DAIICHI SANKYO

ONCOLOGIC DRUGS ADVISORY COMMITTEE BRIEFING DOCUMENT FOR THE MAY 14, 2019, US FDA ONCOLOGIC DRUGS ADVISORY COMMITTEE MEETING

TURALIO (PEXIDARTINIB) CAPSULES

NDA 211810

INDICATION: TENOSYNOVIAL GIANT CELL TUMOR

DATE FINALIZED: APRIL 11, 2019

AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION

Daiichi Sankyo, Inc. 211 Mt. Airy Road Basking Ridge, NJ 07920 United States Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

TABLE OF CONTENTS

1 EXECUTIVE SUMMARY ...... 10 1.1 Overview ...... 10 1.2 Proposed Indication and Dose ...... 11 1.3 Disease Background and Unmet Medical Need ...... 11 1.4 Pexidartinib Development Rationale ...... 13 1.5 Pexidartinib Clinical Development Program ...... 14 1.5.1 Summary of Clinical Pharmacology ...... 14 1.5.2 Summary of Clinical Efficacy ...... 15 1.5.2.1 Phase 3 Study PLX108-10 (ENLIVEN) ...... 15 1.5.2.1.1 Study Design ...... 15 1.5.2.1.2 Results ...... 17 1.5.2.1.3 Primary Efficacy Endpoint Results ...... 18 1.5.2.1.4 Secondary Efficacy Endpoint Results ...... 18 1.5.2.1.5 Efficacy With Longer Pexidartinib Treatment ...... 20 1.5.2.2 Phase 1 Study PLX108-01 (TGCT Extension Cohort) ...... 20 1.5.2.3 Efficacy Conclusions ...... 20 1.5.3 Summary of Clinical Safety ...... 20 1.5.3.1 Exposure ...... 21 1.5.3.2 Treatment-Emergent Adverse Events ...... 21 1.5.3.2.1 Adverse Events of Special Interest: Hepatic Adverse Reactions ...... 22 1.5.3.3 Safety Conclusions...... 24 1.5.4 Dose Justification ...... 24 1.6 Risk Evaluation and Mitigation Strategy ...... 24 1.7 Benefit:Risk Assessment ...... 25 2 BACKGROUND AND SCIENTIFIC RATIONALE ...... 26 2.1 Overview of Tenosynovial Giant Cell Tumor ...... 26 2.1.1 Unmet Medical Need ...... 29 2.1.2 Role of CSF-1 in Tenosynovial Giant Cell Tumor ...... 30 3 PEXIDARTINIB OVERVIEW ...... 32 3.1 Drug Description and Mechanism of Action ...... 32 3.2 Proposed Indication and Dose ...... 34 3.2.1 Indication ...... 34 3.2.2 Dosage and Administration ...... 34 4 PEXIDARTINIB DEVELOPMENT PROGRAM...... 35 4.1 Regulatory History ...... 35 4.2 Nonclinical Overview ...... 35 4.3 Clinical Development Overview ...... 37 5 CLINICAL PHARMACOLOGY ...... 39 5.1 Single- and Multiple-Dose Pharmacokinetics of Pexidartinib ...... 39 5.2 Metabolism and Transporter Studies ...... 40 5.3 Effect of Intrinsic and Extrinsic Factors on the PK of Pexidartinib ...... 41 5.3.1 Effect of Intrinsic Factors ...... 41 5.3.1.1 Demographic Characteristics (Age, Race/Ethnicity, Weight, Sex) .....41 5.3.1.2 Effect of Hepatic Impairment ...... 41

Page 2 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

5.3.1.3 Effect of Renal Impairment ...... 41 5.4 Effect of UGT1A4 Polymorphism ...... 41 5.4.1 Effect of Extrinsic Factors ...... 42 5.4.1.1 Effect of Food, Gastric pH Modification, and Drug-Drug Interaction 42 5.5 Effect of Pexidartinib on QTc Interval ...... 44 5.6 Clinical Pharmacology Conclusions ...... 45 6 CLINICAL EFFICACY ...... 46 6.1 Phase 3 Study PLX108-10 (ENLIVEN) ...... 46 6.1.1 Study Design and Methods ...... 46 6.1.1.1 Dose Selection ...... 48 6.1.1.2 Key Eligibility Criteria ...... 49 6.1.1.3 Statistical Analysis Methods ...... 49 6.1.1.3.1 Sample Size Determination...... 49 6.1.1.3.2 Primary and Secondary Efficacy Analyses ...... 49 6.1.2 Patient Disposition and Analysis Sets ...... 50 6.1.3 Demographic and Other Baseline Characteristics ...... 51 6.1.3.1 Demographic and Disease Characteristics ...... 51 6.1.3.2 Prior Treatment ...... 53 6.1.4 Efficacy Results ...... 54 6.1.4.1 Primary Efficacy Endpoint Tumor Response ...... 54 6.1.4.2 Secondary Efficacy Endpoints ...... 56 6.1.4.3 Missing Clinical Outcomes Assessment Data and Sensitivity Analyses ...... 57 6.1.4.3.1 Prespecified Sensitivity Analyses ...... 58 6.1.4.3.2 Post Hoc Sensitivity Analyses ...... 59 6.1.4.4 Efficacy With Longer Pexidartinib Treatment ...... 60 6.1.4.5 Efficacy Subgroup Analyses ...... 63 6.2 Phase 1 Study PLX108-01 (TGCT Extension Cohort) ...... 65 6.2.1 Study Design and Methods ...... 65 6.2.2 Patient Disposition ...... 66 6.2.3 Demographic and Other Baseline Characteristics ...... 66 6.2.4 Efficacy Results ...... 66 6.2.4.1 Tumor Response ...... 66 6.2.4.2 Central Review Tumor Response by RECIST v1.1 and Tumor Volume Score ...... 67 6.3 Efficacy Across the TGCT Population ...... 67 6.4 Overall Efficacy Conclusions ...... 71 7 CLINICAL SAFETY ...... 72 7.1 Safety Datasets ...... 72 7.2 Safety of Pexidartinib in the TGCT Population...... 72 7.2.1 Phase 3 ENLIVEN Study ...... 72 7.2.1.1 Extent of Exposure ...... 72 7.2.1.2 Overview of Treatment-Emergent Adverse Events ...... 72 7.2.1.3 Deaths, Serious Adverse Events, and Other Significant Adverse Events ...... 75 7.2.1.3.1 Deaths ...... 75

Page 3 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

7.2.1.3.2 Serious Adverse Events ...... 75 7.2.1.3.3 Adverse Events Leading to Study Drug Discontinuation . 76 7.2.1.3.4 Adverse Events Leading to Dose Reduction or Interruption ...... 76 7.2.1.4 Laboratory Abnormalities ...... 78 7.2.1.5 Adverse Events of Special Interest ...... 79 7.2.1.5.1 Hepatic Adverse Reactions ...... 79 7.2.1.5.2 Cognitive Disorder Adverse Events...... 81 7.2.1.5.3 Cardiac Adverse Events ...... 82 7.2.1.5.4 Bone Marrow Suppression Adverse Events ...... 82 7.2.2 Phase 1 Study PLX108-01 (TGCT Extension Cohort) ...... 82 7.2.3 Safety of Long-Term Pexidartinib Treatment in TGCT Population...... 83 7.2.3.1 Summary of Safety Data Through 31 Jan 2018 (NDA Data Cutoff) ..83 7.2.3.2 Summary of Safety Data Through 31 Aug 2018 (90-Day Safety Update) ...... 84 7.2.4 Safety Subgroup Analyses in the TGCT Population ...... 85 7.2.4.1 Intrinsic Factors ...... 85 7.2.4.1.1 Patient Disposition and Reasons for Discontinuation From Treatment ...... 85 7.2.4.1.2 Demographics and Baseline Characteristics ...... 85 7.2.4.1.3 Extent of Study Drug Exposure and Drug Administration 85 7.2.4.1.4 Treatment-Emergent AEs by SOC and PT ...... 85 7.2.4.1.5 Treatment-Emergent AEs by SOC, PT, and Worst Grade 86 7.2.4.1.6 Serious Adverse Events by SOC and PT ...... 86 7.2.4.1.7 Treatment-Related AEs by SOC and PT ...... 86 7.2.4.1.8 Treatment-Emergent AEs Leading to Discontinuation by SOC and PT ...... 86 7.2.4.1.9 Treatment-Emergent AEs Leading to Dose Reduction or Interruption by SOC and PT ...... 86 7.2.4.2 Extrinsic Factors ...... 86 7.3 Safety of Pexidartinib in the Non-TGCT Population ...... 87 7.3.1 Exposure ...... 87 7.3.2 Overview of Treatment-Emergent Adverse Events ...... 87 7.3.3 Mixed or Cholestatic Hepatotoxicity ...... 88 7.4 Overall Safety Conclusions ...... 90 8 RATIONALE FOR PROPOSED DOSING REGIMEN ...... 91 9 RISK EVALUATION AND MITIGATION STRATEGY ...... 92 9.1 Dose Modification and Liver Monitoring ...... 92 9.2 Risk Evaluation and Mitigation Strategy ...... 93 9.2.1 REMS Requirements for Prescribers ...... 93 9.2.2 REMS Requirements for Patients ...... 94 9.2.3 REMS Requirements for Wholesalers and Pharmacies ...... 94 9.2.4 Pexidartinib REMS and Benefit:Risk Ratio ...... 94 10 BENEFIT:RISK SUMMARY...... 95 10.1 Benefits of Pexidartinib ...... 95 10.2 Risks of Pexidartinib ...... 95

Page 4 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

10.3 Benefit:Risk Conclusion ...... 96 11 REFERENCES ...... 97 12 APPENDIX ...... 99 12.1 Efficacy Narratives ...... 99 12.2 Some Important Events of Mixed or Cholestatic Hepatotoxicity with Pexidartinib ....101 12.2.1 TGCT Cases ...... 101 12.2.2 Non-TGCT Cases ...... 106

LIST OF TABLES

Table 4.1: Overview of Clinical Studies in Pexidartinib Development Program ...... 38 Table 5.1: Mean (Standard Deviation) Values of Pexidartinib PK Parameters Following Single and Multiple Doses ...... 39 Table 5.2: Mean (Standard Deviation) Values of ZAAD-1006a PK Parameters Following Single and Multiple Doses ...... 40 Table 6.1: ENLIVEN Study Endpoints ...... 48 Table 6.2: Patient Disposition in Part 1 (Randomized) of ENLIVEN ...... 51 Table 6.3: Demographic and Disease Characteristics in Part 1 (Randomized) of ENLIVEN (ITT Analysis Set) ...... 52 Table 6.4: Prior Treatment in Part 1 (Randomized) of ENLIVEN (ITT Analysis Set) ...... 54 Table 6.5: Tumor Response by RECIST v1.1 at Week 25 in Part 1 (Randomized) of ENLIVEN (ITT Analysis Set) ...... 55 Table 6.6: Secondary Efficacy Endpoints in Part 1 (Randomized) of ENLIVEN at Week 25 (ITT Analysis Set) ...... 57 Table 6.7: Summary of Completed and Missing Clinical Outcome Assessment Data for Part 1 (Randomized) of ENLIVEN ...... 58 Table 6.8: Sensitivity Analysis of Mean Change for ROM, PROMIS-PF, Worst Stiffness, and BPI Pain for Part 1 (Randomized) of ENLIVEN ...... 59 Table 6.9: Results Using the Unconditional Jump to Reference Model for ROM, PROMIS-PF, Worst Stiffness, and BPI Worst Pain for Part 1 (Randomized) of ENLIVEN ...... 60 Table 6.10: RECIST-SLD Best Overall Response and Duration of Response Based on MRI Central Review in ENLIVEN and Phase 1 Extension TGCT Cohort, and Pooled (ITT Analysis Set) ...... 68 Table 6.11: TVS Best Overall Response and Duration of Response Based on MRI Central Review in ENLIVEN and Phase 1 Extension TGCT Cohort, and Pooled (ITT Analysis Set) ...... 69 Table 7.1: Extent of Exposure in Part 1 (Randomized) of ENLIVEN (Safety Population) ...... 72 Table 7.2: Overall Summary of Treatment-Emergent Adverse Events in Part 1 (Randomized) of ENLIVEN (Safety Population) ...... 73 Table 7.3: Treatment-Emergent Adverse Events Occurring in ≥10% of Patients in Either Group by Preferred Term in Part 1 (Randomized) of ENLIVEN (Safety Analysis Set) ...... 73 Table 7.4: Adverse Events Leading to Study Drug Discontinuation in Part 1 (Randomized) of ENLIVEN (Safety Population) ...... 76

