver injury, her laboratory results were: ALP 1636 U/L (ref range 45-125 U/L), ALT 239 U/L (ref. range 9- 50 U/L), AST 335 U/L (ref. range 15-40 U/L), Bilirubin 1.7mg /dL (ref. range 0.09-1.0 mg/dL), LDH 427 U/L (ref range 109-245). Tests were negative for right heart congestive failure, ischemia, hypoxia, alcoholic or autoimmune hepatitis, and hepatobiliary obstruction, intrahepatic cholestasis, and non- alcoholic steatohepatitis, and chronic hepatitis C and disease progression. CT scan showed spleen, pancreas, and liver were normal in size, and no masses or swollen lymph nodes in the retroperitoneal area. On (b) (6) days after stopping dacomitinib, the patient died at home, no autopsy was performed. The increased blood lactate dehydrogenase, increased blood alkaline phosphatase, increased alanine aminotransferase, increased conjugated bilirubin, and increased blood bilirubin were presumed ongoing at the time of death. 3 (b) (6) Multiple 45 yom treated with dacomitinib 45 mg on study Death organ day 84 he had grade 2 acneiform rash requiring a attributed dysfunct dose reduction to 30 mg. On (b) (6) he to disease ion experienced global deterioration, dacomitinib progression syndrom was stopped and he was admitted to the hospital , not

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e diagnosed with disease progression and Grade 4 assessed as multiple organ dysfunction syndrome. Nine days treatment- after his last dose, he had patient had respiratory related. and cardiac arrest and died. 4 (b) (6) Broncho 51 yof treated with dacomitinib 45 mg on study Death pulmon day 29 the patient developed bronchitis and attributed ary grade 1 lymphopenia and was treated with to broncho- aspergill levofloxacin and recovered. On study day 37 she pulmonary osis developed grade 2 rash and the dacomitinib dose aspergill- was reduced to 30 mg. On (b) (6) she osis, not developed influenza and was treated with assessed as oseltamivir and levofloxacin. Study day 110 she treatment- developed a productive cough and was treated related. with levofloxacin. Her symptoms persisted and worsened to include purulent sputum. Levofloxacin was repeated. She took her last dose of dacomitinib on (b) (6) , stopping due to pyrexia, cough and dyspnea and was hospitalized for radiological deterioration. On (b) (6) , she was diagnosed with bronchopulmonary aspergillosis and died on (b) (6) days after her last dose of dacomitinib. 5 (b) (6) Lung 59 yom treated with dacomitinib 45 mg ten days Death due infection prior to the start of dacomitinib, the patient was to lung treated for pneumonia. He started treatment infection, with dacomitinib, and on (b) (6) he was not diagnosed with lung infection. On (b) (6) assessed as he was briefly hospitalized for worsening lung treatment- infection. His last dose of dacomitinib was on related. (b) (6) . He remained hospitalized and continued to have respiratory deterioration. On (b) (6) days after his last dose of dacomitinib, he died at home due to respiratory failure. 6 (b) (6) Pneumo 75 yof treated with dacomitinib 45 mg. Her Death due nia baseline electrocardiogram (ECG) QTc interval of to 367 msec and QTcF interval of 364.93 msec. On pneumonia study day -1 her QTc interval of 365 msec and , not QTcF interval of 366.21 msec. On Study Day 15, assessed as Cycle 1 Day 15), the patient’s ECG was treatment- remarkable for increased QTcF interval of 434.9 related. msec (QTcF interval change from baseline was 68.6 msec). She was asymptomatic, and

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dacomitinib dose was not changed. On study day 129, she developed grade 2 dyspnea that persisted and on (b) (6) she was hospitalized. Her CT scan showed diffuse pneumonia, dacomitinib was stopped on (b) (6) On (b) (6) her dyspnea progressed to grade 4 and she was admitted to intensive care, requiring CPAP for respiratory failure. She died on (b) (6) days after her last dose. 7 (b) (6) Pneumo 58 yom treated with dacomitinib 45 mg. On Death due nia (b) (6) he developed productive cough to and dyspnea, and dacomitinib was held. He was pneumonia admitted to the hospital and continued to and disease decline despite treatment. On (b) (6) progression days after his last dose of dacomitinib he and not had a thoracostomy tube placed with pleural assessed as fluid aspiration cytology showed metastatic treatment- adenocarcinoma. On (b) (6) days related. after the last dose of dacomitinib the patient died due to pneumonia, respiratory failure, disease progression. 8 (b) (6) Urinary 81 yof treated with dacomitinib 45 mg. On study Death due Tract day 8 she developed grade 2 nausea that to infection improved to grade 1 on study day 15 without urosepsis, treatment or dose change. On (b) (6) she aspiration developed diarrhea and vomiting and was pneumonia hospitalized. Her urine culture was positive for and renal Escherichia coli, and she had Grade 2 acute failure, not kidney injury, CTCAE Grade 1 dehydration, CTCAE assessed as Grade 1 hyponatremia, CTCAE Grade 1 mucosal treatment- inflammation, CTCAE Grade 2 asthenia, and related. CTCAE Grade 2 nausea, all resolved on (b) (6) except for mucosal inflammation that worsened to grade 2. Dacomitinib was re-started at the 45-mg dose. On day study days 62-77 she was treated with Lasix for urinary retention, and there was no change to dacomitinib dose. Day 87 she developed grade 1 diarrhea, on (b) (6) dacomitinib was held and she was admitted for grade 2 diarrhea, vomiting, asthenia, grade 3 decreased appetite, grade 1 renal failure and dehydration and grade 4 urinary tract infection. Despite treatment, by (b) (6) her condition

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worsened, and she was diagnosed with acute renal failure, aspiration pneumonia, urinary sepsis, respiratory sepsis, hematuria, opiate toxicity, malnutrition, and multiorgan failure. She died on (b) (6) 9 (b) (6) Drug 57 yom treated with dacomitinib 45 mg for 702 Death due over days. Study day 702, his laboratory results to dose showed sodium 118 mEq/L (ref. range 137-147 overdose, mEq/L), ALP 239 U/L (ref. range 45-125 U/L) LDH unclear if 294 U/L (ref. range 109-245 U/L), Hgb 9.8 g/dL intentional (ref. rang e13-17.5 g/dL), dacomitinib was or stopped permanently for global deterioration, accidental, although radiography did not show overt disease not progression. He took a concomitant medication assessed as (diazepam 1 tablet) for insomnia. (b) (6) treatment- after his last dose of dacomitinib, the patient related. died at home. (b) (6) of diazepam were missing, and the cause of death was presumed to be overdose of diazepam. 10 (b) (6) Meta- 49 yof treated with dacomitinib 45 mg. On study Death due stases to day 559 the patient experience global to disease menin- deterioration and was found to have metastases progression ges to meninges. Dacomitinib was stopped on (b) (6) , not and she died (b) (6) after her last dose due assessed as to global deterioration. treatment- related. 11 (b) (6) Cerebral 67 yof treated with dacomitinib 45 mg. On study Death due infarct- day 367 a CT scan showed progressive disease to cerebral ion and new bone metastases. She continued infarction, dacomitinib and was hospitalized for dry cough not and disease progression and on (b) (6) and assessed as dacomitinib was stopped. She died (b) (6) treatment- after her last dose of dacomitinib due to grade 5 related. cerebral infarction. 12 (b) (6) Pneumo 62 yof treated with dacomitinib 45 mg. On study Death due nitis day 85 she developed grade 1 dyspnea. to Dacomitinib was continued. On study day 123 a pneumo- CT scan showed diverticulitis with perforated nitis, sigmoid colon requiring colon resection. She assessed as recovered from the resection, but on study day treatment- 141 was found to have respiratory insufficiency related. and was diagnosed with grade 4 pneumonitis. She died due to pneumonitis and respiratory

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failure on (b) (6) after the last dose of dacomitinib. 13 (b) (6) Respir- 63 yof was treated with dacomitinib 45 mg for a Cause of atory total of (b) (6) and died at home due to death failure “respiratory failure”. No autopsy was performed. unknown, not assessed as treatment- related. 14 (b) (6) Muscu- 79 yof was treated with dacomitinib 45 mg. On Cause of lar study day 57 she required dose reduction to 30 death weak- mg for grade 3 pruritus, grade 2 rhinitis, grade 3 unknown, ness and stomatitis, grade 3 palmar-plantar erytho- possible resp. dysaesthesa. On (b) (6) she developed disease failure paraplegia to the level of the diaphragm. Brain progression MRI did not show metastasis, and her family , not removed her from study. The cause of the assessed as paraplegia was unclear. The patient died at treatment- home on (b) (6) related. 15 (b) (6) Disease 52 yof treated with dacomitinib 45 mg. On study Death due progress day 30 she developed grade 2 paronychia, on day to disease ion 31 her dacomitinib dose was reduced to 30 mg. progression She tolerated dacomitinib well until day 391 pleural when she was found to have disease effusion progression, dacomitinib was continued and and palliative radiation was started. On study day respiratory 559 dacomitinib was discontinued for failure not deterioration. She was then hospitalized for assessed as pleural effusion and continued to worsen. She treatment- died on (b) (6) after the last dose related. of dacomitinib. 16 (b) (6) Disease 73 yom treated with dacomitinib 45 mg. On Death due pro- study day 1 his echocardiogram showed to disease gression pericardial effusion and cardiac tamponade. The progression effusion and tamponade were considered not , not clinically significant because the patient was assessed as asymptomatic. On (b) (6) the patient treatment- presented to the emergency room (ER) with related. dyspnea and cough without expectoration and was diagnosed with Grade 3 cardiac tamponade. No action was taken with study medication. His dyspnea improved without pericardium drainage. On (b) (6) the cardiac

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tamponade resolved, and the patient was discharged from the hospital on the same day. On study day 29 he developed grade 2 asthenia and dyspnea, and grade 1 pyrexia. On s(b) (6) he went to the ER with cachexia and dysphagia and was found to have progressive disease. He died on (b) (6) due to progressive disease. 17 (b) (6) Disease 79 yom treated with dacomitinib 45 mg. On Cause of progress study day 2 developed dyspnea, no action was death ion taken. On study day 15 he developed asthenia unknown, and stopped taking dacomitinib. On (b) (6) not he died and no autopsy was performed. assessed as treatment- related. 18 (b) (6) Disease 63 yom treated with dacomitinib 45 mg. On Death due progress (b) (6) he went to the ER with grade 4 to disease ion hemoptysis, he was stabilized and on study day progression 113 his condition worsened, and he was found to , not have bilateral DVTs. (b) (6) CT showed assessed as progressive disease and on (b) (6) the treatment- patient died due to progressive disease. related. 19 (b) (6) Disease 56 yom treated with dacomitinib 45 mg until Death due progress objective progression on (b) (6) . to disease ion progression , not assessed as treatment- related. 20 (b) (6) Disease 66 yof treated with dacomitinib 45 mg until Death due progress disease progression on (b) (6) She died to disease ion (b) (6) progression , not assessed as treatment- related. 21 (b) (6) Liver 51 yom treated with dacomitinib 45 mg. On Death due Injury study day (-1) the patient was found to have to sepsis, elevated ALP (155 U/L, ref. range 34-114 U/L), drug- bilirubin WNL. On cycle 2, day 1 his ALP was induced WNL (113 U/L). He was treated uneventfully liver injury, until study day 118 his lab results when his lab pulmonary results were ALT 50 IU/L (ref. range 0-42 IU/L), embolism,

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AST 52 IU/L (ref. range 0-42 IU/L). The patient deep vein was admitted with grade 1 liver injury. He thrombosis recovered (lab results ALP, ALT, AST, bilirubin, and multi- and total bilirubin WNL) and was discharged, and organ on(b) (6) he was re-started on dacomitinib 30 disorder, mg. Study day 165 his lab results were elevated assessed as AST 127 IU/L, ALT 83 IU/L, ALP 96 U/L (ref. range treatment- 34-114 U/L), LDH 749.7 U/L) and bilirubin WNL. related. He was diagnosed with grade 2 liver injury and dacomitinib was held, he recovered to grade 1 and was continued dacomitinib 30mg on study day 178. Grade 1 lab results persisted on dacomitinib 30 mg without worsening. On study day 182 he was found to have left leg DVT. Study day 209 he developed an infection (location unspecified) and grade 3 multi-organ failure he was treated, but his condition worsened, and he was diagnosed with pulmonary embolism and disease progression. His last dose of dacomitinib was on (b) (6) He died on (b) (6) after his last dose of dacomitinib. Infection, drug-induced liver injury, pulmonary embolism, deep vein thrombosis and multi-organ disorder were ongoing at the time of death. 22 (b) (6) Disease 61 yom treated with dacomitinib 45 mg. On Death due progress (b) (6) he was diagnosed with pneumonia to disease ion, with requiring thoracostomy drainage, no action was progression grade 2 taken with dacomitinib. On (b) (6) he , not drug- again required thoracostomy drainage for assessed as induced progressive dyspnea. He was then diagnosed treatment- liver with disease progression. He went on to develop related. injury right lung pneumonia, dyspnea, acidosis, vomiting, hypotension, hemoglobin decreased, and hypoproteinemia and died on (b) (6) the same day as the last dose of study medication. (Reviewer Table)

There were four deaths assessed as treatment-related deaths on the dacomitinib arm, with causes of death reported as diarrhea leading to acute renal failure (1), pneumonitis (1), and liver injury not meeting Hy’s Law criteria (2).