Page 5 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

Table 7.5: Adverse Events Leading to Dose Reduction or Interruption in Part 1 (Randomized) of ENLIVEN (Safety Population) ...... 77 Table 7.6: Clinically Important Laboratory Abnormalities That Are Greater Than Placebo in Patients Receiving Pexidartinib Through Week 25 in Part 1 (Randomized) of ENLIVEN ...... 78 Table 7.7: Overall Summary of Hepatic Adverse Reactions (Laboratory Data) in Part 1 (Randomized) of ENLIVEN ...... 79 Table 7.8: Serious Cases of Mixed or Cholestatic Hepatotoxicity Assessed as Probably Drug Related in TGCT Population (5 out of 140 Patients) ...... 80 Table 7.9: Extent of Exposure in TGCT Population Through 31 Jan 2018 (Safety Population) ...... 83 Table 7.10: Treatment-Emergent Adverse Events Occurring in >10% of TGCT Patients in any Group by Preferred Term Through 31 Jan 2018 (Safety Population) ...... 84 Table 7.11: Overall Summary of Treatment-Emergent Adverse Events in Non-TGCT Monotherapy Population (Safety Analysis Set) ...... 88 Table 7.12: Serious Cases of Mixed or Cholestatic Hepatotoxicity Assessed as Probably Drug Related in Non-TGCT Population ...... 89 Table 7.13: Serious Cases of Mixed or Cholestatic Hepatotoxicity Assessed as Possibly Drug Related in Non-TGCT Population ...... 90 Table 9.1: Dose Reductions ...... 92 Table 9.2: Dose Modifications for Adverse Reactions ...... 93

LIST OF FIGURES

Figure 2.1: Advanced Cases of TGCT That Fit the Proposed Pexidartinib Indication ...... 26 Figure 2.2: Histologic and MRI Features of Localized and Diffuse TGCT ...... 27 Figure 2.3: Objective Assessment Measures of TGCT ...... 28 Figure 2.4: Diagnosis and Treatment Challenges ...... 30 Figure 2.5: Role of CSF-1 in TGCT Formation ...... 31 Figure 3.1: Pexidartinib Mechanism of Action...... 32 Figure 3.2: 3D Molecular Structure of Pexidartinib ...... 33 Figure 3.3: Kinome Map ...... 33 Figure 4.1: Pexidartinib Regulatory History and Milestones ...... 35 Figure 5.1: Forest Plot of the Effect of Concomitant Medication on the Exposure of Pexidartinib ...... 43 Figure 5.2: Forest Plot of the Effect of Pexidartinib on the Exposure of Various CYP and Transporter Substrates ...... 44 Figure 6.1: ENLIVEN Study Design ...... 46 Figure 6.2: Waterfall Plot of Sum of the Longest Diameter for Part 1 (Randomized) of ENLIVEN (ITT Analysis Set) ...... 56 Figure 6.3: Waterfall Plot of Tumor Volume Score in Part 1 (Randomized) of ENLIVEN (ITT Analysis Set) ...... 57 Figure 6.4: Waterfall Plot Based on RECIST for Randomized Pexidartinib and Crossover Cohorts in ENLIVEN (ITT Analysis Set) ...... 61

Page 6 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

Figure 6.5: Kaplan-Meier Estimate of Time to Response According to RECIST v1.1 in ENLIVEN (ITT Analysis Set) ...... 62 Figure 6.6: Kaplan-Meier Estimate of Duration of Response According to RECIST v1.1 in ENLIVEN (ITT Analysis Set) ...... 62 Figure 6.7: Percentage Change in Baseline of Sum of Longest Diameters According to RECIST v1.1 (ITT Analysis Set) ...... 63 Figure 6.8: Prespecified Subgroup Analysis of Response Rate (RECIST v1.1) in Part 1 (Randomized) of ENLIVEN ...... 64 Figure 6.9: Exploratory Subgroup Analysis of Response Rate (RECIST v1.1) in Part 1 (Randomized) of ENLIVEN ...... 65 Figure 6.10: Waterfall Plot of Best Tumor Response in Phase 1 Extension TGCT Cohort ...... 67 Figure 6.11: Proportion of Patients Experiencing Benefit via TVS in ENLIVEN and Phase 1 Extension TGCT Cohort ...... 70 Figure 6.12: Kaplan-Meier Estimates of Time to Response and Duration of Response According to RECIST v1.1 in ENLIVEN and Phase 1 Extension TGCT Cohort ...... 71 Figure 7.1: eDISH Plot of Maximum Postbaseline Total Bilirubin versus Maximum Postbaseline Alanine Aminotransferase in Part 1 (Randomized) of ENLIVEN ...... 81 (b) (6) Figure 12.1: Case Report DSU-2016-125207 (PLX108-10 Subject ID ): Hepatic

Clinical Laboratory Results During Study Treatment ...... (b) (6) ...... 102 Figure 12.2: Case Report DSU-2016-129240 (PLX108-10 Subject ID ): Hepatic

Clinical Laboratory Results During Study Treatment ...... (b) (6) ...... 103 Figure 12.3: Case Report DSU-2016-133478 (PLX108-10 Subject ID : Hepatic

Clinical Laboratory Results During Study Treatment ...... (b) (6) ...... 104 Figure 12.4: Case Report DSU-2016-130954 (PLX108-10 Subject ID : Hepatic

Clinical Laboratory Results During Study Treatment ...... 105(b) (6) Figure 12.5: Case Report DSU-2018-140587 (PLX3397-A-U126 Subject ID : Hepatic Clinical Laboratory Results During Study Treatment ...... 106 (b) (6) Figure 12.6: Case Report DSU-2017-118366 (PLX108-13 Subject ID : Hepatic

Laboratory Parameters by Day ...... (b) (6) ...... 107 Figure 12.7: Case Report DSU-2015-135086 (IST3397-006 Subject ID ): Hepatic Laboratory Parameters by Day ...... 108

Page 7 of 108

Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

1 EXECUTIVE SUMMARY

1.1 Overview Tenosynovial giant cell tumor (TGCT) is a rare, nonmalignant neoplasm of the synovium, bursae, or tendon sheaths that is driven by overexpression of colony-stimulating factor-1 (CSF-1). The current standard of care for TGCT is surgical resection.1,2 However, diffuse disease often has more extensive involvement and a poorer likelihood of successful cure with surgery, and therefore often may not be amenable to surgical resection due to the risk of morbidity or high risk of recurrence (lifetime recurrence rate of up to 55%) in diffuse disease.3 In diffuse disease, the tumor mass grows and gradually expands within the intra- or extra- articular space and surrounding tissue; symptoms such as pain, stiffness, swelling, and reduced range of motion (ROM) of the affected joint can become severe and result in debilitating functional limitations. Currently, no approved systemic therapies exist for TGCT. Pexidartinib is an oral small-molecule tyrosine kinase inhibitor (TKI) that targets CSF-1 receptor (CSF1R; also known as feline McDonough sarcoma [FMS] kinase). Pexidartinib also inhibits the proto-oncogene receptor tyrosine kinase, c-Kit, and FMS-like tyrosine kinase 3 harboring an internal tandem duplication (FLT3-ITD). Daiichi Sankyo is seeking approval of pexidartinib for the treatment of adult patients with symptomatic TGCT, also referred to as giant cell tumor of the tendon sheath (GCT-TS) or pigmented villonodular synovitis (PVNS), which is associated with severe morbidity or functional limitations, and which is not amenable to improvement with surgery. The pivotal Phase 3 Study PLX108-10 (ENLIVEN) was a two-part, multicenter, double-blind, randomized, placebo-controlled study in patients with locally advanced, symptomatic TGCT for whom surgical resection would be associated with potentially worsening functional limitation or severe morbidity. In Part 1, the double-blind phase, eligible patients were centrally randomized in a 1:1 ratio to receive either pexidartinib or placebo for 24 weeks. Pexidartinib was given at a dose of 1000 mg/day (400 mg in the morning, 600 mg in the evening) for 2 weeks, then 400 mg twice daily (BID). Patients who completed Part 1 were to enter Part 2 for efficacy and safety assessment of long-term pexidartinib treatment. In Part 2, patients received open-label pexidartinib at the same pexidartinib dose or equivalent dose of placebo as at the end of Part 1. Part 2 also evaluated efficacy and safety of pexidartinib in patients starting pexidartinib after crossover from placebo; all started pexidartinib at the 400-mg BID dose. The ENLIVEN study met its primary endpoint of tumor response rate at Week 25 per blinded independent central review by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The overall response rate (ORR) was 39.3% (95% confidence interval [CI]: 28.1%, 51.9%) for pexidartinib versus 0 (95% CI: 0.0, 6.1%) for placebo (P < 0.0001). The study also met the first four of its five comparative secondary endpoints of joint ROM, tumor volume score (TVS), and patient-reported outcomes (PROs) of physical function, stiffness, and pain. Pexidartinib demonstrated statistically significant and clinically meaningful efficacy based on tumor response, as well as symptom and functional outcomes. The cohort of patients who crossed over to pexidartinib from placebo at the end of the randomized phase of this study also experienced tumor responses and durable clinical benefit. Notably, with an additional 10 months of follow- up (median time from first pexidartinib dose of 20 months [range, 16 to 31]), best overall response (BOR) increased to 53% (95% CI: 40%, 64%). Further evidence of tumor response and

Page 10 of 108

Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

initially may be minimal due to the slowly progressive nature of the disease. However, as the tumor mass grows and gradually expands within the intra- and extra-articular space, symptoms such as pain, stiffness, swelling, and reduced ROM of the affected joint can become severe and result in debilitating functional limitations. The diagnosis of TGCT is based on pathologic evaluation; however, features highly suggestive of the disease may be found on radiologic imaging (ie, magnetic resonance imaging [MRI]). Figure A illustrates several extreme cases of TGCT wherein the burden of disease is highest and clearly evident.

Figure A: Advanced Cases of TGCT That Fit the Proposed Pexidartinib Indication

Photographs of TGCT tumors in the ankle, wrist/hand, and knee among three patients in the pexidartinib clinical program. The MRI corresponds to the tumor in the knee. Abbreviations: MRI = magnetic resonance imaging; TGCT = tenosynovial giant cell tumor. Ankle and knee MRI images courtesy of Tap WD, et al. ASCO 2018, abstract 11502. Hand image courtesy of Tap WD, et al. Lancet, in press. Knee image at far right reprinted from Tap WD, et al. Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor. N Engl J Med. 2015;373:428-437. Copyright © 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Tenosynovial giant cell tumor manifests as localized or diffuse disease. The localized type (known as GCT-TS) constitutes 80% to 90% of TGCT cases and is usually a benign neoplasm that most commonly occurs in the digits.3,4 Localized TGCT can usually be treated effectively with surgery. The diffuse type (known as PVNS) constitutes 10% to 20% of cases and is a locally aggressive, nonmalignant neoplasm composed of synovial-like mononuclear cells, multinucleate giant cells, foam cells, siderophages, and inflammatory cells that may be intra- or extra-articular. Diffuse TGCT most commonly occurs in large joints, particularly the knee, ankle, and hip. In the United States (US), the annual incidence of new cases is estimated to be ~15,000 for localized TGCT and ~1500 for diffuse TGCT.4-6 A more recent survey in Denmark provides an incidence of 4.4 per million for localized TGCT and 1.1 per million for diffuse TGCT,3 whereas a study in the Netherlands reports incidence rates (per million patient-years) of 34 for localized TGCT in the digits, 11 for localized disease in other extremities, and 5 for diffuse TGCT.4 The current standard of care for TGCT is surgical resection.1,2 However, diffuse disease is often not amenable to complete surgical resection due to the risk of morbidity and concordant high risk of recurrence (lifetime recurrence rate of up to 55%).3 Patients with diffuse-type disease often have more extensive involvement and a poorer likelihood of success with surgery. Patients with diffuse disease and undergoing a first surgical attempt for disease control have an estimated relapse risk of ~50%, with an average of two subsequent surgeries in the next 5 years; patients already in relapse will likely experience three such subsequent surgeries as the only option to control the disease. Surgical resection in diffuse cases involves synovectomy and may involve (partial) removal of major tendons such as the anterior cruciate ligament or meniscus in the knee,

Page 12 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

leading to intense, prolonged (6 to 9 months) postoperative physical therapy to regain the preoperative joint function, analogous to full joint reconstruction post-injury such as in the knee. Surgical resection could also involve/approach critical neurovascular structures such as in the elbow or wrist/ankle, leading to significant postoperative morbidity. Hip diffuse disease often results in total joint replacement due to the deep location of the joint, and thus leaves the patients of young age with the prospect of an artificial joint life expectancy much less than their own. Limb amputation may be required in severe, recurrent cases that extend beyond the joint itself; eg, in the tibial and femoral adjacent bone regions.4 Currently, no systemic antitumor agents are approved for this indication,7 and pexidartinib is the only agent to be evaluated in a randomized Phase 3 study. In a retrospective series of 29 TGCT patients treated with imatinib, the ORR was 19%.8 In an uncontrolled study of nilotinib, the response rate was 6%.9 Anti-inflammatory and analgesic medications, including opioids, are commonly used as supportive therapy. Given the severe disease burden of TGCT that is not amenable to surgery, a systemic therapy that provides a meaningful clinical benefit is highly needed.

1.4 Pexidartinib Development Rationale Tenosynovial giant cell tumor consists predominantly of mononuclear and multinucleated giant cells. Expansion of the tumor mass appears to be driven by the presence of abundant CSF-1 expressed in a subset of neoplastic cells within the tumor and is often associated with genetic translocations; eg, linking the collagen 6A3 gene on chromosomal locus 2q35 with the CSF-1 gene on chromosomal locus 1p13.1,10-12 The majority of cells in the tumor mass are non- neoplastic inflammatory cells that do not express CSF-1 but are attracted to the tumor site because they express CSF1R. Pexidartinib (PLX3397; PLX3397-HCl) is a novel, orally active, small-molecule TKI that selectively inhibits CSF1R, thereby blocking the recruitment of macrophages to the tumor (Figure B).13 Pexidartinib is significantly more potent than conventional type 2 inhibitors, including imatinib and nilotinib. As a selective CSF1R TKI, pexidartinib provides an important new therapeutic option for patients with TGCT.

Page 13 of 108

Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

5′-diphosphate glucuronyltransferase (UGT)1A4 and cytochrome P450 (CYP)3A and undergoes minimal urinary excretion. Its major plasma metabolite is N-glucuronide (ZAAD-1006), with exposure higher than the parent compound, but N-glucuronide has minimal pharmacological activity. Concurrent administration of pexidartinib with strong CYP3A or UGT1A4 inhibitors increased pexidartinib exposure. Therefore, the pexidartinib dose should be reduced in patients receiving strong CYP3A and UGT1A4 inhibitors. Inducers of CYP3A should be avoided as these decrease pexidartinib exposure. Systemic pH modifiers (eg, esomeprazole) should also be avoided as concomitant administration of these agents with pexidartinib decreases pexidartinib exposure. If needed, antacids can be given >2 hours after pexidartinib dosing. Administration of pexidartinib with food resulted in approximately twice the exposure. Therefore, it is recommended to dose pexidartinib BID at least 1 hour before or 2 hours after a meal. No dose adjustment is needed for renal impairment, including patients on routine hemodialysis. Pexidartinib does not prolong the QTc interval.

1.5.2 Summary of Clinical Efficacy Evidence for the efficacy of pexidartinib in the treatment of TGCT is derived primarily from the pivotal Phase 3 ENLIVEN study and the supportive Phase 1 extension TGCT cohort. Efficacy of pexidartinib was observed consistently across the studied TGCT population.

1.5.2.1 Phase 3 Study PLX108-10 (ENLIVEN)

1.5.2.1.1 Study Design ENLIVEN is a Phase 3, randomized, placebo-controlled, two-part, multicenter study conducted in patients with symptomatic TGCT for whom surgical resection would be associated with potentially worsening functional limitation or severe morbidity (locally advanced disease) (Figure C). In Part 1, the double-blind phase, eligible patients were centrally randomized in a 1:1 ratio to receive either pexidartinib or placebo for 24 weeks. Randomization was stratified by geographic region (US vs non-US study sites) and disease location (upper- vs lower-extremity involvement). Patients who completed Part 1 could enter Part 2, a long-term treatment phase wherein all patients were to be transitioned to open-label pexidartinib with regular efficacy and safety assessments to evaluate long-term pexidartinib treatment. Efficacy assessments included tumor imaging by MRI, assessment of ROM of the affected joint, and PRO assessments. For the first 2 weeks in Part 1, patients took 400 mg of pexidartinib in the morning and 600 mg in the evening (total of 1000 mg/day pexidartinib) or matching placebo. Thereafter, dosing was reduced to 400 mg BID (800 mg/day) or matching placebo. Dose reductions and interruptions were implemented according to the protocol. The pexidartinib dose for Part 2 was the same as the pexidartinib dose or pexidartinib-equivalent dose of placebo at the end of Part 1. Because patients on the placebo arm were not expected to have dose reductions due to toxicity beyond the protocol-defined reduction at 2 weeks, the study design provided efficacy and safety data for an alternate pexidartinib starting dose of 800 mg/day. After database lock and unblinding, it was revealed that all 30 patients who crossed over from placebo in Part 1 to open-label pexidartinib in Part 2 started pexidartinib at a dose of 800 mg/day (400 mg BID), the proposed dose for pexidartinib.

Page 15 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

Figure C: ENLIVEN Study Design

Abbreviations: bid = twice daily; MRI = magnetic resonance imaging; PRO = patient-reported outcome; ROM = range of motion.

The primary and secondary endpoints of this study are summarized in Table A. Prespecified secondary endpoints were analyzed using a hierarchical (“gatekeeping”) testing procedure. If the test for a particular endpoint failed to reach statistical significance (P<0.05, 2-sided or P<0.025, 1-sided for binary endpoints), the inference for all subsequent endpoints in the hierarchy was not performed. Testing of the key secondary efficacy endpoints proceeded sequentially in the order shown with treatment comparisons at the Week 25 visit in the intent-to-treat (ITT) analysis set.

Page 16 of 108

Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

or imatinib. Approximately half of patients in each arm used concomitant analgesics at the time of enrollment.

1.5.2.1.3 Primary Efficacy Endpoint Results The study met its primary efficacy endpoint of response rate based on blinded, independent central review of ORR at the end of Part 1 for the ITT analysis set. The response rate was statistically significantly higher in the pexidartinib group (39.3%) compared with the placebo group (0) (1-sided Fisher’s exact test, P<0.0001). The primary endpoint reflected a substantial reduction in tumor size (Figure D). Figure D: Tumor Response by RECIST v1.1 at Week 25 (Primary Endpoint) in ENLIVEN (Blinded, Central MRI Review; ITT Analysis Set)

Complete Partial Stable Progressive Not Overall response rate Treatment, n (%) response response disease disease evaluable [95% CI] Pexidartinib (n=61) 9 (15) 15 (25) 24 (39) 1 (2) 12 (20) 24 (39) [28.1, 51.9] P<0.0001 Placebo (n=59) 0 0 46 (78) 1 (2) 12 (20) 0 [0, 6.1]

25 25 ORR = 39% ORR = 0% 0 0

-25 -25

-50 -50

-75 -75 Pexidartinib (n=61) Placebo (n=59) Change in tumor diameter, % diameter, tumor in Change -100 -100 Note: Mean baseline sum of the longest tumor diameters was 10.1 and 10.6 cm for pexidartinib and placebo, respectively. Abbreviations: CI = confidence interval; MRI = magnetic resonance imaging; ITT = intent-to-treat; RECIST = Response Evaluation Criteria in Solid Tumors.

1.5.2.1.4 Secondary Efficacy Endpoint Results As shown in Table B, the first four of the five secondary endpoints were statistically significant for pexidartinib versus placebo, demonstrating that pexidartinib provides statistically significant and clinically meaningful improvement of joint function and disease symptoms. The responder analysis of BPI-30 Worst Pain was most impacted by the missing PRO data at Week 25 because patients who did not provide Week 25 BPI Worst Pain data were assigned nonresponder status. A prespecified exploratory analysis of the BPI Worst Pain endpoint was performed using a mixed-effect model for repeated measures (MMRM) analysis of the mean change from baseline, the method used for the other clinical outcome assessment (COA) secondary endpoints (ROM, PROMIS-PF, and Worst Stiffness). This analysis demonstrated improvement with pexidartinib of –2.44 (95% CI: -3.1, -1.8) compared with placebo of –0.55 (95% CI: –1.19, 0.09), for an LS mean treatment difference of -2.2 (95% CI: –3.0, -1.4).

Page 18 of 108

Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

1.5.2.1.5 Efficacy With Longer Pexidartinib Treatment At the time of the primary analysis at the 27 Mar 2017 data cutoff, duration of response was still immature. With an additional 10 months of follow-up at the 31 Jan 2018 data cutoff (median time from first pexidartinib dose of 20 months [range, 16 to 31]), BOR by RECIST v1.1 increased to 53% (95% CI: 40%, 64%) in the 61 patients randomized to pexidartinib and 53% (95% CI: 36%, 70%) in the 30 patients who crossed over to pexidartinib. Best overall response (95% CI) by TVS was 64% (95% CI: 51%, 75%) and 67% (95% CI: 49%, 81%), respectively. Median duration of response was still not reached for RECIST v1.1 or TVS in pexidartinib randomized and crossover patients (range, [2.8+, 24.9+] and [0+, 27.6+] months, respectively). Only one patient developed tumor progression by RECIST. Tumor assessments showed that the vast majority of patients experienced a reduction in tumor size with continuing treatment.

1.5.2.2 Phase 1 Study PLX108-01 (TGCT Extension Cohort) The efficacy results observed in the ENLIVEN study are consistent with data from the Phase 1 study in TGCT. Study PLX108-01 was a first-in-human study with a dose-escalation phase (Part 1) and extension cohort phase (Part 2) conducted in patients with solid tumors. In Part 2, the recommended Phase 2 dose of 1000 mg/day was evaluated in six tumor cohorts, including TGCT (n=39). At the data cutoff for the NDA (31 Jan 2018), 13 of the 39 TGCT patients had been on pexidartinib treatment for approximately 3 to 5 years and continued to receive pexidartinib treatment. The best ORR by central radiographic review was 51% by RECIST v1.1 and 56% by TVS. In 21 patients for whom PRO data were available, the mean pain level improved by Day 15, and this improvement was generally sustained for the duration of treatment.

1.5.2.3 Efficacy Conclusions In ENLIVEN, the primary efficacy endpoint and four of the five secondary efficacy endpoints showed statistically significant treatment effects of pexidartinib compared with placebo at Week 25. Part 2 of ENLIVEN demonstrated the long-term durability of these clinically meaningful benefits based on tumor response and improvement in joint function and disease symptoms. Tenosynovial giant cell tumor rarely progressed or became refractory to pexidartinib. Tumor response and clinical improvement observed in the TGCT extension cohort of the Phase 1 study were consistent with the ENLIVEN results. Tumors continued to regress with long-term pexidartinib treatment.

1.5.3 Summary of Clinical Safety Pexidartinib has a well-established safety profile, consistent with its mechanism of action, across 13 sponsored clinical studies that enrolled 630 patients with cancer or TGCT. The safety profile of pexidartinib in TGCT was well defined in the pivotal Phase 3 ENLIVEN study, with additional information on the risk of mixed or cholestatic hepatotoxicity derived from the overall clinical program. The Sponsor proposes a REMS focused on weekly monitoring of liver function with prompt discontinuation and effective communication to physicians, pharmacists, and patients to mitigate the risk (see Section 1.6 for REMS overview).

Page 20 of 108

Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

Figure E: Most Common TEAEs (>10%) Reported in Part 1 (Randomized) of ENLIVEN (Safety Population)

Abbreviations: GI = gastrointestinal; TEAE = treatment-emergent adverse event.

Safety data reported from the Phase 3 ENLIVEN study were generally consistent with the results from the Phase 1 extension TGCT cohort (see Section 7.2.2 of the Briefing Document for safety data from the TGCT extension cohort). Additional follow-up with continued pexidartinib treatment did not reveal any new, concerning safety findings. Most adverse reactions were manageable with dose interruptions and reductions, but some resulted in discontinuation.

1.5.3.2.1 Adverse Events of Special Interest: Hepatic Adverse Reactions Pexidartinib is associated with two clinically distinct types of hepatic adverse reactions. The first is aminotransferase elevations, which occur in the absence of significant bilirubin and ALP elevations, are frequent, dose dependent, generally low-grade, and related to the mechanism of action of pexidartinib. The onset of these elevations primarily has been observed during the first 8 weeks of treatment. This adverse effect is manageable with liver monitoring and dose modifications. The second hepatic adverse reaction is mixed or cholestatic hepatotoxicity, defined as aminotransferase increase with concurrent increase in bilirubin and ALP. This event type can be characterized as uncommon and idiosyncratic, and while they are rarely serious, they can be life threatening. Hepatic adverse reactions (laboratory data) are summarized in Table D.

Page 22 of 108

Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

The mechanism of mixed or cholestatic hepatotoxicity associated with pexidartinib is unknown and its occurrence cannot be predicted. Therefore, in new clinical studies of pexidartinib, patients with baseline elevations of serum transaminases or bilirubin, or active liver or biliary tract disease, are excluded. In addition, weekly monitoring of liver function tests during the first 8 weeks of pexidartinib treatment and then biweekly for 1 month has been implemented with strict dose interruption, dose reduction, and dose discontinuation criteria.