Reviewer’s Comment: Reviewer agrees with Pfizer’s determination of attribution of grade 5

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pneumonitis and diarrhea induced renal failure as related to dacomitinib. The reviewer does not agree with Pfizer’s assessment of the 2 cases of grade 5 liver toxicity as described below.

Reviewer's Comment: Hy's Law criteria includes three components:  3-fold or greater elevations above the ULN of ALT or AST  2-fold or greater elevation above the ULN of serum total bilirubin (TBL), without initial findings of cholestasis (elevated serum ALP)  Exclusion of other reason can be found to explain the combination of increased AT and TBL, such as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of causing the observed injury

1 Patient (b) (6) had grade 1 increased ALP noted on cycle 2, cycle 4,5,6,7,8 with no other hepatic laboratory elevations. On study day 367 the laboratory results were:  ALT 4 times the ULN (199.7 U/L) (ref. range 9-50 U/L)  AST 6.2 times the ULN (248.6 U/L) (ref. range 15-40 U/L)  Bilirubin WNL (0.87 mg/dL) (ref. range 0.099-1.00 mg/dL)  ALP 9.8 times the ULN (1227.9 U/L) (ref. range 45-125 U/L)

Other causes of liver enzyme elevation were adequately ruled out. The last dose of dacomitinib was on (b) (6) .

(b) (6) after the last dose), the laboratory results were:  ALT 4.8 times the ULN (239.9 U/L)  AST 8.4 times the ULN (335.6 U/L)  Bilirubin 1.7 times the ULN (1.7 mg/dL)  ALP 13 times the ULN (1636 U/L)

While the ALT, AST, and ALP were markedly increased on cycle 14, the patient’s bilirubin level never exceeded 1.7 x ULN. The narrative and CRF did not report if the patient had bone metastases that could explain the increase ALP. Also, the time course is not consistent with DILI as the death occurred (b) (6) after discontinuation.

2 Patient ID (b) (6) had abnormal laboratory results prior to taking dacomitinib. He required a dose reduction for grade 2 livery injury, and then tolerated dacomitinib at a reduced dose for over 100 days with grade 1 hepatic laboratory elevation. He died due to sepsis on (b) (6) . His final laboratory results are from study day 224:  ALT 2.2 times the ULN (93 U/L) (ref. range 0-42 U/L)  AST 1.3 times the ULN (56 U/L) (ref. range 0-42 U/L)  Bilirubin WNL (0.66 mg/dL) (ref. range 0.35 -1.23 mg/dL)  ALP 1.5 times the ULN (171 U/L) (34-114 U/L)

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 LDH 2 times the ULN (488 U/L) (114-240 U/L)

Overall, these laboratory values are not consistent with Hy’s Law criteria. It is unlikely that the cause of death is attributed only to drug induced hepatotoxicity given the patient’s complicated medical condition (DVT, PE, infection, multi-organ failure).

Table 54 below contains a comparison of deaths on ARCHER 1050 and in the three safety pools. In ARCHER 1050, deaths due to treatment emergent events (TEAE) were observed at similar rates on the dacomitinib arm (10%) and the gefitinib arm (9%). The rate of deaths due to TEAEs in safety pools A and First-line Pool were also similar those in ARCHER 1050. The largest safety pool, Pool B, consisted of patients who had been treated with any number of prior lines of therapy had a higher rate of death related to TEAEs (17%).

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Table 54. Death Due to Treatment Emergent Adverse Events (TEAE)

Grade 5 ARCHER ARCHER Safety Safety First Line Treatment Dacomitinib Gefitinib Pool A Pool B Pool Emergent N=227 N=224 N=394 N=1473 N=225 Adverse Events 22 (10) 20 (9) 44 (11) 246 (17) 24 (10) Disease 8 (4) 11 (5) 10 (3) 90 (6) 9 (4) progression Pneumonia 2 (1) 1 (0.4) 2 (1) 6 (0.4) 2 (1) Respiratory failure 2 (1) 0 2 (1) 8 (0.5) 2 (1) Bronchopulmonary 1 (0.4) 0 1 (0.3) 1 (0.1) 1 (0.4) aspergillosis Cerebral infarction 1 (0.4) 1 (0.4) 1 (0.3) 1 (0.1) 1 (0.4) Death 1 (0.4) 1 (0.4) 2 (1) 8 (1) 1 (0.4) Diarrhea 1 (0.4) 0 1 (0.3) 1 (0.1) 1 (0.4) Lung infection 1 (0.4) 0 5 (1) 10 (1) 1 (0.4) Metastases to 1 (0.4) 0 1 (0.3) 1 (0.1) 1 (0.4) meninges Multiple organ 1 (0.4) 0 1 (0.3) 1 (0.1) 1 (0.4) dysfunction syndrome Pneumonitis 1 (0.4) 0 1 (0.3) 2 (0.1) 1 (0.4) Overdose 1 (0.4) 0 1 (0.3) 1 (0.1) 1 (0.4) Urinary tract 1 (0.4) 0 1 (0.3) 1 (0.1) 1 (0.4) infection Dyspnea 0 2 (1) 0 2 (0.1) 0 General physical 0 1 (0.4) 0 0 0 health deterioration Malignant 0 1 (0.4) 0 0 0 neoplasm progression Malnutrition 0 1 (0.4) 0 0 0 Pleural effusion 0 1 (0.4) 0 0 0 *Percentages Rounded (Source: Adapted from Pfizer’s Table, NDA 211288, ARCHER Interim CSR, ISS Table 14.1.2.1.1.A, and Table 14.1.2.1.1.B)

Reviewer’s Comment: The higher rate of grade 5 TEAE in safety Pool B is likely because while 29% were treated with dacomitinib in the first-line setting, the remaining 71% had more advanced disease (previously treated with systemic therapies, including 35% of these patients treated in the fourth-line setting and beyond).

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Serious Adverse Events (SAE)

Serious adverse events (SAE) are defined as an AE occurring during any study phase that results in death, is immediately life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in significant disability, is a congenital abnormality or birth defect. The incidence of SAEs on ARCHER 1050 occurring in at least 2 patients are provided in Table 55. Overall, there were more SAEs on the dacomitinib arm than the gefitinib arm (27% vs 22%). The most common treatment-related SAEs (>1%) on the dacomitinib arm were diarrhea and interstitial lung disease.

Table 55. ARCHER 1050 SAE in >1% Patients on the Dacomitinib Arm Serious Adverse Events by Preferred DACOMITINIB GEFITINIB Term N=227 (%) N=224 (%) Diarrhea 5 (2.2) 0 Interstitial Lung Disease 2 (1.3) 2 (1) (Source: NDA 211288, ARCHER, Interim datasets, JReview, ADAE)

Dose Interruptions, Dose Reductions, and Permanent Drug Discontinuations Due to Adverse Effects

In ARCHER 1050, 57% (N=130) of dacomitinib-treated patients and 27% (N=60) of the gefitinib- treated patients interrupted treatment due to an AE. The most common AEs leading to drug interruption on the dacomitinib arm were skin toxicities, followed by nail toxicities and diarrhea. See Table 56 for a list of AEs by preferred term occurring in at least one patient on the dacomitinib treatment arm leading to dose interruption.

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Table 56. Dacomitinib Drug Interruptions Due to AE by Preferred Term (PT) Drug Interruptions ARCHER ARCHER Safety Safety for Adverse Events Dacomitinib Gefitinib Pool A Pool B N=227 N=224 N=394 N=1473 Preferred Term 130 (57) 60 (27) 179 (45) 510 (34) Dermatitis 32 (14) 4 (2) 37 (9) 67 (5) acneiform Paronychia 28 (12) 2 (1) 35 (9) 53 (4) Diarrhea 22 (10) 1 (0.4) 36 (9) 156 (11) Rash 11 (5) 1 (0.4) 16 (4) 48 (3) Stomatitis 10 (4) 0 15 (4) 34 (2) Rash maculo- 9 (4) 2 (1) 10 (3) 15 (1) papular Decreased appetite 6 (3) 0 8 (2) 22 (2) Dermatitis 6 (3) 1 (0.4) 6 (2) 6 (0.4) Rash pustular 6 (3) 0 7 (2) 10 (1) Acne 5 (2) 0 8 (2) 11 (1) Asthenia 5 (2) 2 (1) 6 (2) 15 (1) Dry skin 5 (2) 0 5 (2) 14 (1) Mucosal 5 (2) 0 7 (2) 17 (1) inflammation Pruritus 5 (2) 2 (1) 5 (1) 14 (1) Vomiting 5 (2) 1 (0.4) 8 (2) 30 (2) Abdominal pain 4 (2) 0 5 (1) 8 (0.5) Bronchitis 3 (1) 0 3 (1) 5 (0.3) Conjunctivitis 3 (1) 0 3 (1) 6 (0.4) Hypokalemia 3 (1) 0 4 (1) 7 (0.5) Lung infection 3 (1) 0 4 (1) 12 (1) Nausea 3 (1) 0 6 (2) 24 (2) Acute kidney injury 2 (1) 0 3 (1) 7 (0.5) Alanine 2 (1) 19 (9) 3 (1) 3 (0.2) aminotransferase increased Cheilitis 2 (1) 0 2 (1) 4 (0.3) Drug eruption 2 (1) 0 2 (1) 3 (0.2) Dyspnea 2 (1) 1 (0.4) 3 (1) 22 (2) Folliculitis 2 (1) 0 2 (1) 3 (0.2) Hypocalcemia 2 (1) 0 2 (1) 2 (0.1) Ileus 2 (1) 0 2 (1) 2 (0.1) Malaise 2 (1) 1 (0.4) 3 (1) 4 (0.3) Pleural effusion 2 (1) 1 (0.4) 2 (1) 7 (0.5)

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Pneumonia 2 (1) 2 (1) 2 (1) 11 (0.7) Pneumonitis 2 (1) 0 2 (1) 3 (0.2) Vertigo 2 (1) 0 2 (1) 2 (0.1) White blood cell 2 (1) 0 2 (1) 2 (0.1) counts increased *Percentages rounded. (Source: NDA 211288, Interim dataset ADAE, ISS dataset)

Reviewer’s Comment: Percentages in the above table for paronychia and rash may differ slightly from the incidence reported in the USPI as negotiations were ongoing at the time of the creation of this table regarding the exact terms to be included in composite terms used for paronychia and rash.

Dose reductions Due to AE There were eight times more dose reductions due to AEs on the dacomitinib arm compared to the gefitinib arm. The median time to first dose reduction was 15 weeks and 27% of dacomitinib-treated patients required at least two dose reductions. Comparatively, most gefitinib-treated patients tolerated the recommended dose, with less than 10% of gefitinib- treated patients requiring a dose reduction.

Table 57. ARCHER 1050 Dose Reductions Dacomitinib Gefitinib N=227 (%) N=224 (%) Any Dose reduction 150 (66) 18 (8) 1 dose reduction 84 (37) 11 (5) 2 dose reductions 61 (27) 6 (3) >2 dose reductions 5 (2) 1 (0.4) (Source: NDA 211288, ARCHER 1050, Interim dataset, ADAE, AESTDRG)

The most common AEs leading to dose reduction on the dacomitinib arm were skin toxicity (40%; rash 29% using a composite term agreed upon with Pfizer for labeling), followed by nail toxicity (17%), and diarrhea (8%).

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Table 58. TEAE Leading to Dose Reduction in at least 2% of Patients by System Organ Class (SOC) and PT ARCHER: Treatment Emergent Adverse Dacomitinib Gefitinib Events leading to dose reduction in at least N=227 N=224 2% of patients by System Organ Class and Preferred Term Any TEAEs 150 (66) 18 (8) Skin and subcutaneous tissue disorders 91 (40) 4 (2) Dermatitis acneiform 46 (20) 3 (1) Rash maculo-papular 11 (5) 0 Rash 10 (4) 0 Dermatitis 7 (3) 0 Dry skin 7 (3) 0 Palmar-plantar erythrodysaesthesia 5 (2) 0 syndrome Infections and infestations 53 (23) 2 (1) Paronychia 38 (17) 2 (1) Rash pustular 9 (4) 0 Gastrointestinal disorders 27 (12) 3 (1) Diarrhea 19 (8) 3 (1) Stomatitis 6 (3) 0 Investigations 4 (2) 7 (3) Alanine aminotransferase increased 0 6 (3) Aspartate aminotransferase increased 0 5 (2) (Source: NDA 211288, ARCHER 1050, Interim dataset, ADAE)

Permanent Drug Discontinuations for Adverse Effects In ARCHER 1050, 18% (N=40) of dacomitinib-treated patients and 12% (N=27) of gefitinib- treated patients discontinued treatment due to an AE. The most common AE leading to drug discontinuation in either treatment arm was disease progression. Other AEs leading to dacomitinib discontinuation occurring in ≥ 2 patients were rash, interstitial lung disease/pneumonitis, stomatitis, and diarrhea.

Reviewer Comment: Pneumonia, which is listed in the table below with an incidence of 2% for dacomitinib-treated patients, was not considered related to dacomitinib. One patient had preexisting pneumonia prior to starting study treatment, 3 patients had diagnosis of pneumonia concurrent with disease progression, and 1 patient had pneumonia reported in the follow-up phase (while not taking dacomitinib).