1.5.3.3 Safety Conclusions Pexidartinib was generally well tolerated and associated with mostly low-grade and reversible AEs. Adverse events that occurred most frequently with pexidartinib compared with placebo included hair color changes, fatigue, and dysgeusia. Pexidartinib is associated with two clinically distinct types of hepatic adverse reactions. The first is frequent but manageable aminotransferase elevations that are a pharmacologic effect of CSF1R inhibition. The second hepatic adverse reaction is an idiosyncratic risk of serious mixed or cholestatic hepatotoxicity. This risk was <2% across the development program, and a few cases were prolonged and rarely irreversible. There were no Hy’s Law cases and no serious hepatocellular injury. Prolonged pexidartinib treatment did not reveal any new, concerning safety findings. Although the potentially life-threatening risk of severe mixed or cholestatic hepatotoxicity cannot be eliminated completely, the goal is to reduce the risk of hepatotoxicity through careful monitoring of liver function, early intervention with dose modification, and other measures according to the proposed label and REMS.

1.5.4 Dose Justification The proposed dose regimen of 800 mg/day (400 mg BID) is revised from the dose regimen of 1000 mg/day for 2 weeks followed by 800 mg/day (400 mg BID) used in Part 1 of ENLIVEN. A lower starting dose will reduce the dose-dependent aminotransferase elevations but will not alter the risk for idiosyncratic hepatotoxicity. However, it is unlikely that a starting dose of 800 mg/day versus 1000 mg/day for the first 2 weeks of treatment will substantively reduce the overall efficacy, given the long-term duration of therapy for most patients, the slow growth dynamics of TGCT, the time to maximum treatment effect that spans many months, and the identical clinical activity observed in the crossover cohort of 30 patients who began treatment with pexidartinib at 800 mg/day. With this in mind, and the serious nature of the hepatotoxicity primarily observed in the first 8 weeks of therapy, the initial 2-week treatment with the higher (1000-mg/day) dose of pexidartinib is not justifiable. The proposed pexidartinib dose regimen of 400 mg (2 × 200-mg capsules) BID is also supported by exposure-response modeling of efficacy and safety.

1.6 Risk Evaluation and Mitigation Strategy The pexidartinib REMS aims to mitigate the risk of serious and potentially fatal hepatotoxicity by ensuring that healthcare providers and patients are well informed about these risks. Key stakeholders include prescribers, patients, and dispensers, and key modalities are to promote education and limit distribution. The overall goals of the proposed REMS are to ensure prescribers are educated on the approved indication, risk of serious and potentially fatal hepatotoxicity, requirements for liver monitoring and associated dose modifications, and need to counsel patients on the risk of serious and potentially fatal hepatotoxicity. The patient guide will

Page 24 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019 inform patients about the risk of serious and potentially fatal hepatotoxicity associated with pexidartinib, as well as the frequency of liver monitoring, dose modifications, and the importance of reporting any signs and/or symptoms of hepatotoxicity to their physician. Wholesalers will be educated on compliance with distribution only to pharmacies, and pharmacies will be educated on the content of the REMS document and requirements to dispense pexidartinib. The proposed REMS supports safety information communicated in the labeling, which includes a black-box warning and medication guide. The Sponsor is committed to working with the Agency to optimize the elements of the REMS, labeling, and medication guide, as appropriate.

1.7 Benefit:Risk Assessment For some patients with diffuse TGCT, the tumor results in severe pain, stiffness, swelling, and reduced ROM, resulting in debilitating functional limitations and reduced quality of life. No systemic therapies are approved for TGCT, and pexidartinib is the only agent that has demonstrated a high tumor response rate with improved clinical outcomes. When considering the totality of the data and the significant unmet medical need in TGCT, the Sponsor concluded that the clear and durable benefits afforded by pexidartinib offer an important treatment option for carefully selected TGCT patients who are suffering from severe morbidity or functional limitations and for whom no proven treatment options exist. The proposed pexidartinib labeling, REMS, and required laboratory monitoring will provide physicians and patients with the requisite information for a robust benefit:risk assessment on an individual patient basis.

Page 25 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

2 BACKGROUND AND SCIENTIFIC RATIONALE

2.1 Overview of Tenosynovial Giant Cell Tumor Tenosynovial giant cell tumor (TGCT), also referred to as giant cell tumor of the tendon sheath (GCT-TS) or pigmented villonodular synovitis (PVNS), is a rare nonmalignant neoplasm of the synovium, bursae, or tendon sheaths, affecting generally young adults (<40 years of age) of both sexes.4 Tenosynovial giant cell tumor is usually a monoarticular disease that involves the bone, soft tissue, synovium, or tendon sheath of small or large joints.14 Symptoms initially may be minimal due to the slowly progressive nature of the disease, but as the tumor mass grows and gradually expands within the intra-articular space and surrounding tissue, symptoms such as pain, stiffness, swelling, and reduced range of motion (ROM) of the affected joint can become severe and result in debilitating functional limitation (Figure 2.1), which threatens the quality of life of the relatively young patient population.15-17

Figure 2.1: Advanced Cases of TGCT That Fit the Proposed Pexidartinib Indication

Photographs of TGCT tumors in the ankle, wrist/hand, and knee among three patients in the pexidartinib clinical program. The MRI corresponds to the tumor in the knee. Disease history, baseline characteristics, tumor response, and clinical benefit associated with pexidartinib treatment are described in Section 12.1 for the ankle and hand/wrist tumors and in Giustini et al, 201818 for the knee tumor. Abbreviations: MRI = magnetic resonance imaging; TGCT = tenosynovial giant cell tumor. Ankle and knee MRI images courtesy of Tap WD, et al. ASCO 2018, abstract 11502. Hand image courtesy of Tap WD, et al. Lancet, in press. Knee image at far right reprinted from Tap WD, et al. Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor. N Engl J Med. 2015;373:428-437. Copyright © 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Tenosynovial giant cell tumor manifests as localized or diffuse disease (Figure 2.2). The localized type (known as GCT-TS) constitutes 80% to 90% of TGCT cases and is usually a benign neoplasm that most commonly occurs in the digits.3,4 Localized TGCT can usually be treated effectively with surgery. The diffuse type (known as PVNS) constitutes 10% to 20% of cases and is a locally aggressive, nonmalignant neoplasm composed of synovial-like mononuclear cells, multinucleate giant cells, foam cells, siderophages, and inflammatory cells that may be intra- or extra-articular. Diffuse TGCT most commonly occurs in large joints, particularly the knee, ankle, and hip. In the United States (US), the annual incidence of new cases is estimated to be ~15,000 for localized TGCT and ~1500 for diffuse TGCT.4-6 The incidence appears to be similar worldwide. In a review of a Scottish hospital case series, Monaghan et al14 suggested an incidence of 20 cases of GCT-TS per million. Similarly, Ushijima et al19 described an incidence of 25 cases per million in Kyushu, Japan. A more recent survey in Denmark provides an incidence of 4.4 per million for localized TGCT and 1.1 per million for diffuse TGCT,3 while one in the Netherlands reports incidence rates per million

Page 26 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

patient-years of 34 for localized TGCT in the digits, 11 for localized disease in other extremities, and 5 for diffuse TGCT.4 Figure 2.2: Histologic and MRI Features of Localized and Diffuse TGCT

Abbreviations: MRI = magnetic resonance imaging; TGCT = tenosynovial giant cell tumor. Images reprinted from Lucas DR. Arch Pathol Lab Med. 2012;136:901-906.

Tenosynovial giant cell tumor is a highly irregular shaped tumor that is not as accurately measured via traditional Response Evaluation Criteria in Solid Tumors (RECIST). Tumor volume score (TVS) calculates tumor volume as a percentage of the entire synovium, using the synovial cavity for standardization (Figure 2.3). For example, partial response is at least 50% reduction in TVS versus baseline, whereas progressive disease is at least 30% increase in TVS versus the nadir.

Page 27 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

Figure 2.3: Objective Assessment Measures of TGCT

TVS

Abbreviations: TGCT = tenosynovial giant cell tumor; TVS = tumor volume score. Left image from Tap WD, et al. Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor. N Engl J Med. 2015;373:428-437. Copyright © 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Right image courtesy of Tap WD, et al. ASCO 2018, abstract 11502.

Patients are usually diagnosed between the ages of 20 and 60 years and most often present with pain and swelling at the affected joint. The diagnosis of TGCT is definitively made from pathologic evaluation; however, features highly suggestive of the disease may be found on radiologic imaging (ie, magnetic resonance imaging [MRI]). In extremely rare cases, TGCT can be malignant, and fatal metastatic TGCT has been reported.20 Physical joint examination is generally nonspecific in the clinical diagnosis of TGCT. A specialized musculoskeletal radiologist can however diagnose TGCT on MRI, which is the most distinctive imaging technique. Magnetic resonance imaging can also be a differentiating tool to determine tumor severity staging and for evaluation of disease extent during follow-up. The TGCT severity classification defines TGCT extension on MRI to classify disease severity.21 The TGCT severity classification on MRI contains four distinct severity stages: (1) mild localized contains localized- type, either intra- or extra-articular involvement without involvement of muscular/tendinous tissue/ligaments; (2) severe localized includes localized-type, either intra- or extra-articular lesions and either or both involvement of muscular/tendinous tissue/ligaments; (3) moderate diffuse comprises diffuse type with intra- and/or extra-articular disease without involvement of muscular/tendinous tissue/ligaments; and (4) severe diffuse is diffuse type including intra- and extra-articular involvement and involvement of at least one of the three structures (muscular/tendinous tissue/ligaments). Tenosynovial giant cell tumor onset is typically slow, and patients present with unspecified symptoms. Pain, swelling, and stiffness of the involved joint might be misinterpreted as osteoarthritis, rheumatoid arthritis, a meniscal tear, or other ligamentous injury. Because of the rarity of the disease, definitive diagnosis may take several years and patients present with extensive disease. After several (arthroscopic or open) synovectomies and even radiotherapy, patients are still referred to a tertiary hospital. Besides declined functional outcome and health- related quality of life, these patients are at risk of repeated recurrences, therapy-resistant disease, and higher risk of complications. Continued inflammation, joint usuration, and bone involvement may lead to articular destruction that might worsen (pre-existing) secondary osteoarthritis. Specialized centers treat multiple patients with TGCT, and this rare disease is

Page 28 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

considered daily practice. Therefore, all members of the multidisciplinary team are highly trained to recognize disease specifics. Members of the multidisciplinary TGCT team include dedicated physicians with experience in musculoskeletal oncology in the fields of pathology, radiology, orthopedic oncology, arthroscopic orthopedics, radiotherapy, medical oncology, and, if necessary, pediatric orthopedics. To prevent end-stage treatment options, such as limb amputation, centralization of treatment should become state of the art.2

2.1.1 Unmet Medical Need The current standard of care for TGCT is surgical resection of the tumor as completely as possible to (1) reduce pain, stiffness, and joint destruction caused by the disease process; (2) improve function; and (3) minimize the risk of recurrence.22 Diagnosis and treatment challenges are illustrated in Figure 2.4. Depending on the extensiveness of the disease, complete resection is frequently impossible, especially in diffuse TGCT (van de Sande, personal communication). Important structures for limb and joint function are often involved and cannot be removed without having severe impact on joint function, pain, mobility, and quality of life. Therefore, TGCT recurrence rates are commonly driven by the impossibility to remove all mutated tumor cells from in and around the joint. Patient outcome following surgery depends on multiple factors, including the location and extent of the disease. The overall recurrence rate for patients with localized disease is low, ranging from 0 to 6%. However, diffuse disease carries a risk of multiple recurrences, with an estimated lifetime recurrence rate of up to 55% in diffuse disease.3 Patients with diffuse-type disease often have more extensive involvement and a poorer likelihood of success with surgery. Recurrent cases show an even worse prognosis for relapse- free survival, which is estimated around 25% at 5 years. Surgical resection may involve removal of major tendons or neurovascular structures, leading to significant postoperative morbidity. Some reports consider arthroscopic management of TGCT superior to open surgery, because of less morbidity and a shorter recovery period. Standard arthroscopy of the knee using the anteromedial and anterolateral approaches, however, does not allow surgical access to all areas where diseased tissue could be present. A systematic review showed lower recurrence rates for open synovectomy (average 14%, maximum 67%) compared with arthroscopic synovectomy (average 40%, maximum 92%) in diffuse TGCT.22 In patients with extensive and/or recurrent TGCT, other available treatment modalities include radiation synovectomy with 90-yttrium, external beam radiation therapy, and cryosurgery (van de Sande, personal communication). Their therapeutic value has only been assessed in retrospective, mostly small single-center series, and their long-term side effects and complications are poorly described. Limb amputation may be required in severe, recurrent cases.4

Page 29 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

Figure 2.4: Diagnosis and Treatment Challenges

Abbreviations: Ortho = orthopedic; PCP = primary care physician; Rheum = rheumatologist; TGCT = tenosynovial giant cell tumor.