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Table 59. ARCHER 1050 Permanent Discontinuation for AE in at Least 1 Dacomitinib Treated Patient Permanent ARCHER ARCHER Safety Safety Discontinuation of Dacomitinib Gefitinib Pool A Pool B Dacomitinib for N=227 N=224 N=394 N=1473 Adverse Event Preferred Term 40 (18) 27 (12) 60 (15) 213 (15) Disease 6 (3) 1 (0.4) 7 (2) 22 (2) progression Pneumonia 5 (2) 1 (0.4) 6 (2) 12 (1) Dermatitis 3 (1) 0 3 (1) 5 (0.3) acneiform Diarrhea 2 (1) 0 2 (0.5) 9 (1) Interstitial lung 2 (1) 1 (0.4) 3 (1) 5 (0.3) disease Pneumonitis 2 (1) 2 (1) 2 (0.5) 4 (0.3) Rash maculo- 2 (1) 0 2 (0.5) 2 (0.1) papular Stomatitis 2 (1) 0 2 (0.5) 7 (0.5) Bronchopulmonary 1 (0.4) 0 1 (0.3) 1 (0.1) aspergillosis Cellulitis 1 (0.4) 0 1 (0.3) 1 (0.1) Cerebral infarction 1 (0.4) 0 1 (0.3) 1 (0.1) Death 1 (0.4) 1 (0.4) 2 (0.5) 6 (0.4) Infection 1 (0.4) 0 1 (0.3) 1 (0.1) Keratitis 1 (0.4) 0 1 (0.3) 1 (0.1) Keratolysis 1 (0.4) 0 1 (0.3) 1 (0.1) exfoliativa acquired Liver injury 1 (0.4) 0 1 (0.3) 1 (0.1) Lung infection 1 (0.4) 0 4 (1) 10 (1) Lymphocyte count 1 (0.4) 0 1 (0.3) 1 (0.1) decreased Malaise 1 (0.4) 0 1 (0.3) 1 (0.1) Malnutrition 1 (0.4) 1 (0.4) 1 (0.3) 1 (0.1) Muscular 1 (0.4) 0 1 (0.3) 1 (0.1) weakness Rash 1 (0.4) 0 1 (0.3) 6 (0.4) Respiratory failure 1 (0.4) 0 1 (0.3) 4 (0.3) Urinary tract 1 (0.4) 0 1 (0.3) 1 (0.1) infection *Percentages rounded. (Source: NDA 211288, Interim dataset ADAE, ISS dataset)

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Significant Adverse Events

The most significant adverse events across studies in Pool A were diarrhea, rash and interstitial lung disease. All grade diarrhea occurred in 86% of dacomitinib-treated patients and grade 3 to 4 diarrhea occurred in 11% of dacomitinib-treated patients. All grade rash occurred in 78% of dacomitinib-treated patients and grade 3 to 4 rash occurred in 21% of dacomitinib-treated patients. Grade 3 to 4 interstitial lung disease (ILD) occurred in 0.5% of dacomitinib-treated patients. These significant adverse events are highlighted in product labeling under warnings and precautions.

Hy’s Law Evaluation To evaluate the potential significant event of drug-induced liver injury (DILI) for dacomitinib- treated patients, a Hy’s Law plot was created. The upper right quadrant shows representations for patients with laboratory values that may meet Hy’s Law criteria. The blue round figure represents Patient ID (b) (6) . This patient was a 49-year-old female treated with dacomitinib (b) (6) and was taken off study for disease progression. Her laboratory results are not consistent with DILI, as indicated by the blue color on the plot. The pink round figure in the upper right quadrant represents Patient ID (b) (6) This patient’s laboratory values are presented in Table 53 Deaths, and with a bilirubin value that never met 2xULN, and therefore this patient does not meet the Hy’s Law criteria. Overall, there were fewer hepatic laboratory elevations on the dacomitinib arm compared to the gefitinib arm.

Figure 11. ARCHER 1050 Hy’s Law Plot

(Source: NDA 211288, ARCHER 1050, Interim dataset, ADAE, JReview)

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Treatment Emergent Adverse Events and Adverse Reactions

Table 60 lists the TEAEs observed in ARCHER 1050 and the two large safety pools. All grade AEs by preferred term reported in ≥ 20% of dacomitinib-treated patients on ARCHER 1050 are: diarrhea (87%), rash (69%), paronychia (64%), stomatitis (45%), decreased appetite (31%), dry skin (30%), decreased weight (26%), alopecia (23%), cough (21%) and pruritus (21%).

All grade AEs by preferred term reported in ≥ 20% of dacomitinib-treated patients in Pool A are: diarrhea (86%), rash (86%), paronychia (55%), stomatitis (44%), decreased appetite (28%), dry skin (50%), decreased weight (22%), alopecia (17%) and pruritus (21%).

All grade AEs by preferred term reported in ≥ 20% of dacomitinib-treated patients in Pool B are: diarrhea (80%), rash (77%), paronychia (%), stomatitis (34%), decreased appetite (32%), dry skin (28%), decreased weight (16%), alopecia (7%) and pruritus (17%). The incidence of AE observed on Pool B is similar to ARCHER 1050 and Pool A, despite the median duration of exposure to dacomitinib for patients in Pool B being only 12 weeks.

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Table 60. Treatment Emergent Adverse Events for ARCHER, Pool A and Pool B

ARCHER 1050 Study Pool A Pool B Treatment Emergent Dacomitinib Gefitinib N=394 N=1473

Adverse Events N=227 N=224 All Grade Grade 3-4 All Grade Grade 3-4 All Grade Grade 3-4 All Grade Grade 3-4 Any TEAE 226 (99.6) 140 (61.7) 220 (96 9) 87 (38.8) 393 (99.7) 239 (60.7) 1464 (99.4) 814 (55.3) Gastrointestinal disorders 212 (93.4) 36 (15.9) 175 (78.1) 6 (2.7) 366 (92.9) 69 (17.5) 1314 (89.2) 265 (18) Diarrhoea 198 (87.2) 20 (8.8) 125 (55.8) 2 (0.9) 340 (86.3) 43 (10.9) 1179 (80) 173 (11.7) Stomatitis 99 (43.6) 8 (3.5) 40 (17.9) 1 (0.4) 173 (43.9) 12 (3) 498 (33.8) 38 (2.6) Nausea 43 (18.9) 3 (1.3) 49 (21.9) 1 (0.4) 80 (20.3) 4 (1) 367 (24.9) 26 (1.8) Constipation 30 (13.2) 0 (0) 31 (13.8) 0 (0) 53 (13.5) 0 (0) 173 (11.7) 3 (0.2) Mouth ulceration 28 (12.3) 0 (0) 13 (5.8) 0 (0) 32 (8.1) 0 (0) 35 (2.4) 0 (0) Vomiting 20 (8.8) 2 (0.9) 29 (12.9) 0 (0) 50 (12.7) 6 (1.5) 284 (19.3) 26 (1.8) Skin and subcutaneous tissue disorders 208 (91.6) 65 (28.6) 167 (74.6) 5 (2.2) 359 (91.1) 103 (26.1) 1268 (86.1) 244 (16.6) Dermatitis acneiform 111 (48.9) 31 (13.7) 64 (28.6) 0 (0) 195 (49.5) 50 (12.7) 685 (46.5) 118 (8) Dry skin 63 (27.8) 3 (1.3) 38 (17) 0 (0) 120 (30.5) 5 (1.3) 405 (27.5) 10 (0.7) Alopecia 53 (23.3) 1 (0.4) 28 (12.5) 0 (0) 66 (16.8) 1 (0.3) 101 (6.9) 1 (0.1) Pruritus 45 (19.8) 1 (0.4) 32 (14.3) 3 (1.3) 84 (21.3) 3 (0.8) 243 (16.5) 15 (1) Rash 40 (17.6) 10 (4.4) 24 (10.7) 0 (0) 62 (15.7) 14 (3.6) 285 (19.3) 42 (2.9) Palmar-plantar erythrodysaesthesia syndrome 33 (14.5) 2 (0.9) 7 (3.1) 0 (0) 60 (15.2) 6 (1.5) 152 (10.3) 15 (1) Rash maculo-papular 28 (12.3) 10 (4.4) 27 (12.1) 1 (0.4) 50 (12.7) 12 (3) 121 (8.2) 24 (1.6) Dermatitis 25 (11) 4 (1.8) 9 (4) 1 (0.4) 29 (7.4) 5 (1.3) 38 (2.6) 7 (0.5) Infections and infestations 180 (79.3) 44 (19.4) 115 (51.3) 11 (4.9) 300 (76.1) 62 (15.7) 818 (55.5) 160 (10.9) Paronychia 140 (61.7) 17 (7.5) 45 (20.1) 3 (1.3) 218 (55.3) 28 (7.1) 471 (32) 45 (3.1) Conjunctivitis 43 (18.9) 0 (0) 9 (4) 0 (0) 57 (14.5) 0 (0) 143 (9.7) 6 (0.4) Upper respiratory tract infection 28 (12.3) 3 (1.3) 28 (12.5) 0 (0) 43 (10.9) 3 (0.8) 82 (5.6) 3 (0.2) Investigations 134 (59) 18 (7.9) 140 (62.5) 34 (15.2) 169 (42.9) 26 (6.6) 393 (26.7) 61 (4.1) Weight decreased 58 (25.6) 5 (2.2) 37 (16.5) 1 (0.4) 85 (21.6) 6 (1.5) 229 (15.5) 10 (0.7) Alanine aminotransferase increased 44 (19.4) 2 (0.9) 88 (39.3) 19 (8.5) 49 (12.4) 4 (1) 63 (4.3) 8 (0.5) Aspartate aminotransferase increased 42 (18.5) 0 (0) 81 (36.2) 9 (4) 46 (11.7) 1 (0.3) 69 (4.7) 4 (0.3) Respiratory, thoracic and mediastinal disorders 124 (54.6) 16 (7) 98 (43.8) 9 (4) 221 (56.1) 23 (5.8) 791 (53.7) 147 (10) Cough 48 (21.1) 0 (0) 42 (18.8) 1 (0.4) 78 (19.8) 0 (0) 237 (16.1) 2 (0.1) Dyspnoea 30 (13.2) 5 (2.2) 30 (13.4) 5 (2.2) 57 (14.5) 10 (2.5) 294 (20) 92 (6.2) General disorders and administration site conditio 118 (52) 14 (6.2) 104 (46.4) 7 (3.1) 206 (52.3) 30 (7.6) 850 (57.7) 149 (10.1) Asthenia 29 (12.8) 5 (2.2) 28 (12.5) 3 (1.3) 38 (9.6) 8 (2) 120 (8.1) 26 (1.8) Chest pain 22 (9.7) 0 (0) 32 (14.3) 0 (0) 31 (7.9) 0 (0) 73 (5) 7 (0.5) Metabolism and nutrition disorders 106 (46.7) 20 (8.8) 80 (35.7) 13 (5.8) 163 (41.4) 31 (7.9) 622 (42.2) 131 (8.9) Decreased appetite 70 (30.8) 7 (3.1) 56 (25) 1 (0.4) 111 (28.2) 8 (2) 466 (31.6) 39 (2.6) Musculoskeletal and connective tissue disorders 84 (37) 6 (2.6) 86 (38.4) 2 (0.9) 149 (37.8) 13 (3.3) 434 (29.5) 50 (3.4) Pain in extremity 31 (13.7) 0 (0) 26 (11.6) 0 (0) 49 (12.4) 2 (0.5) 121 (8.2) 8 (0.5) Musculoskeletal pain 26 (11.5) 2 (0.9) 28 (12.5) 0 (0) 38 (9.6) 2 (0.5) 72 (4.9) 5 (0.3) Back pain 18 (7.9) 0 (0) 35 (15.6) 1 (0.4) 36 (9.1) 4 (1) 123 (8.4) 17 (1.2) Psychiatric disorders 33 (14.5) 1 (0.4) 45 (20.1) 3 (1.3) 56 (14.2) 2 (0.5) 181 (12.3) 13 (0.9) Insomnia 24 (10.6) 1 (0.4) 33 (14.7) 0 (0) 35 (8.9) 1 (0.3) 89 (6) 1 (0.1)

*Percentages rounded. (Source: NDA 211288, Interim dataset ADAE, ISS dataset)

Reviewer’s comment: In the paragraph above Table 60 and in product labeling preferred terms were combined to create composite terms for certain toxicities to more accurately reflect the incidence of AEs. The percentages from Table 60 cannot simply be combined to calculate the actual incidence of AE due to duplicate reporting. For example, the composite term “Rash” includes dermatitis acneiform, rash, rash maculopapular. Using Table 60, addition of the percentages for these terms yields 78%, but with duplicates removed the incidence for the

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grouped term “rash” is 69%. Paronychia is a grouped term that includes nail infection, nail toxicity, onychoclasis, onycholysis, onychomadesis, paronychia. Dry skin is a grouped term that includes dry skin, xerosis. Stomatitis is a grouped term that includes mucosal inflammation and stomatitis, however mouth ulceration is listed separately.

Laboratory Findings

In ARCHER 1050, laboratory tests to assess serum chemistry (sodium, potassium chloride, serum creatinine, glucose, magnesium, phosphorus, calcium), liver function (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP] and bilirubin), and complete blood count (CBC) were obtained at screening (day -1 to -14) and day 1 of each cycle. Laboratory alterations, graded per NCI CTCAE v.4.0, from baseline through any time during the study were analyzed and the findings are shown in Table 60. Overall, the incidence of laboratory abnormalities that were shifts from baseline to Grade 3 or 4 were uncommon for dacomitinib-treated patients. Hematologic alteration from baseline to Grade 3 or 4 on the dacomitinib arm were observed for anemia (0.9%) and lymphopenia (6%). Shifts to Grade 3 or 4 for hepatic laboratory parameters (ALT, AST and alkaline phosphatase) were more common on the gefitinib arm than on the dacomitinib arm. The incidence of hepatic parameters to Grade 3 or 4 were less than 2% on the dacomitinib arm, and were 13%, 8% and 2% respectively on the gefitinib arm. There were more Grade 3 or 4 shifts from baseline on the gefitinib arm for hyperglycemia and hypocalcemia compared to dacomitinib. There were more shifts to Grade 3 or 4 hypokalemia and hyponatremia on the dacomitinib arm, likely due to the high rate of diarrhea for dacomitinib-treated patients.

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Table 61. Laboratory abnormalities Worsening from Baseline in ≥20% of Patients in ARCHER 1050

Laboratory Test Dacomitinib Gefitinib Abnormality Change from Change from Change from Change from Baseline All Baseline to Baseline All Baseline to Grades Grade 3 or 4 Grades Grade 3 or 4 (%) (%) (%) (%) Hematology Anemia 44 0.9 26 2.7 Lymphopenia 42 6 35 2.7 Hepatic Increased ALT 40 1.4 63 13 Increased AST 35 0.5 57 8 Increased ALP 22 0.5 21 2 Hyperbilirubinemia 16 0.5 22 0.5 Chemistry Hyperglycemia 36 1 38 2.5 Hypocalcemia 33 1.4 28 2 Hypokalemia 29 7 18 2 Hyponatremia 26 2.9 20 1.5 Hypomagnesemia 22 0.5 9 0 Hypoalbuminemia 44 0 34 0 Renal Increased creatinine* 24 0 16 0.5 *Increased creatinine does not include Grade 1 elevations if value was still less than upper limit of normal (Source: NDA 211288, ARCHER 1050, Interim dataset, LB)

Reviewer’s Comment: TEAE hepatic elevations occurred more frequently on the gefitinib arm compared to the dacomitinib arm. See Appendix 2 for summary and individual laboratory shift tables.

Vital Signs

Overall, there were no clinically significant trends in the vital signs of dacomitinib-treated patients. Weight loss (decrease from baseline of 10% or more) was observed in 20% of dacomitinib-treated patients and 13% of gefitinib-treated patients. The mean seated pulse rate for dacomitinib treated patients varied from 72 – 82 beats per minute, the seated mean systolic blood pressure varied from 113-130 mmHg, and the seated mean diastolic blood pressure varied from 72-85mmHg.

Reviewer's Comment: See Appendix 3 for graphics of mean heart rate, systolic and diastolic

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blood pressure.

Electrocardiograms (ECGs)

For details, please refer to the review by the Clinical Pharmacology team, Section 6. See also the review by the QT-IRT team.

QT

For full details, please see the review by FDA’s Interdisciplinary Review Team (IRT)-QT Team. Dacomitinib did not prolong QTc to any clinically relevant extent (90% CIs of mean ΔQTcF <20 ms) at therapeutic maximum concentrations expected following the recommended 45 mg once daily dose.

Immunogenicity

Not applicable.

8.2.5 Analysis of Submission-Specific Safety Issues

Diarrhea

Diarrhea was observed on both treatment arms of ARCHER 1050. TEAE diarrhea was observed in 87% of dacomitinib-treated patients and 56% of gefitinib-treated patients. Ten percent of dacomitinib-treated patients required dose interruption for diarrhea and 0.4% of gefitinib- treated patients required dose interruption. Eight percent of dacomitinib-treated patients required dose reduction for diarrhea and 1% of gefitinib-treated patients required dose reduction. One percent of dacomitinib-treated patients required permanent discontinuation for diarrhea while no gefitinib-treated patients required permanent discontinuation. There was one dacomitinib-treated patient death attributed to diarrhea that lead to dehydration and acute renal failure. There were no deaths related to diarrhea on the gefitinib treatment arm.

Rash

Rash was observed on both treatment arms of ARCHER 1050. TEAE rash was observed in 69% of dacomitinib-treated patients and 47% of gefitinib-treated patients. Twenty-three percent of dacomitinib-treated patients required dose interruption for rash and 3.4% of gefitinib-treated patients required dose interruption. Twenty-nine percent of dacomitinib-treated patients required dose reduction for rash and 1% of gefitinib-treated patients required dose reduction. Two and a half percent of dacomitinib-treated patients required permanent discontinuation for rash while no gefitinib-treated patients required permanent discontinuation. There were no deaths attributed to rash on either treatment arm. Skin exfoliation was reported for 7

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dacomitinib-treated patients (3.1%). Skin exfoliation was not observed on the gefitinib- treatment arm.

Stomatitis

Stomatitis was observed on both treatment arms of ARCHER 1050. TEAE stomatitis was observed in 45% of dacomitinib-treated patients and 19% of gefitinib-treated patients. Four percent of dacomitinib-treated patients required dose interruption for stomatitis while no gefitinib-treated patients required dose interruption. Three percent of dacomitinib-treated patients required dose reduction for stomatitis and 1% of gefitinib-treated patients required dose reduction. One percent of dacomitinib-treated patients required permanent discontinuation for stomatitis while no gefitinib-treated patients required permanent discontinuation. There were no deaths attributed to stomatitis on either treatment arm.

Interstitial Lung Disease (ILD)

ILD was observed on both treatment arms of ARCHER 1050. TEAE ILD was observed in 1.3% of dacomitinib-treated patients and 1% of gefitinib-treated patients. One percent of dacomitinib- treated patients required dose interruption for ILD while no gefitinib-treated patients required dose interruption. Two percent of dacomitinib-treated patients required permanent discontinuation for ILD while 1.4% gefitinib-treated patients required permanent discontinuation. On the dacomitinib arm, there was one death due to ILD.

Keratitis

Keratitis was observed only on the dacomitinib treatment arm of ARCHER 1050. Of the dacomitinib-treated patients, 1.8% had TEAE keratitis. One patient (0.4%) permanently discontinued treatment with dacomitinib for keratitis.

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

Patient reported outcomes (PRO) were collected on day 1 of each cycle and at the end of treatment visit and at the post-treatment follow up visit.

To assess health related quality of life and disease and treatment-related symptoms two questionnaires were used: • European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–30 (items) (EORTC QLQ-C30) • European Organization for Research and Treatment of Cancer Lung Cancer Module of the Quality of Life Questionnaire-13 (items) (EORTC QLQ-LC13)

To assess general health status one questionnaire was used: • EuroQol-5 Dimensions (EQ-5D)23 questionnaire

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Questionnaire compliance rate was >90% for most treatment cycles. Overall, there was no statistically significant difference in the patient’s report of time to deterioration for pain, dyspnea, fatigue, or cough between the study arms. Dacomitinib-treated patients reported worse scores for symptoms of diarrhea, sore mouth, dysphagia, peripheral neuropathy, and alopecia compared to gefitinib-treated patients.

Reviewer Comment: PRO questionnaire results did not show improvement in QOL for dacomitinib-treated patients. Patients treated with dacomitinib reported more diarrhea, sore mouth, dysphagia, peripheral neuropathy and alopecia compared to patients treated with gefitinib.

8.2.7 Safety Analyses by Demographic Subgroups

ARCHER 1050 Demographic Subgroup: Gender An exploratory subgroup analysis of AEs from ARCHER 1050 was conducted based upon gender. The all grade AE with ≥5% difference in incidence between female and male reported higher in females and were: diarrhea (89% vs. 84%), stomatitis (71% vs. 67%), nausea (22% vs. 14%), rash (84% vs. 75%), nail disorder (70% vs. 58%), alopecia (30% vs. 12%), hypokalemia (14% vs. 4%), decreased weight (29% vs. 20%), and conjunctivitis (30% vs. 14%).

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Table 62. ARCHER 1050: Adverse Events by Gender Male Female (N=81) (N=146) Adverse \System Organ Class Reactions All Grade Grade All Grade Grade Grades 3 4 Grades 3 4

% % % % % % Diarrhea 84 6 0 89 10 0 Gastrointestinal disorders Stomatitis 67 2.5 1.2 71 6 0 Nausea 14 1.2 0 22 1.4 0 Rashd 75 16 0 84 30 0 Skin and subcutaneous tissue Nail disorder 58 4.9 0 70 10 0 disorders Dry skin 27 0 0 31 2.7 0 Alopecia 12 0 0 30 0.7 0 Decreased 30 1.2 0 32 4.1 0 Metabolism and nutrition appetite disorders Hypokalemia 3.7 1.2 0 14 5.5 1.4 Weight Investigations 20 1.2 0 29 2.7 0 decreased Eye disorders Conjunctivitis 13 0 0 30 0.7 0 General disorders and Asthenia 12 2.5 0 13 2.1 0 administration site conditions (Source: NDA 211288, ARCHER 1050, Interim dataset, ADAE)

Reviewer Comment: Analyses based on gender in ARCHER 1050 are exploratory and based on the small sample size for males, the observed differences are difficult to interpret.

ARCHER 1050 Demographic Subgroup: Race An exploratory subgroup analysis of adverse events from ARCHER 1050 was conducted based upon race (Asian vs. Non-Asian). The all grade AE with ≥5% difference in incidence between Asian and Non-Asian that were higher in Asians were: diarrhea (91% vs. 77%), stomatitis (76% vs. 51%), rash (82% vs. 79%), nail disorder (67% vs. 61%), decreased appetite (34% vs. 23%), and decreased weight (34% vs. 0). The AE reported higher in Non-Asian compared to Asian race were: dry skin (44% vs.25%), conjunctivitis (30% vs. 22%) and asthenia (35% vs. 5%).

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Table 63. ARCHER 1050: Adverse Events by Race Asian Non-Asian (N=170) (N=57) Adverse System Organ Class Reactions All Grade Grade All Grade Grade Grades 3 4 Grades 3 4

% % % % % % Diarrhea 90.6 7.1 0 77.2 12.3 0 Gastrointestinal disorders Stomatitis 75.9 4.7 0 50.9 3.5 1.8 Nausea 18 1.2 0 21.1 1.8 0 Rash 82 25 0 79 26 0 Skin and subcutaneous tissue Nail disorder 67 9 0 61 5 0 disorders Dry skin 25 1.8 0 44 1.8 0 Alopecia 24 0.6 0 23 0 0 Decreased 34 2.9 0 23 3.5 0 Metabolism and nutrition appetite disorders Hypokalemia 9 3.5 0.6 12 5 1.8 Weight Investigations 34 2.9 0 0 0 0 decreased Eye disorders Conjunctivitis 22 0.6 0 30 0 0 General disorders and Asthenia 5 0.6 0 35 7 0 administration site conditions (Source: NDA 211288, ARCHER 1050, Interim dataset, ADAE)

Reviewer Comment: Analyses based on race in ARCHER 1050 are exploratory and based on the small sample size for Non-Asians, the observed differences are difficult to interpret.

ARCHER 1050 Demographic Subgroup: Age An exploratory subgroup analysis of adverse events from ARCHER 1050 was conducted based upon age over 65 years compared to age 65 years and younger. The AE with ≥5% difference between patients over age 65 and those 65 years and younger that were higher in patients over age 65 were: dry skin (37% vs. 25%), decreased appetite (40% vs. 25%), conjunctivitis (28% vs. 22%) and asthenia (20% vs. 8%). The AE with a higher incidence in patients aged 65 years or younger was decreased weight (28% vs. 21%).

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Table 64. ARCHER 1050: Adverse Events by Age > 65 <= 65 (N=89) (N=138) Adverse System Organ Class Reactions All Grade Grade All Grade Grade Grades 3 4 Grades 3 4

% % % % % % Diarrhea 85 10 0 88 7 0 Gastrointestinal disorders Stomatitis 72 3.4 1.1 68 5 0 Nausea 18 0 0 20 2.2 0 Rash 79 27 0 83 24 0 Skin and subcutaneous tissue Nail disorder 64 7 0 67 9 0 disorders Dry skin 37 3.4 0 25 0.7 0 Alopecia 25 0 0 23 0.7 0 Decreased 40 6 0 25 1.4 0 Metabolism and nutrition appetite disorders Hypokalemia 8 3.4 1.1 12 4 0.7 Weight Investigations 21 1.1 0 28 2.9 0 decreased Eye disorders Conjunctivitis 28 0 0 22 0.7 0 General disorders and Asthenia 20 6 0 8 0 0 administration site conditions (Source: NDA 211288, ARCHER 1050, Interim dataset, ADAE)

Reviewer Comment: While increased incidences of asthenia and decreased appetite are not unexpected in the older subgroup of patients, analyses based on age in ARCHER 1050 are exploratory and based on the relatively small sample size for those over age 65 years, the observed differences are difficult to interpret.

Pool A Demographic Subgroup: Age

There were fewer SAE, grade 3 or 4 AE, drug discontinuations, and dose reductions in dacomitinib-treated patients aged less than 65 years than those 65 years and older. All grade AE and grade 5 AE were equal between younger and older patients.

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Table 65. Overview of TEAEs in Dacomitinib – Treated Patients Age <65 Age ≥65 N=236 N=158

All Grade Adverse Events 236 (100) 157 (99)

Serious Adverse Events 60 (25) 54 (34)

Grade 3 or 4 Adverse Events 133 (56) 106 (67)

Grade 5 Adverse Events 26 (11) 18 (11)

Drug Discontinued for 23 (10) 38 (24) Adverse Events Dose Reduced for 98 (42) 70 (44) Adverse Events Drug Interrupted for 99 (42) 37 (23) Adverse Events (Source: NDA 211288, ISS, ADAE dataset.)

8.2.8 Specific Safety Studies/Clinical Trials

There were no specific safety studies included as part of this NDA submission.

8.2.9 Additional Safety Explorations

Human Carcinogenicity or Tumor Development

See Pharmacology/ Toxicology Review.