No systemic antitumor agents are approved for TGCT, and no investigational agents have been evaluated in a randomized study with measures of symptoms or joint function.7 In a retrospective series of 29 TGCT patients treated with imatinib, the overall response rate (ORR) was 19%.8 In an uncontrolled study of nilotinib, the response rate was 6%.9 Imatinib has been used in this population2; however, it is not approved for use in TGCT and its use is limited due to the modest efficacy along with significant side effects, such as fluid retention and rare but serious risk of hepatotoxicity. In support, only 8.3% of patients entering the pexidartinib Phase 3 ENLIVEN study in TGCT had received prior imatinib therapy (see Section 6.1.3.2). Anti-inflammatory and analgesic medications, including opioids, are commonly used as supportive therapy.

Considering the severe morbidity that a patient can experience with TGCT, and the limitations of available treatment modalities when the disease is not amenable to surgery, a systemic therapy that provides meaningful clinical benefit is highly needed, particularly for those patients with symptomatic TGCT in whom the disease is associated with severe morbidity or functional limitations, and which is not amenable to improvement with surgery.

2.1.2 Role of CSF-1 in Tenosynovial Giant Cell Tumor Tenosynovial giant cell tumors predominantly consist of mononuclear and multinucleated giant cells. Expansion of the tumor mass appears to be driven by the presence of abundant colony- stimulating factor-1 (CSF-1) expression by a subset of neoplastic cells within the tumor (Figure 2.5). The majority of cells in the tumor mass are non-neoplastic inflammatory cells that do not express CSF-1 but are attracted to the tumor site because they express the CSF-1 receptor (CSF1R). The high CSF-1 expression is often associated with genetic translocations; eg, linking the collagen 6A3 gene on chromosomal locus 2q35 with the CSF-1 gene on chromosomal locus 1p13.1,10-12 Biomarker analysis of 25 TGCT tumor specimens from the pexidartinib clinical program demonstrated elevated CSF-1 mRNA expression in all, and a genetic rearrangement eliminating the 3′-UTR regulatory region was detected in 23 of the specimens. Similar results of

Page 30 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

a study of 25 TGCT specimens were recently published; all had elevated CSF-1 expression and a gene rearrangement was detected in 75%.1 Figure 2.5: Role of CSF-1 in TGCT Formation

Abbreviations: CSF-1 = colony-stimulating factor-1; CSF1R = colony-stimulating factor-1 receptor; TGCT = tenosynovial giant cell tumor. Image courtesy of Tap WD, et al. ASCO 2018, abstract 11502.

Evidence that CSF-1 is an important driver of TGCT pathogenesis was shown by the activity of CSF1R-selective inhibitors. Pexidartinib, as well as the investigational CSF1R monoclonal antibodies emactuzumab and cabiralizumab, demonstrated strong tumor response in TGCT in Phase 1 clinical studies.12,13,23 These early clinical results provided preliminary proof-of-concept of the therapeutic potential of CSF1R inhibition in TGCT.

Page 31 of 108

Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

3.2 Proposed Indication and Dose

3.2.1 Indication TURALIO is indicated for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT), also referred to as giant cell tumor of the tendon sheath (GCT-TS) or pigmented villonodular synovitis (PVNS), which is associated with severe morbidity or functional limitations, and which is not amenable to improvement with surgery.

3.2.2 Dosage and Administration The recommended dose of TURALIO is 400 mg (2 × 200 mg capsules) taken twice daily (BID) on an empty stomach (at least 1 hour before or 2 hours after a meal).

Page 34 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

4 PEXIDARTINIB DEVELOPMENT PROGRAM

4.1 Regulatory History The development program for pexidartinib was discussed with the US Food and Drug Administration (FDA) at various milestones throughout the development program. Figure 4.1 highlights key interactions. Pexidartinib was granted orphan drug status on 14 Feb 2014 for the treatment of PVNS/GCT-TS. On 28 Oct 2015, pexidartinib was granted Breakthrough Therapy Designation for the treatment of patients with PVNS or GCT-TS where surgical resection was associated with potentially worsening functional limitation or severe morbidity. The October 2016 partial clinical hold was due to two cases of reported hyperbilirubinemia with concurrent transaminase increase in ENLIVEN, and other cases across the pexidartinib development program. This partial clinical hold was lifted after the Sponsor provided additional safety information, a risk analysis for hepatotoxicity, a risk mitigation plan, and a revised protocol, informed consent, and Investigator’s Brochure. In September 2017, after consultation with the US FDA, the Sponsor reordered the secondary endpoints in the ENLIVEN protocol, due to the number of missing patient-reported outcomes (PROs), which had the most impact on the Brief Pain Inventory (BPI)-30 pain response endpoint. The November 2017 partial clinical hold required that the risk mitigation measures implemented as a result of the October 2016 partial clinical hold be applied to all pexidartinib studies in the development program. This hold was lifted in January 2018, based on submission of revised protocols incorporating the risk mitigation measures. The NDA was filed for regular approval via a rolling review process, with the final part of the submission being filed on 3 Dec 2018 Figure 4.1: Pexidartinib Regulatory History and Milestones

Abbreviations: FDA = US Food and Drug Administration; IND = Investigational New Drug application; NDA = New Drug Application.

4.2 Nonclinical Overview In vitro, pexidartinib showed selectivity as a dual inhibitor of CSF1R and c-Kit. In vitro studies confirmed pexidartinib was a potent inhibitor of the catalytic activities of CSF1R and c-Kit and also of the ITD mutant of FLT3-ITD. In vivo studies further confirmed the potent inhibition of CSF1R kinase by pexidartinib. There was no additional off-target activity in a screening assay

Page 35 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

for inhibitory activity by pexidartinib against nine families including neurotransmitter related, immunologic factors, steroids, ion channels, second messengers, prostaglandins, growth factors/hormones, brain/gut peptides, and enzymes. In nonclinical pharmacokinetics (PK) and metabolism studies, pexidartinib was found to bind extensively to albumin in four species (human, dog, rat, and mouse) and to penetrate into the central nervous system in rats. After intravenous administration, terminal half-life (t1/2) values varied according to body surface area; t1/2 values of 1.9, 3.5, and 5.1 hours were observed in dogs, mice, and rats, respectively. Pexidartinib was found to be metabolically stable and not susceptible to rapid metabolism. The compound was primarily metabolized by cytochrome P450 (CYP)3A4 in liver tissue in vitro, with CYP1A2 and 2C9 also playing a minor role in the metabolism. Pexidartinib was not a CYP inhibitor to an important extent and was unlikely to be a P-glycoprotein (P-gp) substrate. In safety pharmacology studies, pexidartinib was found to inhibit the human ether-a-go-go channel (half-maximal inhibitory concentration = 0.7 μM in serum-free media). However, pexidartinib had no effect on repolarization, action potential amplitude, or speed of cardiac depolarization in an isolated rabbit Purkinje fiber study, no effect on QT interval in dogs, and no effect on the central nervous system and respiratory function in rats. Two 4-week general toxicology studies were conducted with oral administration of pexidartinib in rats (0, 20, 60, and 200 mg/kg/day) and dogs (0, 100, 300, and 1000 mg/kg/day), with 16-day (rat) or 14-day (dog) recoveries. Significant adverse pexidartinib-related observations appeared to be associated with pexidartinib-mediated inhibition of CSF1R and c-Kit. Pexidartinib-related histopathologic observations included testicular spermatogonia reduction, bone marrow hypocellularity, thymic lymphoid reduction, bone hyperostosis and hypertrophy, ovarian follicular degeneration, and liver hepatocellular hypertrophy. All findings were partially or fully reversible. In two additional 4-week toxicology studies in rats (0.5, 2, and 10 mg/kg/day) and dogs (0, 1, 6, and 30 mg/kg/day), the no-observed-adverse-effect levels (NOAELs) of pexidartinib were determined to be 10 mg/kg/day in rats and 6 mg/kg/day in dogs. Two 13-week toxicology studies involved oral administration of pexidartinib in rats (0, 0.5, 4, and 20 mg/kg/day) and dogs (0, 1, 6, and 30 mg/kg/day). The NOAELs were determined to be 4 mg/kg/day in rats and 6 mg/kg/day in dogs. No new target organ toxicities were seen in either study. In rats, anemia and bone marrow depletion, as well as hepatocellular vacuolation associated with increased liver enzymes, were seen. In dogs, findings of reversible spermatogonial reduction and increased incidence of emesis were seen at 30 mg/kg. Two chronic toxicology studies involved daily oral administration of pexidartinib for 6 months in rats (0.5, 4, 20, and 60 mg/kg/day) and 9 months in dogs (1, 6, 30, and 100 mg/kg/day), with 16-week recoveries in both studies. The NOAELs were determined to be 0.5 mg/kg/day in male rats, 6 mg/kg/day in male dogs, and 100 mg/kg/day in female dogs. A NOAEL could not be determined in female rats because necrosis of corpora lutea of the ovaries was observed at ≥0.5 mg/kg/day. In rats, in addition to the findings observed in the previous studies, necrotizing inflammation of hepatocytes and biliary cysts in liver and vascular inflammation were observed. No new target organ toxicities were defined in dogs. Pexidartinib was not genotoxic in the bacterial reverse mutation, chromosomal aberration, and micronucleus studies. The carcinogenic potential of pexidartinib was evaluated in a 2-year study in rats (1, 3, and 10 mg/kg/day) and a 6-month study in hemizygous Tg.rasH2 mice (10, 30, and

Page 36 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

100 mg/kg/day). In both studies, oral administration of pexidartinib resulted in no increase in the incidence of any type of tumors. Therefore, pexidartinib was considered noncarcinogenic. In the reproductive toxicity study for fertility and early embryonic development in rats, pexidartinib affected reproductive performance, pre- and postimplantation loss, and mean number and litter proportion of viable embryos at 40 mg/kg/day. Pexidartinib caused embryofetal defects in rats and rabbits. Fetal defects included external and visceral malformations, and skeletal developmental variations at 40 mg/kg/day in pregnant rats; and soft tissue, skeletal malformations and skeletal variations at 60 mg/kg/day in rabbits. Therefore, pexidartinib was judged to be teratogenic in rats and rabbits. Oral administration of pexidartinib at 10 mg/kg/day to bred female rats resulted in no effects on prenatal and postnatal development, including maternal function. Toxic potential of the N-glucuronide metabolite of pexidartinib was evaluated in monkeys, which were the only animal species showing high systemic exposure of the metabolite similar to that in humans. Oral administration of pexidartinib at up to 100 mg/kg/day to monkeys for 13 weeks resulted in no pexidartinib-related changes under the exposure condition, with much lower parent and 1.3 times higher N-glucuronide metabolite compared with the clinical dose (800 mg/day). Pexidartinib had no phototoxic potential in an in vitro 3T3 neutral red uptake phototoxicity study. Together, these toxicology studies provided an appropriate characterization of the toxicologic profile of pexidartinib, including identification of target organs and the characterization of reversibility and monitorability of the pexidartinib-related effects.

4.3 Clinical Development Overview The pexidartinib clinical development program, as of the 31 Jan 2018 NDA data cutoff, includes 27 completed or ongoing studies sponsored by Daiichi Sankyo or its subsidiary Plexxikon Inc (Table 4.1). Across these studies, 630 patients with cancer or TGCT received pexidartinib for assessment of safety and efficacy in 13 sponsored clinical studies; two of these studies were focused on TGCT. A total of 338 patients received pexidartinib in 14 sponsored clinical pharmacology studies. Two of these studies were conducted in patients with renal (Study PL3397-A-U124) or hepatic impairment (Study PL3397-A-U123); all other clinical pharmacology studies were conducted in healthy volunteers with single or a small number of doses of pexidartinib. In addition, 138 patients have received pexidartinib in eight investigator- initiated studies. The most relevant clinical safety and efficacy results for TGCT are provided by the Phase 3 ENLIVEN study in TGCT patients and the TGCT extension cohort in the Phase 1 study (PLX108-01).

Page 37 of 108

Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

commitment as agreed to with the FDA. The perpetrator DDI risk of pexidartinib for CYP2B6, CPY2C8, CYP2C19, CYP3A4, P-gp, OATP1B1, OATP1B3, MATE1, and MATE2-K was also evaluated using a physiologically based PK model. Overall, pexidartinib does not have any clinically meaningful DDI risk as a DDI perpetrator.

5.3 Effect of Intrinsic and Extrinsic Factors on the PK of Pexidartinib

5.3.1 Effect of Intrinsic Factors

5.3.1.1 Demographic Characteristics (Age, Race/Ethnicity, Weight, Sex) The effect of age, race/ethnicity, weight, and sex on pexidartinib PK was evaluated through a PopPK analysis. None of these demographic characteristics had any clinically meaningful effect on pexidartinib exposure. The maximum effect was observed with body weight, for which, at a body weight of 53 kg, pexidartinib area under the plasma concentration-time curve from time 0 to 24 hours, steady state (AUC0-24ss) was 36% higher (95% CI: 27%, 46%) compared with the reference patient with a body weight of 80 kg. Based on the PopPK analysis, no dose adjustment has been recommended in adult patients with TGCT based on age, weight, and sex.