Human Reproduction and Pregnancy

See Pharmacology/ Toxicology Review.

Pediatrics and Assessment of Effects on Growth

Dacomitinib was not studied in pediatric patients.

Overdose, Drug Abuse Potential, Withdrawal, and Rebound

There is no available data on overdose of dacomitinib. There is no drug abuse potential with dacomitinib. Withdrawal and rebound are not relevant to dacomitinib.

120 Day Safety Update The 120-day safety update provides additional safety data from the original data cut-off (July 29, 2016) through February 17, 2017. The treatment duration for both dacomitinib and 148 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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gefitinib are unchanged from the original data cut-off. Three deaths occurred during this period. On the dacomitinib arm, there was one additional death due to disease progression. On the gefitinib arm, there were two additional deaths due to disease progression. There were no safety signals. For SAE on the dacomitinib arm, there was 1 additional case of decreased appetite and 1 additional case of metastases to the meninges. SAEs for the gefitinib arm included 4 additional cases of disease progression, 2 additional cases of cerebral infarction and 2 additional cases of malignant neoplasm progression. For TEAE on the dacomitinib arm, there was 1 additional case of anemia and 1 additional case of nausea. There were no additional TEAE for the gefitinib arm.

8.2.10 Safety in the Post Marketing Setting

Safety Concerns Identified Through Post Marketing Experience

Not applicable, dacomitinib has not previously been approved in any country.

Expectations on Safety in the Post Marketing Setting

Safety of dacomitinib in the post-market setting is not expected to differ significantly from that observed in the studies assessed during the safety review of this NDA as the study populations are reflective of the patients expected to be treated with dacomitinib in the post-market setting.

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8.2.11 Integrated Assessment of Safety As of July 29, 2016, (data cut-off) 2148 patients have received dacomitinib. A total of 1975 patients received single-agent dacomitinib, while 173 patients received dacomitinib in combination with other drugs. The largest safety pool is Pool B consisting of previously treated or first-line patients with NSCLC who received single-agent dacomitinib at a starting dose of 45 mg daily in the presence or absence of EGFR-activating mutations (1473 treated patients in 10 completed studies).

The treatment duration for ARCHER 1050 was 67 weeks for the dacomitinib arm and 52 weeks for the gefitinib arm. The treatment duration for the largest safety pool, Pool B was 12 weeks. Adverse events were observed in similar frequencies between ARCHER 1050 and Pool B, see table 66 below.

Table 66. Adverse Events ≥30% in ARCHER 1050 and Safety Pool B

All Grade Adverse Events by Archer 1050 Pool B Preferred Term N=227 N=1473 Diarrhea 80% 87% Dermatitis acneiform 47% 49% Stomatitis 34% 44% Paronychia 32% 62% Decreased Appetite 32% 31% Source: NDA 211288 ISS, ADAE dataset.

Grade 5 AE were observed in similar frequencies between ARCHER 1050 and Pool B. Ten percent of patients on ARCHER 1050 had grade 5 AE, the most frequent attribution was disease progression (4%). Seventeen percent of patients in Pool B had grade 4 AE, the most frequent attributions were disease progression (6%) and NSCLC (5%).

SAEs were reported for 27% of dacomitinib-treated patients on ARCHER 1050 and 35% of patients in Pool B. For dacomitinib-treated patients on ARCHER 1050, the most frequently reported SAEs (frequency ≥2% of patients) in the dacomitinib arm were disease progression (3.5%) and diarrhea, pleural effusion, and pneumonia (2.2% each). The most frequently reported SAEs (frequency ≥3% of patients) in Pool B were disease progression (6%), NSCLC (5%), diarrhea (4%), and dyspnea (3%).

Permanent discontinuations for AEs were required in 18% of dacomitinib-treated patients on ARCHER 1050, and 16% of patients in Pool B. The most common reasons for permanent discontinuation of dacomitinib are disease progression, rash, and pneumonia.

The safety database for dacomitinib is sufficiently large to predict toxicities expected in the post marketing setting. The overall toxicity profile of dacomitinib is similar to other approved tyrosine kinase inhibitors (TKIs). Dacomitinib will be prescribed by oncology health care

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providers who are skilled in managing toxicities associated with TKIs.

10 SUMMARY AND CONCLUSIONS

10.1 Statistical Issues

Dacomitinib was shown to prolong PFS compared to gefitinib based on a stratified log-rank test stratified by the pre-specified stratification factors. The HR is 0.59 (95% CI: 0.47, 0.74) and median PFS was 14.7 months in the dacomitinib arm and 9.2 months in the gefitinib arm.

The secondary endpoints were ORR and OS. According to the protocol, if PFS was statistically significant, then the testing order would be ORR followed by OS. ORR failed to show a statistically significant difference compared with the gefitinib arm. Since the test for ORR was not statistically significant there was no alpha left to test for OS.

The OS curves cross at approximately 12 months. The assumption of proportional hazards is violated. Therefore, hazard ratio may not be appropriate to summarize the treatment effects on OS and the KM-estimated medians are not appropriate to characterize treatment effects on OS. Kaplan-Meier Curves are more appropriate to summarize OS. Various analyses conducted did not identify reasons for the crossing.

10.2 Conclusions and Recommendations

This application relies on the results of ARCHER 1050, a randomized, multicenter, active- controlled trial conducted in patients with untreated EGFR-mutation positive NSCLC (exon 19 deletion or the L858R mutation in exon 21) and patients with previously treated EGFR-mutation positive NSCLC with a minimum of 12-month disease free interval between completion of systemic therapy and recurrence of NSCLC. The clinical review determined that ARCHER 1050 is an adequate and well-controlled trial that demonstrates a statistically significant and clinically meaningful improvement in PFS as compared to gefitinib, a first-generation EGFR TKI. Dacomitinib demonstrated a median PFS of 14.7 months as compared to 9.2 months with gefitinib with a HR 0.59 (95% CI: 0.47, 0.74). There is no suggestion of a detrimental effect of dacomitinib on OS. The safety profile of dacomitinib is acceptable relative to the demonstrated clinical benefits in the context of a life-threatening disease. Adverse reactions observed with dacomitinib are similar to those reported for approved EGFR TKIs. The most common (>20%) adverse reactions in patients treated with dacomitinib were diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus. Serious adverse reactions identified during this review were ILD, diarrhea and dermatologic adverse reactions. These safety concerns are adequately addressed by information in the Warnings and Precautions section and the dose modification recommendations included in the product labeling to allow

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treating oncologists to effectively manage these toxicities. A large proportion of patients in ARCHER 1050 required interruption (57%) or dose reduction (66%) of dacomitinib for adverse reactions; however, only 18% of dacomitinib-treated patients permanently discontinued dacomitinib due to adverse reactions, indicating toxicities can generally be managed through dose modification. The review team recommends regular approval of dacomitinib for the first-line treatment of patients with NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test based on the demonstration of substantial evidence of effectiveness and a favorable benefit-risk profile for a serious and life-threatening disease.

Weishi (Vivian) Yuan, PhD Kun He, PhD

Primary Statistical Reviewer Statistical Team Leader

Barbara Scepura, BSN, MS, CRNP Erin Larkins, MD

Primary Clinical Reviewer Clinical Team Leader

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11. Advisory Committee Meeting and Other External Consultations

No advisory committee meeting was requested for this application and no external consultations were required because the safety profile is acceptable for the treatment of patients with metastatic EGFR mutation-positive NSCLC, the application did not raise significant public health questions on the role of dacomitinib for this indication and outside expertise was not necessary since there were no controversial issues that would benefit from an advisory committee discussion.

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12 Pediatrics

This application is exempt from the requirements under the Pediatric Research Equity Act (PREA). Dacomitinib was granted orphan drug designation on March 3, 2015, for the treatment of non-small cell lung cancer (NSCLC) with EGFR, HER2, HER4, or discoidin domain receptor tyrosine kinase 2 (DDR2) mutations.

APPEARS THIS WAY ON ORIGINAL

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13 Labeling Recommendations

13.1 Prescription Drug Labeling

Labeling negotiations are ongoing at the time of review. Refer to the USPI for dacomitinib once labeling is finalized. The table below summarizes high-level issues regarding the labeling submitted by Pfizer.

Table 67. Summary of Labeling Changes Summary of Significant Labeling Changes (High level changes and not direct quotations) Section Proposed Labeling Approved Labeling (b) (4) Section 1, Indications and Indicated for the first-line Usage treatment of patients with (b) (4) metastatic NSCLC with EGFR- (b) (4) mutations

Section 2.1 Patient Selection Establish EGFR mutation Modified to clarify that status prior to initiation. patients should be selected for treatment based on the presence of EGFR exon 19 deletion or exon 21 L858R substitution mutation in tumor specimens to align with indication

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Section 5, Warnings and Information presented in this Modified to present Precautions section was based on data information based on data from the largest safety pool, from safety Pool A. Pool A Pool B, comprised of patients was comprised of patients with NSCLC regardless of with EGFR mutation-positive EGFR mutation status treated NSCLC treated at the at the recommended dose of recommended dose of VIZIMPRO. VIZIMPRO. Patients in Pool A had similar dose intensity and duration of exposure to the patients in ARCHER 1050. The population in Pool A is more appropriate use, as it is consistent with the patient population expected to be treated with dacomitinib following approval.

Recommendation for Grade 2 Recommendation for Grade 2 (b) (4) diarrhea modified to withhold until recovery to less than or equal to Grade 1 then resume at the same dose level. Added recommendation to withhold until recovery to less than or equal to Grade 1 then resume at a reduced dose for recurrent Grade 2 diarrhea.

Changed to Dermatologic Adverse Reactions Recommendation for Grade 2 dermatologic adverse Recommendation for Grade 2 (b) (4) dermatologic adverse reactions modified to withhold for persistent dermatologic adverse reactions until recovery to less than or equal to Grade 1 then resume at the same dose level. Added recommendation to withhold

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until recovery to less than or equal to Grade 1 then resume at a reduced dose for recurrent persistent Grade 2 dermatologic adverse reactions.

Clinical Trial Experience Section 6.1, Clinical Trials Referenced Pool B when Modified to reference Pool A Experience discussing data which when discussing data which informed Section 5 and informed Section 5 and did included extensive details not include specifics of regarding the patient demographic or patient population in Pool B. characteristics for patients in the pooled safety population.

Adverse reactions table Modified some of the included use of composite composite terms and added terms for some adverse composite terms for nasal reactions (stomatitis, rash, mucosal disorders. Added nail disorder, dry skin, multiple adverse reactions conjunctivitis). (b) (4) with incidence ≥10% which Pfizer had left out of the table. (b) (4)

Laboratory table reported Modified incidence of incidence of creatinine based increased creatinine to on strict interpretation of NCI include only cases with CTCAE v4.03, which includes creatinine increases based on any elevation over baseline upper limit of normal as an event. definition.

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Section 7, Drug Interactions Concomitant use of PPIs with Additional recommendations VIZIMPRO are to be avoided. were included: The effect of H2-receptor antagonists on Antacids have no effect on dacomitinib exposure has not dacomitinib absorption. been studied. Administer H2- The concomitant use of receptor antagonists (e.g., CYP2D6 substrates with a cimetidine, ranitidine, narrow therapeutic index famotidine and nizatidine). with dacomitinib is to be Administer VIZIMPRO at least avoided. If these agents 6 hours before or 10 hours cannot be avoided a dose after taking an H2-receptor reduction or substitution of antagonist. the CYP2D6 substrate may be needed. No starting dose adjustment of VIZIMPRO is needed for patients taking a strong CYP2D6 inhibitor or for patients who are CYP2D6 PMs

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Section 8, Use in Specific Populations  Pregnancy Details included for risks in pregnancy, specifically implantation loss and that EGFR signaling has been shown to result in embryolethality

 Animal Data Details included for risks in pregnancy, specifically implantation loss and that EGFR signaling has been shown to result in embryo lethality

 Lactation Instruction to not breastfeed for 17 days (5 half-lives) after the last dose of VIZIMPRO to prevent transmission to infant Females and Males of Included information on Reproductive Potential females and infertility. Added instruction to verify pregnancy status in female prior to starting VIZIMPRO. Geriatric Use Proposed Pool B findings, stated that AEs were FDA used Pool A, and consistent between older included exploratory analyses and younger patients suggesting higher incidence of Grade 3 and 4 AE, more dose interruptions, and more dose discontinuations for patients aged over 65 years.

(b) (4)

Section 12.2, Cardiac electrophysiology Review based edits to the Pharmacodynamics effects cardiac electrophysiology effects language. In addition, the exposure-response relationships were also included in the labeling.

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Section 12.3, Some edits were made in the Pharmacokinetics Pharmacokinetics section, not major (b) (4) (b) (4) Section 14, Clinical Studies

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14 Risk Evaluation and Mitigation Strategies (REMS)

Dacomitinib will be prescribed by health care professionals with experience in managing toxicities associated with targeted therapies. All serious adverse reactions, with appropriate dose modifications and adequate recommendations for monitoring to mitigate risks, are described in product labeling. Thus, the clinical review determined that risk mitigation and evaluation strategies under FDAAA are not required to ensure safe and effective use.

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15 Post marketing Requirements and Commitment

Complete a pharmacokinetic trial to determine an appropriate dose of dacomitinib 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/Gui dances/UCM072123.pdf.

16 Division Director (DHOT)

John Leighton, Ph.D.

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17 Division Director (OCP)

Nam Atiq Rahman

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18 Division Director (OB)

Kun He, Ph.D.

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19 Division Director (Clinical)

I concur with the conclusions reached in this document and in the Integrated Quality Assessment that the applicant, Pfizer Pharmaceutical, has demonstrated evidence of appropriate controls and consistency of manufacture and that the application contains substantial evidence of effectiveness for the proposed indication based on a clinically meaningful and statistically robust improvement in progression-free survival as compared to an active control in an adequate and well-controlled study. The risks are acceptable given the life-threatening nature of the indicated disease and the risk:benefit assessment is favorable.

I recommend approval with the agreed-upon labeling and the requirement to conduct a post- marketing study to assess the effects of hepatic impairment on the pharmacokinetics of dacomitinib.

Patricia Keegan, M.D. Director, Division of Oncology Products 2

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20 Office Director

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.

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21 Appendices

Appendix 1

The following is the Pfizer’s list of preferred terms for adverse events.

Tier 1 Clustered Terms o Diarrhea and associated adverse events  Acute prerenal failure, azotemia, blood urea nitrogen / creatinine ratio increased, dehydration, diarrhea, electrolyte imbalance, hypovolemia, prerenal failure o Acute renal failure  Acute kidney injury, anuria, blood creatinine increased, blood urea increased, oliguria, renal failure, renal impairment o Interstitial Lung Disease  Acute interstitial pneumonitis, alveolar proteinosis, alveolitis, alveolitis allergic, alveolitis necrotizing, bronchiolis, combined pulmonary fibrosis and emphysema, diffuse alveolar damage, eosinophilia myalgia syndrome, eosinophilic granulomatosis with polyangitis, eosinophilc pneumonia, eosinophilic pneumonia acute and chronic, idiopathic interstitial pneumonia, idiopathic pneumonia syndrome, idiopathyic pulmonary fibrosis, interstitial lung disease, lung infiltration, necrotizing bronchiolitis, obliterative bronchitis, pneumonitis, progressive massive fibrosis, pulmonary fibrosis, pulmonary necrosis, pulmonary radiation toxicity, pulmonary vasculitis, radiation alveolitis, radiation fibrosis, radiation pneumonitis, respiratory syncytial virus bronchiolitis, transfusion related lung injury o Severe Skin Toxicity  acute generalized exanthematous pustulosis, cutaneous vasculitis, dermatitis bullous, dermatitis exfoliative, dermatitis exfoliative generalized, drug reaction with eosinophilia and systemic symptoms, epidermal necrosis, erythema multiforme, exfoliative rash, oculkomucocutaneous syndrome, skin exfoliation, skin necrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxic skin eruption o Rash/ Dermatitis Acneiform  Acne, acne, cosmetic, acne cystic, acne fulminans, acne infantile, acne occupational, acne pustular, acne varioliformis, drug eruptions, mechanical acne, oil acne, rash, rash erythematous, rash generalized, rash maculopapular, rash pruritic o Other Skin Toxicity  Dry skin, nail disorder, palmar-plantar erythrodysaethesia syndrome, paronychia, skin fissures, skin ulcer, xerosis o Hepatotoxicity  Acute fatty liver of pregnancy, acute hepatic failure, acute on chronic liver failure, acute yellow liver atrophy, ascites, asterixis, bacterascites  Biliary cirrhosis, biliary cirrhosis primary, biliary fibrosis, cholestatic liver injury, chronic hepatic failure, coma hepatic, cryptogenic cirrhosis, diabetic hepatopathy, drug-induced

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liver injury, duodenal varices, gallbladder varices, gastric variceal injection, gastric variceal ligation, gastric varices, gastric varices hemorrhage, hepatectomy, hepatic atrophy, hepatic calcification, hepatic cirrhosis, hepatic encephalopathy, hepatic encephalopathy prophylaxis, hepatic failure, hepatic fibrosis, hepatic hydrothorax, hepatic infiltration eosinophilic, hepatic lesion, hepatic necrosis, hepatic steato-fibrosis, hepatic steatosis, hepatitis fulminant, hepatobiliary disease, hepatocellular foamy cell syndrome, hepatocellular injury, hepatopulmonary syndrome, hepatorenal failure, hepatorenal syndrome, hepatotoxicity, intestinal varices, intestinal varices hemorrhage, intra-abdominal fluid collection, liver and small intestine transplant, liver dialysis, liver disorder, liver injury, liver operation, liver transplant, lupoid hepatic cirrhosis, minimal hepatic encephalopathy, mixed liver injury, nodular regenerative hyperplasia, non- alcoholic fatty liver, non-alcoholic steatohepatitis, non-cirrhotic portal hypertension, edema due to hepatic disease, esophageal varices hemorrhage, peripancreatic varices, portal fibrosis, portal hypertension, portal hypertensive enteropathy, portal hypertensive gastropathy, portal tract inflammation, portal vein cavernous transformation, portal vein dilatation, portopulmonary hypertension, renal and liver transplant, Retrograde portal vein flow, Reye's syndrome, Reynold's syndrome, splenic varices, splenic varices hemorrhage, steatohepatitis, subacute hepatic failure, varices esophageal, varicose veins of abdominal wall, white nipple sign o Liver-related laboratory tests  Alanine aminotransferase abnormal, alanine aminotransferase increased, aspartate aminotransferase abnormal, aspartate aminotransferase increased, bilirubin conjugated abnormal, bilirubin conjugated increased, blood bilirubin abnormal, blood bilirubin increased, hepatic enzyme abnormal, hepatic enzyme increased, hyperbilirubinemia, hypertransaminasemia, liver function test abnormal, transaminases abnormal, transaminases increased o Keratitis  Corneal erosion, corneal perforation, keratitis, ulcerative keratitis o Gastrointestinal perforation  Abdominal abscess, abdominal hernia perforation, abdominal wall abscess, abscess intestinal, acquired tracheo-oesophageal fistula, anal abscess, anal fistula, anal fistula excision, anal fistula infection, anastomotic ulcer perforation, anovulvar fistula, aorto- duodenal fistula, aorto-oesophageal fistula, appendiceal abscess, appendicitis perforated, arterioenteric fistula, atrio-oesophageal fistula, chemical peritonitis, colon fistula repair, colonic abscess, colonic fistula, diverticular fistula, diverticular perforation, Douglas' abscess, duodenal perforation, duodenal ulcer perforation, duodenal ulcer perforation, obstructive, duodenal ulcer repair, enterocolonic fistula, enterocutaneous fistula, enterovesical fistula, fistula of small intestine, gastric fistula, gastric fistula repair, gastric perforation, gastric ulcer perforation, gastric ulcer perforation, obstructive, gastrointestinal anastomotic leak, gastrointestinal fistula, gastrointestinal fistula repair, gastrointestinal perforation, gastrointestinal ulcer perforation, gastropleural fistula, gastrosplenic fistula, ileal perforation, ileal ulcer perforation, infectious colitis, inguinal hernia perforation, intestinal fistula, intestinal fistula infection, intestinal fistula repair,

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intestinal perforation, intestinal ulcer perforation, jejunal perforation, jejunal ulcer perforation, large intestinal ulcer perforation, large intestine perforation, lower gastrointestinal perforation, mesenteric abscess, neonatal intestinal perforation, noninfectious peritonitis, esophageal fistula, esophageal fistula repair, esophageal perforation, esophageal rupture, esophageal ulcer perforation, esophagobronchial fistula, esophagopleural fistula, paraoesophageal abscess, peptic ulcer perforation, peptic ulcer perforation, obstructive, perforated peptic ulcer oversewing, perforated ulcer, perineal abscess, perirectal abscess, peritoneal abscess, peritonitis, peritonitis bacterial, procedural intestinal perforation, rectal abscess, rectal fistula repair, rectal perforation, rectoprostatic fistula, rectourethral fistula, retroperitoneal abscess, small intestinal perforation, small intestinal ulcer perforation, umbilical hernia perforation, upper gastrointestinal perforation o Stomatitis  Aphthous ulcer, cheilitis, contact stomatitis, mouth ulceration, mucosal inflammation, nicotinic stomatitis, oral mucosa erosion, oral pain, oropharyngeal discomfort, oropharyngeal pain, palatal ulcer, pyostomatitis vegetans, stomatitis, stomatitis hemorrhagic, stomatitis necrotizing o QT interval prolongation  Cardiac arrest, cardiac death, cardiac fibrillation, cardio-respiratory arrest, electrocardiogram QT interval abnormal, electrocardiogram QT prolonged, electrocardiogram U-wave abnormality, electrocardiogram repolarization abnormality, long QT syndrome, long QT syndrome congenital, loss of consciousness, presyncope, sudden cardiac death, sudden death, syncope, torsade de pointes, ventricular arrhythmia, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, ventricular tachycardia, left ventricular dysfunction

Tier 2 Events: Common adverse events not included in Tier 1 o MedDRA preferred terms were defined as a Tier-2 event if they were reported in at least 10% of the patients, regardless of grade, in any treatment arm. For Grade 3/4/5 analysis, the events were reported in at least 5% of the patients in any treatment arm

Tier 3 Events Events that were neither Tier 1 or Tier 2

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Appendix 2 Laboratory Shift Tables for ARCHER 1050

Summary Laboratory Shift Table: Baseline to Grade 3 or 4 for ARCHER 1050 Study DACOMITINIB GEFITINIB N=227 N=224 Shift from Shift from Shift from Shift from Baseline to Baseline to Baseline to Baseline to Grades 3 Grade 4 Grades 3 Grade 4 Toxicity 3 4 3 4 Increased Alanine 3 (1.3%) 0 26 (12%) 2 (0.9%) aminotransferase Increased Alkaline 2 (0.9%) 0 4 (1.8%) 0 phosphatase Anemia 2 (0.9%) 0 6 (2.7%) 0 Increased Aspartate 1 (0.4%) 0 15 (7%) 2 (0.9%) aminotransferase Increased Blood bilirubin 1 (0.4%) 0 1 (0.4%) 0 Increased Creatinine 0 0 1 (0.4%) 0 Increased Hemoglobin 0 0 1 (0.4%) 0 Hypercalcemia 1 (0.4%) 0 0 0 Hyperglycemia 2 (0.9%) 0 5 (2.2%) 0 Hyperkalemia 0 0 0 2 (0.9%) Hypermagnesemia 7 (3.1%) 0 6 (2.7%) 0 Hypocalcemia 3 (1.3%) 0 4 (1.8%) 0 Hypoglycemia 0 1 (0.4%) 2 (0.9%) 0 Hypokalemia 13 (6%) 2 (0.9%) 5 (2.2%) 0 Hypomagnesemia 2 (0.9%) 0 0 0 Hyponatremia 5 (2.2%) 1 (0.4%) 4 (1.8%) 1 (0.4%) Leukocytosis 1 (0.4%) 0 0 0 Lymphopenia 14 (6%) 1 (0.4%) 9 (4.0%) 0 Decreased Neutrophil count 0 0 2 (0.9%) 0 Urine Protein 0 0 1 (0.4%) 0 Decreased White blood cell 0 0 1 (0.4%) 0 (Source: NDA 211288, ARCHER Interim dataset, JReview, LB)

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Renal Laboratory Shift Table

Increased Creatinine ARCHER 1050 Dacomitinib Gefitinib N=220 N=221 Shift from Shift from Shift from Shift from Baseline to All Baseline to Baseline to All Baseline to Grade Increased Grade 3 or 4 Grade Increased Grade 3 or 4 Creatinine Increased Creatinine Increased Creatinine Creatinine 52 (24%) 0 16% 0.5% (Source: NDA 211299, ARCHER 1050, Table 14.3.4.1.5.4.10.C)

Hepatic Laboratory Shift Tables

Increased Alkaline Phosphatase (ALP) ARCHER 1050 Laboratory Baseline Shift from DACOMITINIB GEFITINIB Shift Toxicity Grade Baseline to N=205 N=205 Increased ALP Maximum Toxicity Grade Grades 0 or 1 1 42 (21%) 35 (17%)

2 3 (2%) 5 (2%) 3 1 (0.5%) 1 (0.5%) (Source: NDA 211288, ARCHER 1050 Interim dataset, JReview, LB)

Increased Alanine Aminotransferase (ALT) ARCHER 1050 Laboratory Shift Baseline Shift from DACOMITINIB GEFITINIB Toxicity Grade Baseline to N=205 N=205 Maximum Toxicity Grade Alanine Grades 0 or 1 2 7 (3%) 28 (14%) aminotransferase increased 3 3 (2%) 26 (13%) 4 0 2 (1%) (Source: NDA 211288, ARCHER 1050 Interim dataset, JReview, LB)

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Increased Aspartate Aminotransferase (AST) ARCHER 1050 Laboratory Shift Baseline Shift from DACOMITINIB GEFITINIB Toxicity Grade Baseline to N=205 N=205 Maximum Toxicity Grade Aspartate Grades 0 or 1 2 3 (2%) 17 (8%) Aminotransferase increased 3 1 (0.5%) 15 (7%) 4 0 2 (1%) (Source: NDA 211288, ARCHER 1050 Interim dataset, JReview, LB)

Increased Bilirubin ARCHER 1050 Laboratory Baseline Shift from DACOMITINIB GEFITINIB Shift Toxicity Grade Baseline to N=220 N=221 Maximum Toxicity Grade Increased Grades 0 or 1 2 13 (6%) 11 (5%) Blood Bilirubin 3 1 (0.5%) 1 (0.5%) (Source: NDA 211288, ARCHER 1050 Interim dataset, JReview, LB)

Hematologic Laboratory Shift Tables

Anemia ARCHER 1050 Toxicity Baseline Shift from DACOMITINIB GEFITINIB Toxicity Grade Baseline to N=221 N=222 Maximum Toxicity Grade Anemia Grades 0 or 1 1 74 (34%) 41 (19%) 2 23 (10%) 12 (5%) 3 2 (0.9%) 6 (2.7%) (Source: NDA 211288, ARCHER 1050 Interim dataset, JReview, LB)

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Decreased White Blood Cell (WBC) ARCHER 1050 Toxicity Baseline Shift from DACOMITINIB GEFITINIB Toxicity Grade Baseline to N=221 N=222 Maximum Toxicity Grade White blood Grades 0 or 1 2 5 (2.3%) 12 (5%) cell decreased 3 0 1 (0.5%) (Source: NDA 211288, ARCHER 1050 Interim dataset, JReview, LB)

Leukocytosis ARCHER 1050 Toxicity Baseline Shift from DACOMITINIB GEFITINIB Toxicity Grade Baseline to N=221 N=222 Maximum Toxicity Grade Leukocytosis Grades 0 or 1 3 1 (0.5%) 0

4 0 0

(Source: NDA 211288, ARCHER 1050 Interim dataset, JReview, LB)

Reviewer’s Comment: Note the number of patients with results does not equal the safety population (Dacomitinib N=227, Gefitinib N=225). The reason for this discrepancy is protocol violation of missed laboratory test.