5.3.1.2 Effect of Hepatic Impairment Pexidartinib PK was not affected by mild and moderate hepatic impairment. However, there were increases in ZAAD-1006a AUCs of up to 50% and metabolite/parent (M/P) molar ratios of up to 40%. These effects are not considered clinically meaningful because of the minimal pharmacological activity of the metabolite. Therefore, no dose adjustment is recommended for pexidartinib in patients with hepatic impairment from a PK perspective. However, because of the risk of mixed or cholestatic hepatotoxicity, it is recommended that pexidartinib is contraindicated in TGCT patients with persistent elevations (> upper limit of normal [ULN]) of serum transaminases or bilirubin, or active liver or biliary tract disease.

5.3.1.3 Effect of Renal Impairment The effect of renal impairment on the PK of pexidartinib was assessed in a dedicated study in patients with varying degrees of renal impairment (ranging from normal to patients with end- stage renal disease [ESRD] on and off dialysis), and in the PopPK assessment that included patients with creatinine clearance down to 15 mL/min. An analysis of these data using the previously developed PopPK model showed, at most, a 38% increase in exposure at the lower limit of severe renal impairment (15 mL/min) compared with patients with normal renal function. ZAAD-1006a exposure (ie, AUC up to the last measurable concentration [AUClast]) in patients with renal impairment increased with worsening of renal impairment (up to 300% increase from AUClast of normal patients). Since ZAAD-1006a has minimal pharmacologic activity and no toxicologic effects, the observed increase in ZAAD-1006a exposure is not expected to be clinically meaningful. Based on these analyses, no dose adjustment is recommended in patients with any degree of renal impairment (including ESRD patients on routine hemodialysis).

5.4 Effect of UGT1A4 Polymorphism In an exploratory pooled analysis, the ratio of geometric means showed that there was only a small (up to 20%) difference in the exposures between UGT1A4 genotypes [wild-type versus

Page 41 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

UGT1A4*2 (poor metabolizer) and UGT1A4*3 (high metabolizer)] with wide 90% CIs (possibly because of high variability associated with data pooling). Overall, no intrinsic factors were found to have a clinically meaningful effect on pexidartinib exposure, and no dose modifications are being recommended for any of the intrinsic factors that were assessed.

5.4.1 Effect of Extrinsic Factors

5.4.1.1 Effect of Food, Gastric pH Modification, and Drug-Drug Interaction Pexidartinib exposure was doubled when administered with a high-fat meal in healthy subjects. Due to the relatively large food effect, pexidartinib is recommended to be taken on an empty stomach at least 1 hour before or 2 hours after a meal. This recommendation was also specified in the conduct of the Phase 3 study. In addition, due to the impact of systemic pH modifiers on pexidartinib exposure, resulting in ~50% decrease in exposure, coadministration of these agents (eg, esomeprazole) should be avoided while on pexidartinib treatment. Gastric pH modifiers such as antacids can be administered approximately 2 hours after pexidartinib administration (Figure 5.1). The effects of various metabolic inhibitors and inducers on pexidartinib PK were evaluated (Figure 5.1). Based on the results, a reduced dose of 400 mg/day (200 mg BID) is recommended when coadministration of pexidartinib with strong CYP3A inhibitors cannot be avoided. The CYP3A inducers are recommended to be avoided when the patient is on pexidartinib treatment. After discontinuation of the strong CYP3A inhibitor or CYP3A inducer, pexidartinib can be resumed at the previous dose after 14 days. A reduced dose of 400 mg/day (200 mg BID) is also recommended when pexidartinib is coadministered with UGT inhibitor. After discontinuation of the UGT inhibitor, pexidartinib can be resumed at the previous dose after 14 days. Based on the available data on the effect of pexidartinib on CYP and transporter substrates (Figure 5.2), it is concluded that, in general, pexidartinib has a low potential for a clinically meaningful effect on the exposure of concomitant drugs that are metabolized or transported by these processes, and no dose adjustment is recommended when pexidartinib is coadministered with substrates of these enzymes and transporter systems.

Page 42 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

Figure 5.1: Forest Plot of the Effect of Concomitant Medication on the Exposure of Pexidartinib

Abbreviations: AUCinf = area under the plasma concentration-time curve from time of dosing extrapolated to infinity; CI = confidence interval; Cmax = maximum observed plasma concentration; PK = pharmacokinetics. Note: Solid black dots represent the geometric least-squares mean ratio of the PK parameter when pexidartinib was administered with the concomitant medication to when pexidartinib was alone; the whiskers represent the 90% CI. Source: 2.5 Clinical Overview, Figure 3.2.

Page 43 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

Figure 5.2: Forest Plot of the Effect of Pexidartinib on the Exposure of Various CYP and Transporter Substrates

Abbreviations: AUC0-12 = area under the plasma concentration-time curve from time 0 to 12 hours postdose; AUC0-24 = area under the plasma concentration-time curve from time 0 to 24 hours postdose; AUC0-48 = area under the plasma concentration-time curve from time 0 to 48 hours postdose; AUC0-96 = area under the plasma concentration-time curve from time 0 to 96 hours postdose; AUCinf = area under the plasma concentration-time curve from time of dosing extrapolated to infinity; CI = confidence interval; Cmax = maximum observed plasma concentration; CYP = cytochrome P450; MATE = multidrug and toxic compound extrusion; OATP = organic anion transporting polypeptide; obs = observed; P-gp = P-glycoprotein; PK = pharmacokinetic; pred = predicted. Note: Solid black dots represent the geometric least-squares mean ratio of the PK parameter when pexidartinib was administered with the concomitant medication to when pexidartinib was alone; the whiskers represent the 90% CI (95% CI marked with *). Source: 2.5 Clinical Overview, Figure 3.3.

5.5 Effect of Pexidartinib on QTc Interval An effect of pexidartinib on ΔQTcF exceeding 10 ms was excluded at an exposure 2.5 times the predicted steady-state exposure in TGCT patients. Therefore, it was concluded that the Thorough QT study was negative as defined in the International Council for Harmonisation E14 guidance.12

Page 44 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

5.6 Clinical Pharmacology Conclusions Pexidartinib is an orally bioavailable drug with a t1/2 of 27 hours. Pexidartinib is metabolized mainly by UGT1A4 and CYP3A and no parent drug was detected in the urine. Strong inhibitors of UGT1A4 and CYP3A increase pexidartinib exposures. Therefore, the pexidartinib dose should be reduced in patients taking strong CYP3A and UGT1A4 inhibitors, if their concurrent use cannot be avoided. Cytochrome P450 3A inducers should be avoided when on pexidartinib therapy. Concurrent administration of systemic pH modifiers (eg, esomeprazole) should also be avoided, and nonsystemic pH modifiers (antacids) should be given >2 hours after pexidartinib dosing. No dose adjustment is needed for patients with renal impairment including patients on routine hemodialysis. Administration of pexidartinib with food increased exposure approximately two-fold. Therefore, it is recommended to dose pexidartinib BID at least 1 hour before or 2 hours after a meal. Pexidartinib does not prolong the QTc interval.

Page 45 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

6 CLINICAL EFFICACY

Evidence for the efficacy of pexidartinib in the treatment of TGCT is derived primarily from the pivotal Phase 3 ENLIVEN study and the supportive Phase 1 extension TGCT cohort. Efficacy of pexidartinib was observed consistently across the studied TGCT population.

6.1 Phase 3 Study PLX108-10 (ENLIVEN)

6.1.1 Study Design and Methods ENLIVEN is a Phase 3, randomized, placebo-controlled, two-part, multicenter study conducted in patients with symptomatic TGCT for whom surgical resection would be associated with potentially worsening functional limitation or severe morbidity (locally advanced disease) (Figure 6.1). In Part 1, the double-blind phase, eligible patients were centrally randomized in a 1:1 ratio to receive either pexidartinib or placebo (1000-mg/day split dose × 2 weeks, then 400 mg BID) for 24 weeks. Randomization was stratified by geographic region (US vs non-US study sites) and disease location (upper- vs lower-extremity involvement). Patients who completed Part 1 could enter Part 2, a long-term treatment phase wherein all patients were to be transitioned to open-label pexidartinib with regular efficacy and safety assessments to evaluate long-term pexidartinib treatment. Figure 6.1: ENLIVEN Study Design

Abbreviations: bid = twice daily; MRI = magnetic resonance imaging; PRO = patient-reported outcome; ROM = range of motion. Source: 2.7.3 Summary of Clinical Efficacy, Figure 2.1.

Page 46 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

For the first 2 weeks in Part 1, patients took 400 mg of pexidartinib in the morning and 600 mg in the evening (total of 1000 mg/day pexidartinib) or matching placebo. Thereafter, dosing was reduced to 400 mg BID (800 mg/day) or matching placebo. Dose reductions and interruptions were implemented according to prespecified guidelines. The pexidartinib dose for Part 2 was the same as the pexidartinib dose or pexidartinib-equivalent dose of placebo at the end of Part 1. Because patients on the placebo arm were not expected to have dose reductions due to toxicity beyond the protocol-defined reduction at 2 weeks, the study design provided efficacy and safety data for an alternate pexidartinib starting dose of 800 mg/day (proposed dose). After database lock and unblinding, it was revealed that all 30 patients who crossed over from placebo in Part 1 to open-label pexidartinib in Part 2 started pexidartinib at a dose of 800 mg/day (400 mg BID). Pexidartinib treatment continued until unacceptable toxicity or disease progression. Supportive medications, including analgesics, were permitted. Patients were allowed to permanently discontinue pexidartinib and undergo surgical resection of their TGCT after Week 25, in which case an MRI was to be performed 4 months after surgery. The primary and secondary endpoints of this study are described in Table 6.1. The primary endpoint was blinded, centrally reviewed ORR (Week 25) by RECIST v1.1. In Part 1, an MRI was performed at screening, Cycle 4, Day 1 (Week 13), and end of Part 1 (Week 25). If disease progression was indicated clinically or by local radiologic assessment according to RECIST v1.1 at or after Week 13 but before Week 25, the investigator may have requested a central review for evaluation of disease progression. Any disease progression before Week 25 had to be verified by a central MRI reading. If a central reading confirmed RECIST-defined disease progression, treatment assignment was unblinded, and patients receiving placebo were eligible for early entry into Part 2 of the study. Secondary endpoints included ORR by TVS according to blinded, central MRI review; ROM of the affected joint assessed at screening, Cycle 4, Day 1 (Week 13), end of Part 1 (Week 25), and 12-week intervals in Part 2; and PROs of Patient-Reported Outcomes Measurement Information System (PROMIS)-Physical Function (PF), Worst Stiffness, and BPI Worst Pain assessed at screening, Cycle 3, Day 1 (Week 9), Cycle 5, Day 1 (Week 17), end of Part 1 (Week 25), and at 12 intervals in Part 2 (PROMIS-PF assessments were completed by the patient during site visits, and Worst Stiffness and BPI Worst Pain assessments were completed by the patient during the 7 days prior to study site visits). Tumor volume score, an assessment of tumor volume as a percentage of the normal volume of the synovial cavity, was included as an alternate measure of tumor response, because of the complex tumor shape of TGCT.

Page 47 of 108

Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

concentrations at this dose. This dose was evaluated in the extension phase of Study PLX108- 01, which enrolled 39 patients with TGCT. The dose chosen for the Phase 3 ENLIVEN study was 1000 mg/day (administered as a split dose of 400 mg in the morning and 600 mg in the evening) for 14 days followed by 800 mg/day (400 mg BID). This dosing regimen was selected mainly based on the observed robust tumor response in the Phase 1 extension TGCT cohort and the high rate of dose modifications after the first 2 weeks of treatment. Specific dose reduction guidelines were defined based on adverse events (AEs) and abnormal clinical laboratory findings.

6.1.1.2 Key Eligibility Criteria The ENLIVEN study enrolled patients ≥18 years of age with a diagnosis of TGCT that (1) was histologically confirmed either by a pathologist at the treating institution or a central pathologist, and (2) for which surgical resection would have been associated with potentially worsening functional limitation or severe morbidity (locally advanced disease), with morbidity having been determined consensually by qualified personnel. Other key inclusion criteria were measurable disease of ≥2 cm as defined by RECIST v1.1; symptomatic disease because of active TGCT; at least 4 of 7 consecutive days of BPI Worst Pain numerical rating scale (NRS) items and Worst Stiffness NRS items completed correctly during 2 weeks prior to randomization; negative serum pregnancy test for women of childbearing potential; use of highly effective contraception during study and for up to 90 days after completion (for males and females of childbearing potential); and adequate hematologic, hepatic, and renal function. Patients were excluded if they met any of the following key exclusion criteria: use of investigational drug within 28 days of randomization; prior use of pexidartinib or any biologic targeting CSF-1 or CSF1R; active cancer requiring therapy (with exceptions); known metastatic TGCT; active hepatitis C or B virus or known active or chronic infection with human immunodeficiency virus; known active tuberculosis; significant concomitant arthropathy in affected joint, serious illness, uncontrolled infection, or medical or psychiatric history that, in the investigator’s opinion, would have likely interfered with study participation or the interpretation of study results; women who were breastfeeding; screening Fridericia’s corrected QT interval ≥450 ms (men) or ≥470 ms (women); and MRI contraindications.