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Appendix 3 Mean Vital Signs by Cycle ARCHER 1050

Mean Pulse Rate by Cycle, ARCHER 1050

(Source: NDA 211288, ARCHER 1050 Interim dataset, JMP Clinical, vs.xpt)

Mean Systolic Blood Pressure by Cycle, ARCHER 1050

(Source: NDA 211288, ARCHER 1050 Interim dataset, JMP Clinical, vs.xpt)

Mean Diastolic Blood Pressure by Cycle ARCHER 1050

(Source: NDA 211288, ARCHER 1050 Interim dataset, JMP Clinical, vs.xpt)

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References

1. Surveillance, Epidemiology, and End Results Program (SEER), Cancer Statistics 2018 (accessed May 2, 2018): https:// seer.cancer.gov 2. Midha, A. Dearden, S. McCormack, R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). American Journal of Cancer Research. 2015; 5 (9): 2892-2911. 3. Zhao, D. Chen, X. Qin, N. et al. The prognostic role of EGFR-TKIs for patients with advanced non-small cell lung cancer. Scientific Reports. 7, 40374; doi : 10.1038/srep40374 (2017). 4. Kamei Y, Tsutsumi O, Yamakawa A, et al. Maternal epidermal growth factor deficiency causes fetal hypoglycemia and intrauterine growth retardation in mice: possible involvement of placental glucose transporter GLUT3 expression. Endocrinology 1999; 140:4236-4243. 5. Sibilia M, Wagner EF. Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 1995; 269:234-238. 6. Miettinen PJ, Berger JE, Meneses J, et al. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature 1995; 376:337-341. 7. Threadgill DW, Dlugosz AA, Hansen LA, et al. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 1995; 269:230-234. 8. Deichmann WB. Toxicology of Drugs and Chemicals. Academic Press, Inc., 1969; p395 9. Seifried HE, Seifried RM, Clarke JJ, Junghans TB, San RH. A compilation of two decades of mutagenicity test results with the Ames Salmonella typhimurium and L5178Y mouse lymphoma cell mutation assays. Chem Res Toxicol 2006; 19(5):627-644. 10. Parris P, Duncan JN, Fleetwood A, Beierschmitt WP. Calculation of a permitted daily exposure value for the solvent 2-methyltetrahydrofuran. Regul Toxicol Pharmacol 2017; 87:54- 63. 11. Ohashi K, Maruvka YE, Michor F, et al. Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J Clin Oncol 2013; 31(8):1070-80. 12. Engelman JA, Zejnullahu K, Gale CM, et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 2007; 67(24):11924-32. 13. Zahonero C, Aguilera P, Ramírez-Castillejo C, et al. Preclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma. Mol Cancer Ther 2015; 14(7):1548-1558. 14. Cheng H, Nair SK, Murray BW, et al. Discovery of 1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl- 1H-pyrazol-4-yl) amino]-7H-pyrrolo[2,3-d] pyrimidin-4-yl} oxy) methyl]-4-methoxypyrrolidin-1- yl} prop-2-en-1-one (PF-06459988), a potent, WT sparing, irreversible inhibitor of T790M- containing EGFR mutants. J. Med. Chem. 2016; 59(5):2005-24.

Financial Disclosure

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Financial Disclosure: ARCHER 1050 (NCT 01774721)

Was a list of clinical investigators provided? Yes No (Request list from Pfizer)

Total number of investigators identified: 642 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): 3 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: 3 Significant payments of other sorts: 3 Proprietary interest in the product tested held by investigator: 0 Significant equity interest held by investigator in Sponsor: 0 Sponsor of covered study: 0 Is an attachment provided with details Yes No (Request details from of the disclosable financial Pfizer) interests/arrangements: Is a description of the steps taken to Yes No (Request information minimize potential bias provided: from Pfizer) Number of investigators with certification of due diligence (Form FDA 3454, box 3) 30 Is an attachment provided with the Yes No (Request explanation reason: from Pfizer)

a. OCP Appendices (Technical documents supporting OCP recommendations)

OFFICE OF CLINICAL PHARMACOLOGY: PHARMACOMETRIC REVIEW

NDA Number 211288

176 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

Reference ID: 4326788 NDA Multi-Disciplinary Review and Evaluation {NDA 211288} VIZIMPRO / dacomitinib

Drug Name VIZIMPRO (Dacomitinib) Dose Regimen 45 mg orally once daily with or without food First-line treatment of patients with (b) (4) metastatic NSCLC with EGFR- Indication (b) (4) mutations as detected by an FDA- approved test Pharmacometrics Reviewer Xiaofeng Wang, Ph.D. Pharmacometrics Team Lead Jiang Liu, Ph.D. Pfizer Pfizer Inc.

1. Summary of Findings Based on data submitted in this application, the proposed starting dose regimen of 45 mg QD is acceptable from the pharmacometrics (PM) perspective. Dose adjustment based on age, body weight, gender, race, mild or moderate renal impairment, or mild or moderate hepatic impairment is not warranted.

1.1 KEY REVIEW QUESTION

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

Yes, the proposed dosing regimen is acceptable for the general population.

The proposed doing regimen of dacomitinib is a starting dose of 45 mg QD with dose reductions by 15 mg decrements as needed based on individual patient tolerability to dacomitinib. 45 mg QD was determined as the MTD in phase 1 dose escalation studies and selected for evaluation in the pivotal Phase 3 Study 1050. Study 1050 met its primary objective by demonstrating that dacomitinib was superior to gefitinib in prolonging PFS in the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR-activating mutations with a 41.4% reduction in risk of disease progression for death. The safety profile of dacomitinib-treated patients in Study 1050 was considered manageable with option of dose interruption/reduction.

Given the fact that only a single dose level was evaluated in the pivotal Study 1050 and the incidence of dose interruption/reduction was high (>60%), E-R analysis, especially for efficacy, would be challenging, therefore unlikely to convincingly justify an alternative dose level.

Significant relationships between dacomitinib exposure and safety endpoints including Grade ≥ 3 Rash/Dermatitis Acneiform, Grade ≥ 3 Other Skin Toxicities, Grade ≥ 3 diarrhea, and Grade ≥ 1 Stomatitis were observed, suggesting higher risk with higher dacomitinib dose/exposure.

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Exposure-response analysis for PFS based on steady-steady dacomitinib exposure or overall average dacomitinib exposure showed inverse relationships. The FDA reviewers believe such inverse ER relationship for PFS is biased and highly likely due to the high dose interruption/reduction rate in the clinical studies. Exploratory E-R analysis for PFS based on dacomitinib exposure after the first dose was conducted by the FDA reviewer and the results showed flat/slightly positive E-R relationship. Furthermore, E-R modeling for the time course of tumor size incorporating longitudinal drug exposure based on actual doses suggested positive E-R relationship between dacomitinib exposure and tumor shrinkage, suggesting greater tumor shrinkage with higher dacomitinib dose/exposure.

In conclusion, given the significant survival benefit, it is acceptable to start treatment at 45 mg QD and adjust the dose on individual patient tolerability as needed.

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

Population PK analysis suggests that intrinsic patient factors, including age (20 to 92 years), sex, race, body weight, EGFR mutation status, baseline aspartate transaminase, baseline albumin, mild or moderate renal impairment (creatinine clearance 30 to 89 mL/min), and mild hepatic impairment [total bilirubin ≤ upper limit of normal (ULN) and AST > ULN, or total bilirubin > 1.0 to 1.5 × ULN and any AST], have no clinically meaningful effect on dacomitinib pharmacokinetics (Figure 12 and Figure 13). Therefore, the proposed no dose adjustment in these specific population is acceptable.

In addition, a dedicated hepatic impairment trial showed that dacomitinib exposure (AUCinf and Cmax) following a single oral dose of 30 mg was unchanged in subjects with mild hepatic impairment (Child-Pugh A; N=8) and decreased by 15% and 20%, respectively in subjects with moderate hepatic impairment (Child-Pugh B; N=9) when compared to subjects with normal hepatic function (N=8). It is determined that mild and moderate hepatic impairment had no clinically important effects on dacomitinib PK. Therefore, no dose adjustment for patients with mild or moderate hepatic impairment is needed.

Figure 12. Effect of Renal Impairment on Dacomitinib CL

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Figure 13. Effect of Hepatic Impairment on Dacomitinib CL

1.2 RECOMMENDATIONS

The Pfizer’s proposed dosing regimen and label claims regarding covariate effect on PK are acceptable from the PM perspective.

2. Sponsor’s Population Pharmacokinetics and E-R Analysis

2.1 PPK ANALYSIS

Objective: •To develop an integrated, predictive population pharmacokinetic model for dacomitinib and its metabolite, PF-05199265, using the data from the available clinical studies in patients and healthy volunteers (HVs). 179 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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•To identify potential covariates which account for the interindividual variability (IIV) in dacomitinib absorption and disposition. •To support a sequential pharmacokinetic-pharmacodynamic (PKPD) analysis, using post-hoc predictions from the final pharmacokinetic (PK) models, described in a separate population modeling analysis plan (PMAP). Data: The population PK analysis was based on pooled data from 21 clinical studies. A summary of the include studies is listed in Table 68. Table 68. Summary of Included Studies

Source: Pfizer’s popPK analysis report PMAR-EQDD-A747f-DP4-635, Table 1 The popPK dataset consisted of 10156 dacomitinib and 6956 PF-05199265 plasma observations from 1381 patients treated with dacomitinib. Of the observations, 806 (7.94%) and 328 (4.72%) were

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Source: Pfizer’s popPK analysis report PMAR-EQDD-A747f-DP4-635, Table 7 Table 70. Summary of Continuous Covariates Creatinine Clearance and Albumin

Source: Pfizer’s popPK analysis report PMAR-EQDD-A747f-DP4-635, Table 8 Table 71. Summary of Baseline Continuous Covariates Alanine Transaminase Aspartate Transaminase and Total Bilirubin

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Source: Pfizer’s popPK analysis report PMAR-EQDD-A747f-DP4-635, Table 9 Table 72. Summary of Categorical Covariates (1 of 3)

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Source: Pfizer’s popPK analysis report PMAR-EQDD-A747f-DP4-635, Table 10 Table 73. Summary of Categorical Covariates (2 of 3)

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Reference ID: 4326788 NDA Multi-Disciplinary Review and Evaluation {NDA 211288} VIZIMPRO / dacomitinib

Source: Pfizer’s popPK analysis report PMAR-EQDD-A747f-DP4-635, Table 11 Table 74. Summary of Categorical Covariates (3 of 3)

Source: Pfizer’s popPK analysis report PMAR-EQDD-A747f-DP4-635, Table 12 Method: 1- and 2-compartment models with first order rate constants for absorption and elimination were tested as the structural model. Different methods for handing data < LLOQ including M1, M2, and M3 methods, were evaluated. Inter-individual variability (IIV) was modelled assuming a 184 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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log-normal distribution for individual PK parameters. Residual variability modeled as additive models on log-transformed dependent variable. A group of potential covariates were selecting for testing in the covariate modeling step based on mechanistic plausibility, exploratory analysis, and clinical interest and are listed in Table 75. Potential covariates were plotted against ETAs to identify any relationship initially. Subsequently, identified covariates were tested for significance in a stepwise manner with forward addition and backward elimination processes. Table 75. Covariates Tested in the Population PK Analysis

Source: Pfizer’s popPK analysis report PMAR-EQDD-A747f-DP4-635, Table 3 Model evaluation and validation were conducted using approached including goodness-of-fit assessment, VPC, and bootstrapping. All modeling was performed using the NONMEM version 7.3 software (ICON Development Solutions, Ellicott City, MD). Results: A 2-compartment PK structural model with first order constant rates for absorption and elimination best described the concentration time profile of dacomitinib in patients with advanced NSCLC or with various solid tumor. The final model PK parameter estimates are shown in Table 76. Dacomitinib Final Model PK Parameter Estimate Summary

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Reference ID: 4326788 NDA Multi-Disciplinary Review and Evaluation {NDA 211288} VIZIMPRO / dacomitinib

Source: Pfizer’s popPK analysis report PMAR-EQDD-A747f-DP4-635, Table 15 Goodness-of-fit plots for the final indicate acceptable fitting (Figure 14). Figure 14. Goodness-of-fit Plots for the Final Model

Source: Pfizer’s popPK analysis report PMAR-EQDD-A747f-DP4-635, Figure 17-19

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Prediction-corrected VPCs were performed for the final model to evaluate the predictive performance. The VPC results for single dose and multiple dose data under QD oral dosing regimen are presented in Figure 15. VPC for Dacomitinib Observations after Single Dose and Multiple QD Dose Administration

Single dose Multiple dose

Source: Pfizer’s popPK analysis report PMAR-EQDD-A747f-DP4-635, Figure 32-33 The equations describing the final function for the Cl and ka values are shown below:

BWT is the baseline body weight (kg), BAST is the baseline aspartate transaminase (U/L) and BALB is the baseline albumin (g/dL). The concomitant use of a CYP2D6 inhibitor is in reference to patients who received a CYP2D6 inhibitor and is equal to 1 if the patient received concomitant treatment and 0 otherwise. Asian takes the value of 1 for Asian ancestry subjects and 0 otherwise. Female takes the value of 1 and 0 otherwise. EFGR+ takes the value of 1 for identified EGFR mutant population and 0 otherwise. EGFRwt takes the value of 1 for identified EGFR wild-type patients and 0 otherwise. Food takes the value of 1 for fed and 0 otherwise.