6.1.1.3 Statistical Analysis Methods

6.1.1.3.1 Sample Size Determination Assumed rates of responders (patients achieving complete response [CR] or partial response [PR]) for the primary endpoint (blinded, centrally reviewed ORR [Week 25] by RECIST v1.1) were 35% for pexidartinib and 10% for placebo. Based on a 2-sided, 2-sample comparison of proportions at the alpha=0.05 level of significance by Fisher’s exact test, a sample size of 126 ITT randomized patients (63 patients per group) would provide 90% power to detect this magnitude of difference.

6.1.1.3.2 Primary and Secondary Efficacy Analyses The primary endpoint and prespecified secondary endpoints were analyzed using a hierarchical “gatekeeping” testing procedure. Thus, if the primary endpoint analysis was statistically significant (P<0.025, 1-sided), then secondary endpoint #1 was analyzed. If key secondary

Page 49 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

endpoint #1 was statistically significant, then the testing procedure proceeded to key secondary endpoint #2, etc. If the test for a particular endpoint failed to reach statistical significance (P<0.05, 2-sided or P<0.025, 1-sided for binary endpoints), the inference for all subsequent endpoints in the hierarchy was not performed. The order of testing was as follows: Treatment comparison of primary endpoint: • The proportion of responders based on MRI (centrally read) responder criteria as defined by RECIST v1.1 at the Week 25 visit Next, testing of key secondary efficacy endpoints proceeded sequentially in the following order with treatment comparison at the Week 25 visit in the ITT analysis set: • Mean change from baseline in ROM of the affected joint, relative to a reference standard for the same joint • The proportion of responders based on centrally evaluated MRI scans and TVS • Mean change from baseline score in the PROMIS-PF scale • Mean change from baseline score in the Worst Stiffness NRS item • Proportion of responders based on BPI Worst Pain NRS item and narcotic analgesic use (BPI-30) The hierarchical gatekeeping testing procedure preserves the study-wide error rate at the 2-sided significance level of 0.05. Based on strictly blinded assessments of the aggregated whole database in advance of database lock and unblinding, it became apparent that a number of patients were missing valid end of Part 1 Week 25 PRO assessments (ie, PROMIS-PF, Worst Stiffness, and BPI Worst Pain). This missingness resulted mainly from two unexpected and important study conduct issues that occurred during execution of this study. One was the emergence of cholestatic hepatotoxicity, and the DMC recommended changes to stop enrollment and discontinue crossover from placebo to pexidartinib at the end of Part 1. The other was missing valid PRO assessment data due to patient noncompliance and technical problems with the electronic diary (LogPad) such as incorrect programming of the reporting period, device malfunction, and data transmission failures. To partially mitigate the statistical impact of these issues on the secondary efficacy endpoint hierarchy, the BPI-30 pain responder analysis, which was most impacted, was moved to the bottom of the comparative secondary endpoints and the ROM endpoint was moved to be analyzed first. The change to the secondary endpoint hierarchy was made in consultation with the FDA and by protocol amendment, prior to database lock and unblinding of the study. The planned statistical methods for analyses of the secondary efficacy endpoints were not changed, but additional exploratory and sensitivity analyses of these endpoints were specified before unblinding and added into the Statistical Analysis Plan to assess the impact of data missingness.

6.1.2 Patient Disposition and Analysis Sets The database cutoff for primary efficacy and safety analyses was 27 Mar 2017. Overall, 120 patients with TGCT in Part 1 were randomly assigned to two treatment groups and treated, with 61 patients assigned to pexidartinib and 59 patients to the placebo control. At the time of the cutoff, 65 patients remained on open-label pexidartinib treatment with continuing collection

Page 50 of 108

Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

Figure 6.2: Waterfall Plot of Sum of the Longest Diameter for Part 1 (Randomized) of ENLIVEN (ITT Analysis Set)

Abbreviations: ITT = intent-to-treat; ORR = overall response rate. Source: 2.5 Clinical Overview, Figure 4.1.

6.1.4.2 Secondary Efficacy Endpoints As described in Section 6.1.1.3, the secondary endpoints were analyzed using a hierarchical (“gatekeeping”) testing procedure. Overall, the first four of the five secondary endpoints were statistically significant (P<0.05 by 2-sided test or P<0.025 by 1-sided test for binary responder endpoints) for pexidartinib versus placebo (Table 6.6). These endpoints included the objective measures of ROM and ORR by TVS, and PROs of PROMIS-PF and Worst Stiffness. The BPI-30 Pain response was not statistically significant; this endpoint was particularly affected by missing data at Week 25 (see Section 6.1.4.3 for a summary of missing COA data and sensitivity analyses).

Page 56 of 108

Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

(95% CI: 40%, 64%) in the 61 patients randomized to pexidartinib and 53% (95% CI: 36%, 70%) in the 30 patients who crossed over to pexidartinib. This result shows consistent response rates between pexidartinib randomized (1000 mg/day for 2 weeks, then 800 mg/day) and crossover (800 mg/day) cohorts (Figure 6.4). Best overall response (95% CI) by TVS was 64% (95% CI: 51%, 75%) and 67% (95% CI: 49%, 81%), respectively. Median duration of response was still not reached for RECIST v1.1 or TVS in Part 1 and crossover patients (range, [2.8+, 24.9+] and [0+ and 27.6+] months, respectively). Figure 6.4: Waterfall Plot Based on RECIST for Randomized Pexidartinib and Crossover Cohorts in ENLIVEN (ITT Analysis Set)

Abbreviations: ITT = intent-to-treat; ORR = overall response rate; RECIST = Response Evaluation Criteria in Solid Tumors; SLD = sum of longest diameter. Source: 2.7.3 Summary of Clinical Efficacy, Figure 5.11.

Figure 6.5 illustrates that continued pexidartinib treatment leads to additional tumor responses over time. Figure 6.6 shows the duration of tumor response is prolonged; only one patient had tumor progression. Tumor size changes over time in individual patients are displayed by the spider plot (Figure 6.7).

Page 61 of 108

Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

Figure 6.7: Percentage Change in Baseline of Sum of Longest Diameters According to RECIST v1.1 (ITT Analysis Set)

Note: Dotted reference lines at –30% and 20% indicate thresholds for PR and progressive disease, respectively. Red line indicates patient with a BOR of CR, blue line indicates a patient with a BOR of PR, and a black line indicates a patient with any other BOR. Only patients with an on-treatment tumor assessment are included in the plot. Abbreviations: BOR =, best overall response; CR = complete response; ITT = intent-to-treat; N = number of patients in the ITT analysis set; n = number of patients with an on-treatment tumor assessment; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors; SLD = sum of longest diameter. Source: 2.5 Clinical Overview, Figure 4.2.

6.1.4.5 Efficacy Subgroup Analyses Prespecified subgroup analyses were performed to assess response rates by disease location (large joint vs small joint vs knee), type of disease (GCT-TS vs PVNS), extremity location (lower vs upper extremity), and geographic location (US vs non-US vs European Union [EU] only). Overall response rate (RECIST v1.1) at Week 25 was similar across these subgroups (Figure 6.8).

Page 63 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

Figure 6.8: Prespecified Subgroup Analysis of Response Rate (RECIST v1.1) in Part 1 (Randomized) of ENLIVEN

Abbreviations: CI = confidence interval; EU = European Union; GCT-TS = giant cell tumor of tendon sheath; ORR = overall response rate; PVNS = pigmented villonodular synovitis; RECIST = Response Evaluation Criteria in Solid Tumors; US = United States. Source: PLX108-10-study-rpt-body.pdf, Table 8-1, Table 14.2.1.3.

Exploratory analyses were performed to assess response rates across demographic subgroups (age [<50 vs 50-65 years], sex [male vs female], and race [white]). Overall response rate (based on RECIST v1.1) at Week 25 was similar across the various subgroups (Figure 6.9).

Page 64 of 108

Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

Efficacy was assessed locally by radiologic scans at study sites according to RECIST v1.1. Radiographic scans were also reviewed post hoc centrally by RECIST v1.1 and TVS. Safety, PK, and PD parameters were also studied. This study was amended to collect PRO data for BPI Worst Pain and Worst Stiffness, which are two of the most reported symptoms for TGCT patients.

6.2.2 Patient Disposition The database for the extension phase of the study was locked using a data cutoff of 03 Mar 2017. At the time of the data cutoff, 17 of the 39 TGCT patients initially enrolled with TGCT had been on pexidartinib treatment for approximately 2 to 4 years and 15 patients were still receiving pexidartinib treatment with continuing collection of safety and efficacy data. An updated analysis of the TGCT cohort was performed with a data cutoff of 31 January 2018.

6.2.3 Demographic and Other Baseline Characteristics In the TGCT cohort, patients were 43.6% male, 84.6% white, and 89.7% not Hispanic or Latino, with a mean age of 45.1 years.

6.2.4 Efficacy Results

6.2.4.1 Tumor Response In the TGCT cohort, 37 of 39 patients (94.4%) were included in the Efficacy Evaluable population. Two patients were non-evaluable (1 due to an AE and 1 due to noncompliance) because they discontinued study treatment during the first cycle and did not have postbaseline assessments. Based upon investigator assessment, a PR or CR as best response was reported in 23 (62.2%) patients (PR in 21 patients [56.8%] and CR in 2 patients [5.4%]), for an ORR of 62.2% (95% CI: 42.1%, 75.2%). In the TGCT cohort, 17 patients (46%) experienced at least a 50% reduction in longest tumor diameter (Figure 6.10). The median progression-free survival for the TGCT patients was not reached at the time of the data cutoff. Fifteen patients remain on treatment, all of whom had been receiving treatment for more than 2 years.

Page 66 of 108

Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

Figure 6.11: Proportion of Patients Experiencing Benefit via TVS in ENLIVEN and Phase 1 Extension TGCT Cohort

Abbreviations: TGCT = tenosynovial giant cell tumor; TVS = tumor volume score. a 110 patients evaluable; 5 patients showed no change and 20 patients did not have either baseline or any post-baseline value.

The meaningful decrease in tumor size across the vast majority of the TGCT population is consistent with biomarker studies of TGCT, which show that nearly all TGCT tumors express CSF-1, and most have a CSF-1 genetic alteration. Many patients remained on treatment with ongoing tumor response. Hence, duration of response remains heavily censored, and it is clear that the duration of response to pexidartinib treatment is prolonged, demonstrating durable efficacy (Figure 6.12). Only 5 of the 130 patients (3.8%) discontinued pexidartinib treatment due to progressive disease, demonstrating that the nonmalignant TGCT does not readily develop resistance to pexidartinib even after prolonged pexidartinib treatment. Median duration of RECIST-SLD or TVS response was only reached in the Phase 1 extension TGCT cohort, which had a longer median duration of follow-up of 49.0 months.

Page 70 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

Figure 6.12: Kaplan-Meier Estimates of Time to Response and Duration of Response According to RECIST v1.1 in ENLIVEN and Phase 1 Extension TGCT Cohort

Abbreviations: RECIST = Response Evaluation Criteria in Solid Tumors; TGCT = tenosynovial giant cell tumor.

For patients who discontinued pexidartinib treatment without disease progression, control of their TGCT appears to persist for a least a few months after the last dose. Thirty patients had a tumor assessment after discontinuation of pexidartinib treatment. These scans were performed to assess the potential for rapid tumor relapse after treatment discontinuation. Of the 30 patients who discontinued pexidartinib treatment and were evaluated by RECIST v1.1 after treatment discontinuation, 1 (3.3%) patient was assessed to have had disease progression at 10 weeks after the last pexidartinib dose. Of the 28 patients who discontinued pexidartinib treatment and were evaluated by TVS after treatment discontinuation, 2 (7.1%) were assessed to have had disease progression at 5 and 10 weeks after the last pexidartinib dose. Two examples of ENLIVEN patients with debilitating disease and benefiting from pexidartinib treatment are provided in Section 12.1. An example from the Phase 1 extension TGCT cohort has been published.13,18 These examples include photographs of the tumor before and during treatment and describe the clinical impact of the disease and its treatment with pexidartinib on the patients. These examples highlight the unmet medical need of TGCT patients in extreme cases.