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Effect of Baseline Body Weight on CL: Relative to the typical CL value of 19.952 L/h for a typical subject with BWT value of 70 kg, CL decreased by 23% and increased by 22% at BWT values of 49.6 kg and 90.8 kg, which are the 10th and 90th percentiles in the analysis population. Effect of Baseline Albumin on CL: Relative to the typical value of CL (19.952 L/h) for a typical subject with BALB value of 4.0 g/dL, CL increased by 8% and decreased by 10% at BALB values of 4.6 g/dL and 3.3 g/dL, which are the 10th and 90th percentiles in the analysis population, respectively. Effect of baseline Aspartate Aminotransferase on CL: Relative to the typical value of CL (19.952 L/h) for a typical subject with BAST value of 22.0 U/L, CL increased by 3% and decreased by 2% at BAST values of 38.0 U/L and 14.4 U/L, which are the 10th and 90th percentiles in the analysis population, respectively. Effect of Sex on CL: Females have 11.5% lower CL relative to males. Effect of Racial Designation on CL: The Asian population had 8.5% faster CL relative to the non- Asian population. Effect of EGFR Mutation Status on CL: EGFR mutants have 9% faster CL relative to unknown EGFR population status. On the contrary, EGFR wild-type exhibited a 5% slower CL relative to subjects with unknown EGFR status. Effect of Concomitant Use of CYP2D6 Inhibitors on CL: Results from this popPK analysis show that subjects taking paroxetine have 33% lower CL relative to subjects not taking any CYP2D6 inhibitor agent. The result was mainly driven by the dedicated DDI study A7471021, which concluded that paroxetine, a CYP2D6 inhibitor, significantly inhibited dacomitinib metabolism via CYP2D6 and this inhibition translated into approximately a 90% reduction in metabolite exposure and an approximate 37% increase in dacomitinib exposure.

Food Effect on ka: Results from this popPK analysis show subjects taking a high-fat, high-calorie meal before dacomitinib administration have 23% higher ka relative to subjects fasting or without regards of food. In addition, a food effect study A7471015 concluded that the increase in exposure of single dose dacomitinib when administered 30 minutes after consumption of a high-fat, high-calorie meal compared with administration under overnight fasting conditions was 14.2% and 24% increase in AUCInf and Cmax, respectively. Effect of Renal Impairment: Based on the popPK analysis, the effect of BCCL was not statistically significant on CL. summarizes the individual dacomitinib post-hoc CL categorized into 4 renal function groups based on BCCL. The estimated median clearances without baseline body weight correction by renal function were 20.23, 19.66, 18.13 and 17.02 L/h for patients in the normal, mild, moderate, and severe groups, respectively. Table 77. Dacomitinib Individual Clearances by Renal Function

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Source: Pfizer’s popPK analysis report PMAR-EQDD-A747f-DP4-635, Table 16 Effect of Hepatic Impairment: Hepatic impairment classification was not identified as a statistically significant covariate on dacomitinib PK. The effect of hepatic impairment as defined by the NCI criteria was assessed by summarizing individual estimates of dacomitinib CL in each hepatic impairment group and the results are shown in Table 78. Dacomitinib Individual Clearances by Hepatic Function (NCI Criteria)

Source: Pfizer’s popPK analysis report PMAR-EQDD-A747f-DP4-635, Table 17 Reviewer’s comments: The PK model for parent drug was developed first and then the PK model for the active metabolite, PF-05199265, was developed sequentially by using individual parent drug post-hoc PK parameter estimates as input parameters for the active metabolite PK model. This review focused on the parent drug model because abundance of the active metabolite is substantially lower than (~20%) that of the parent drug and hence is not considered a significant contributor for efficacy or safety in the general population. Overall, the Pfizer’s population PK analysis for dacomitinib is reasonable. The reviewer agrees with the Pfizer’s conclusion that baseline body weight, baseline albumin, baseline aspartate aminotransferase, sex, race, EGFR mutation status, food, mild to moderate renal impairment, and mild hepatic impairment has no clinically meaningful effect on dacomitinib PK, therefore no dose adjustment is warranted The popPK analysis provided limited information regarding the effect of moderate hepatic impairment on dacomitinib PK given the small number of subjects with moderate hepatic impairment in the popPK dataset (N=5). Nevertheless, results from a dedicated hepatic impairment study A7471018 showed that dacomitinib exposure in subjects with Child-Pugh class A was similar to that in subjects with normal hepatic function with an adjusted mean ratio of 100.8 and 103.5% for AUC and Cmax, respectively. Dacomitinib exposure in patients with Child- Pugh class B was reduced marginally when compared to subjects with normal hepatic function (15.3% and 20% for AUC and Cmax, respectively). Based on the study A7471018results, no dose adjustment is warranted when administering dacomitinib to patients with Child-Pugh class A or Child-Pugh class B. For the effect of concomitant use of CYP2D6 inhibitors, although popPK analysis results showed that subjects taking paroxetine have 33% lower CL relative to subjects not taking any CYP2D6 inhibitor agent, results from the dedicated DDI Study A7471021 suggested that

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coadministration of a single 45 mg dose of dacomitinib with multiple doses of paroxetine in healthy subjects increased the total AUCinf of dacomitinib plus its active metabolite (O- desmethyl dacomitinib) in plasma by 6%. Therefore, the effect of concomitant use of CYP2D6 inhibitors is not considered clinically relevant and no dose adjustment is needed.

2.2 EXPOSURE RESPONSE (ER) ANALYSIS FOR EFFICACY Objective: To evaluate the potential relationship between dacomitinib exposure and the efficacy endpoints, such as objective response rate (ORR) and progression free survival (PFS) in patients with locally advanced/metastatic NSCLC with EGFR-activating mutations. Data and Methods: Exposure-efficacy relationships were assessed based on data from 272 subjects in Study A7471017 and Study A7471050. Exposure-ORR relationship was evaluated using a logistic regression approach. Exposure-PFS relationship was evaluated using parametric time-to-event modeling. Covariates listed in Table 79 were evaluated for both ORR and PFS. Dacomitinib exposure metrics were derived from the final popPK model. Table 79. Potential Covariates

Source: Pfizer’s ER analysis report PMAR-EQDD-A747f-DP4-636, Table 4 Results: ER Analysis for ORR: A multivariate logistic regression analysis was conducted using the variables in Table 79. No dacomitinib exposure metrics were found to be statistically significant predictors of achieving an objective response. Age and the occurrence of OTHER SKIN TOXICITIES (MAEGRST) were tested statistically significant in the final model. The final model

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parameter estimates are shown in Table 80. Figure 16 illustrates the probability of achieving an objective response by age and by maximum grade of other Table 80. Final Model for Dacomitinib Exposure-Response Analysis of ORR

Source: Pfizer’s ER analysis report PMAR-EQDD-A747f-DP4-636, Table 4 Figure 16. Probability of Achieving Objective Response: Dacomitinib Exposure-Response Analysis

Source: Pfizer’s ER analysis report PMAR-EQDD-A747f-DP4-636, Figure 12 ER Analysis for PFS: A parametric time-to-event (TTE) analysis was performed with a Weibull hazard function as shown below:

The survival function is expressed using the function below:

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A base TTE model was first developed and then stepwise covariate analysis using the variables listed in Table 79 was conducted. In the final model, 5 variables were identified as statistically significant predictors of PFS including BALB, BLDH, the occurrence of RASH/DERMATITIS/ACNEIFORM (MAEGRDA), MAEGRST, and Cavg,Overall. The final model equation describing the influence of each significant factor on the survival function is presented below:

MAEGRDA < 1 increased covbase by 55% which was associated with shorter PFS. Values of Cavg,Overall > median 52.3 ng/mL would increase covbase resulting, when all other covariates are fixed, in a decrease in PFS relative to values of Cavg,Overall ≤ 52.3 ng/mL. Values of BALB > median 4.11 g/dL would decrease covbase resulting, when all other covariates are fixed, in an increase in PFS relative to values of BALB ≤ 4.11 g/dL. Values of log(BLDH) > median 5.36 would increase covbase resulting, when all other covariates are fixed, in a decrease in PFS relative to values of log(BLDH) ≤ 5.36. Reviewer’s Comments: No significant E-R relationship between dacomitinib exposure and ORR was identified using multivariate logistic regression analysis in patients with locally advanced/metastatic NSCLC with EGFR-activating mutations. An inverse E-R relationship between dacomitinib overall average exposure up to the PFS event and PFS was identified using the parametric time-to-event model. The Pfizer’s exposure-efficacy analyses are highly likely biased due to the high dose interruption/reduction rate (>60%) in the clinical studies. Exploratory E-R analysis for PFS based on dacomitinib exposure after the first dose conducted by the FDA reviewer showed flat/slightly positive E-R relationship. In addition, E-R modeling for the time course of tumor size incorporating longitudinal drug exposure based on actual doses suggested positive E-R relationship between dacomitinib exposure and tumor shrinkage. In addition, one problem with the Pfizer exposure-efficacy analyses needs to be noted, which is that the safety events, i.e. RASH/DERMATITIS/ACNEIFORM and Other Skin Toxicities, were tested and included in the final E-R models. In this case, the correlation between dacomitinib 192 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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exposure and the safety events is highly likely to cause confounding and multicollinearity issues. Therefore, including safety events which are correlated with drug exposure in the E-R analysis for efficacy should be avoided. Again, this review focused on the parent drug model because abundance of the active metabolite is substantially lower than (~20%) that of the parent drug.

2.2 EXPOSURE RESPONSE (ER) ANALYSIS FOR SAFETY Objective: To evaluate the relationship between dacomitinib exposure and the incidence of selected safety endpoints including Diarrhoea, RASH/DERMATITIS ACNEIFORM, STOMATITIS, and OTHER SKIN TOXICITY adverse events (AEs). Data and Methods: Data from patients who received at least 1 dose of dacomitinib in Studies 1017 or 1015 were used for this analysis. E-R analyses of the occurrence of selected AEs was conducted using logistic regression. Covariates listed in Table 81 were tested. Dacomitinib exposure metrics were derived from the final popPK model. Table 81. Table of Potential Covariates

Source: Pfizer’s ER analysis report PMAR-EQDD-A747f-DP4-678, Table 4 Results: PK and safety data from 269 dacomitinib-treated patients in Studies 1017 and 1050 were used for this analysis. A summary of the frequency of the maximum grade occurrence for each adverse event cluster are presented in Table 82. Summary of Adverse Events Frequency

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Source: Pfizer’s ER analysis report PMAR-EQDD-A747f-DP4-678, Table 5 The logistic regression models determined there is a significant E-R relationship between the occurrence of a Grade ≥3 AE for RASH/DERMATITIS ACNEIFORM, OTHER SKIN TOXICITY, and Diarrhoea with the Cavg of dacomitinib up to the day of the event. For Grade ≥1 STOMATITIS there was a significant E-R relationship with the Cmax of dacomitinib on the day of the event (Figure 17, Figure 18, Figure 19, and Figure 20). Figure 17. Predicted Probability for max AE Grade ≥3 for RASH/DERMATITIS ACNEIFORM

Source: Pfizer’s ER analysis report PMAR-EQDD-A747f-DP4-678, Figure 8 Figure 18. Predicted Probability for max AE Grade ≥3 for OTHER SKIN TOXICITY

Source: Pfizer’s ER analysis report PMAR-EQDD-A747f-DP4-678, Figure 9 Figure 19. Predicted Probability for max AE Grade ≥3 for Diarrhea

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Source: Pfizer’s ER analysis report PMAR-EQDD-A747f-DP4-678, Figure 10 Figure 20. Predicted Probability for AE Grade _1 for STOMATITIS

Source: Pfizer’s ER analysis report PMAR-EQDD-A747f-DP4-678, Figure 11 Reviewer’s comments: Overall, the Pfizer’s ER analysis for safety is acceptable. Positive correlation between dacomitinib exposure and various safety endpoints were identified, suggesting higher risk with higher dacomitinib dose/exposure. A logistic regression analysis was also performed using the active metabolite, PF-05199265, exposure with each of the adverse event endpoints. The analysis did not show any relationship between PF-05199265 and the occurrence of Grade ≥3 AEs. Again, this review focused on the parent drug model because abundance of the active metabolite is substantially lower than (~20%) that of the parent drug.

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APPEARS THIS WAY ON ORIGINAL

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