6.4 Overall Efficacy Conclusions Results from ENLIVEN showed that pexidartinib imparts a meaningful clinical benefit compared with placebo in advanced, symptomatic TGCT patients. This is based on meeting the primary endpoint of ORR by RECIST v1.1 for pexidartinib at 39% versus 0% for placebo at Week 25. The efficacy was confirmed by the secondary endpoint of response via TVS, where 56% of pexidartinib patients achieved response compared with 0 for placebo at Week 25. Both results were highly statistically significant. The benefits observed with pexidartinib were not only durable, but the objective response observed in these patients correlated well with improvements in disease symptoms and joint function. Tenosynovial giant cell tumor rarely progressed or became refractory to pexidartinib. Moreover, tumor response and clinical improvement observed in the Phase 1 extension TGCT cohort were consistent with the Phase 3 ENLIVEN study results.

Page 71 of 108

Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

Based upon review of individual cases, it is concluded that pexidartinib treatment is associated with hepatotoxicity that manifests typically as mild to moderate mixed or cholestatic hepatotoxicity but can be prolonged, and rarely severe. No risk factors or mechanism for the toxicity could be identified. In most patients, serum transaminases normalized rapidly when the drug was held. Alkaline phosphatase declined once the drug was held, but the time to normalization was prolonged over weeks to months. In patients with serum transaminase elevations, restarting pexidartinib at a lower dose was accompanied by either trivial to mild elevations or no elevations of liver tests. An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot analysis was performed to show the distribution of patients by liver test abnormality in ENLIVEN (Figure 7.1). Three patients had ALT >3 × ULN with bilirubin >2 × ULN, and all three patients had ALP >2 × ULN, reflective of mixed or cholestatic hepatotoxicity. Each of these patients had a clinically significant hepatic event and discontinued pexidartinib treatment. No patient met the criteria for Hy’s Law. Figure 7.1: eDISH Plot of Maximum Postbaseline Total Bilirubin versus Maximum Postbaseline Alanine Aminotransferase in Part 1 (Randomized) of ENLIVEN

Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; eDISH, evaluation of Drug-Induced Serious Hepatotoxicity; TBL = total bilirubin; ULN = upper limit of normal. *Indicates ALP ≥2× ULN. Source: 2.5 Clinical Overview, Figure 5.1.

7.2.1.5.2 Cognitive Disorder Adverse Events In Part 1 of ENLIVEN, there were 3 (4.9%) patients in the pexidartinib group who experienced a cognitive disorder TEAE. Similarly, there were 3 (5.1%) patients in the Part 1 placebo group who experienced a cognitive disorder TEAE. No patients from either group experienced a TEAE of Grade ≥3. Over Part 1 and Part 2, there were 6 (6.6%) patients in the all pexidartinib group (n=91) who experienced any cognitive disorder TEAE, none of which were Grade ≥3.

Page 81 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

7.2.1.5.3 Cardiac Adverse Events In Part 1 of ENLIVEN, there were 12 (19.7%) patients in the pexidartinib group who experienced any cardiac TEAE compared with 7 (11.9%) patients in the placebo group. No patients in the pexidartinib group compared with 1 (1.7%) patient in the placebo group experienced a Grade ≥3 cardiac TEAE. Overall, with the exception of edema peripheral (8 [13.1%] patients with Grade 1 edema peripheral in the pexidartinib treatment group compared with 2 [3.4%] patients with a Grade 1 and a Grade 2 event in the placebo treatment group), the nature and severity were similar between both treatment groups. Over Part 1 and Part 2, there were 24 (26.4%) patients in the all-pexidartinib group who experienced any cardiac evaluation TEAE. Two (2.2%) patients experienced TEAEs of Grade ≥3 (cardiac arrest and syncope). The cardiac arrest was fatal (see Section 7.2.1.3.1).

7.2.1.5.4 Bone Marrow Suppression Adverse Events In Part 1 of ENLIVEN, there were 13 (21.3%) patients in the pexidartinib group who had any bone marrow suppression TEAEs compared with 2 (3.4%) patients in the placebo group who experienced a bone marrow suppression TEAE. Four (6.6%) patients in the pexidartinib group compared with 1 (1.7%) patient in the placebo group experienced a Grade ≥3 bone marrow suppression TEAE. Of the patients who experienced Grade ≥3 bone marrow suppression TEAEs in the pexidartinib group in Part 1, 1 (1.6%) patient each experienced anemia, neutropenia, neutrophil count decreased, and lymphocyte count decreased. Over Part 1 and Part 2, there were 25 (27.5%) patients in the all-pexidartinib group who experienced any bone marrow suppression TEAE. Four (4.4%) patients in the all-pexidartinib group experienced a Grade ≥3 bone marrow suppression TEAE. During Part 2, no additional patients had a Grade ≥3 bone marrow suppression TEAE.

7.2.2 Phase 1 Study PLX108-01 (TGCT Extension Cohort) In the Phase 1 extension TGCT cohort, 39 subjects were exposed to pexidartinib. At the time of the 03 Mar 2017 database cutoff, 15 TGCT patients were still receiving pexidartinib. The median duration of treatment for all patients was 111.0 days, range (1–1480 days). In the TGCT cohort, the median duration of treatment was 511.0 days (range 15–1480 days). All 39 (100%) patients experienced at least 1 TEAE and at least 1 TEAE assessed by the investigator as treatment related. The most frequently reported AEs were fatigue (89.7%), hair color changes (71.8%), nausea (64.1%), and arthralgia (53.8%), and the most frequently occurring treatment-related TEAEs were fatigue (74.4%), hair color changes (71.8%), and nausea (53.8%). Most patients experienced at least 1 TEAE of Grade 2 or Grade 3 severity (Grade 2: 48.7%; Grade 3: 38.5%). The most frequently occurring Grade 3 TEAEs were hypophosphatemia (n=4; 10.3 %), ALT increased (n=4; 10.3%), AST increased (n=3; 7.7%), and diarrhea (n=3; 7.7%). Two (5.1%) patients had Grade 4 TEAEs (hyponatremia [n=1] and blood creatinine increased [n=1]). The most common Grade ≥3 treatment-related AEs were hypophosphatemia (10.3%), ALT increased (10.3%), AST increased (7.7%), and fatigue and diarrhea (2.6% each). No deaths were reported in the Phase 1 extension TGCT cohort. Four (10.3%) patients treated with pexidartinib experienced treatment-emergent SAEs. These events were cholecystitis, renal cell carcinoma, hyponatremia, neck pain, and renal failure acute.

Page 82 of 108

Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

800 mg/day after the NDA data cutoff. Safety data were included in the 90-day safety update. Results included one case of mixed hepatotoxicity in a patient with TGCT (Section 7.2.1.5.1.2). Overall, the updated and new safety information presented in the 90-safety update is consistent with the safety profile of pexidartinib presented in the NDA. No cases of mixed or cholestatic hepatotoxicity have occurred among patients continuing on long-term pexidartinib treatment.

7.2.4 Safety Subgroup Analyses in the TGCT Population

7.2.4.1 Intrinsic Factors Subgroup analyses were performed by age, race, and sex for the following categories: patient disposition and reasons for discontinuation from treatment; demographics and baseline characteristics; study drug exposure and drug administration; overall summary of TEAEs; TEAEs by system organ class (SOC), preferred term (PT), and worst grade; treatment-related AEs by SOC and PT; SAEs by SOC and PT; TEAEs leading to discontinuation by SOC and PT; and TEAEs leading to dose reduction or interruption by SOC and PT. In the composite TGCT population treated with pexidartinib (N=130), the number of patients >65 years of age (n=8) was small and patients were predominantly white (n=115). Therefore, results are described for the <50-year age group (n=84), 50- to 65-year age group (n=38), females (n=73), and males (n=57).

7.2.4.1.1 Patient Disposition and Reasons for Discontinuation From Treatment In the pooled analyses of all pexidartinib-treated patients, the proportion of patients discontinuing study treatment was not substantively different in the <50-year age group (28.6%, 24 patients) and the 50- to 65-year age group (44.7%, 17 patients). The proportion of females and males who discontinued study treatment was 31.5% (23 patients) and 40.4% (23 patients).

7.2.4.1.2 Demographics and Baseline Characteristics In the pooled analyses of all pexidartinib-treated patients, the mean ages of males (44.6 years) and females (46.2 years) were not substantively different. There were 84 patients in the <50-year age group; 38 patients in the 50- to 65-year age group; and 8 patients in the >65-year age group.

7.2.4.1.3 Extent of Study Drug Exposure and Drug Administration In the pooled analyses of all pexidartinib-treated patients, median duration of exposure was similar between the <50-year age group (42.6 weeks) and the 50- to 65-year age group (46.4 weeks) but lower for the >65-year age group (33.3 weeks). The median duration of exposure was similar between males and females (40.3 and 45.9 weeks, respectively).

7.2.4.1.4 Treatment-Emergent AEs by SOC and PT In the pooled analyses of all pexidartinib-treated patients, the proportion of hair color changes was higher in males (77.2%; 44 patients) than in females (71.2%; 52 patients). The proportion of pruritus, rash, rash maculopapular, fatigue, face or peripheral edema, and liver function enzymes (ALT increase, AST increase, and ALP increase) was higher in females than in males.

Page 85 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

7.2.4.1.5 Treatment-Emergent AEs by SOC, PT, and Worst Grade In the pooled analyses of all pexidartinib-treated patients, no notable differences were observed by age or race in Grade ≥3 events. The proportion of patients with Grade ≥3 events was higher for females (57.5%; 42 patients) than for males (24.6%; 14 patients).

7.2.4.1.6 Serious Adverse Events by SOC and PT In the pooled analyses of all pexidartinib-treated patients, the proportion of treatment-emergent SAEs was 4.8% (4 patients) for the <50-year age group; 21.1% (8 patients) for the 50- to 65-year age group; and 50.0% (4 patients) for the >65-year age group. The proportion of treatment- emergent SAEs was higher for females (15.1%; 11 patients) than for males (8.8%; 5 patients). The reported treatment-emergent SAEs in females were cholecystitis, hepatotoxicity, liver disorder, hepatic enzyme abnormal, liver function test abnormal, transaminases increased, rash, rash papular, hepatitis A or E, hyponatremia, adenosquamous carcinoma of the cervix, endometrial cancer, migraine, and renal failure acute. The reported treatment-emergent SAEs in males were rectal adenocarcinoma, renal cell carcinoma, cardiac arrest, liver function test abnormal, and neck pain.

7.2.4.1.7 Treatment-Related AEs by SOC and PT No notable differences were observed by age, race, or sex for the TGCT population.

7.2.4.1.8 Treatment-Emergent AEs Leading to Discontinuation by SOC and PT In the pooled analyses of all pexidartinib-treated patients, the proportion of TEAEs that resulted in discontinuation was not substantively different in the <50-year age group (19.0%, 16 patients) and the 50- to 65-year age group (18.4%, 7 patients). The proportion of TEAEs that resulted in discontinuation was similar between males (17.5%, 10 patients) and females (21.9%, 16 patients).

7.2.4.1.9 Treatment-Emergent AEs Leading to Dose Reduction or Interruption by SOC and PT In the pooled analyses of all pexidartinib-treated patients, the proportion of TEAEs that resulted in dose reduction or interruption was higher for the 50- to 65-year age group (65.8%, 25 patients) than the <50-year age group (47.6%, 40 patients). The proportion of TEAEs that resulted in dose reduction or interruption was higher for females (61.6%, 45 patients) than males (43.9%, 25 patients). Overall, analysis of safety in the TGCT population revealed that females tended to have more severe and more serious AEs relative to males. There were no notable safety differences between patients age <50 years relative to patients age 50 to 65 years in the TGCT population; the number of patients >65 years of age was too few to provide meaningful assessment.

7.2.4.2 Extrinsic Factors No effect of prior therapy or medical history was identified as a risk factor for hepatotoxicity or other AEs. The adverse effect of pexidartinib on hepatic function can be severe and prolonged. Thus, careful assessment of baseline liver function, medical history, and concomitant

Page 86 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

medications is required to evaluate the potential clinical impact in an individual patient of liver function impairment by pexidartinib.

7.3 Safety of Pexidartinib in the Non-TGCT Population This section provides a high-level summary of AEs from the supportive pooled non-TGCT monotherapy population. Hepatic AEs from the non-TGCT monotherapy and combination therapy populations are presented.

7.3.1 Exposure In the non-TGCT monotherapy population, 258 patients received pexidartinib: 168 patients with solid tumors and 90 patients with AML. Median duration of exposure was 7.9 weeks (range, <1 to 82 weeks) for the pooled non-TGCT solid tumor patients who received pexidartinib doses that ranged from 200 to 1200 mg/day, and 6.3 weeks (range, 1 to 88 weeks) for the AML patients who received pexidartinib at doses ranging from 800 to 5000 mg/day.

7.3.2 Overview of Treatment-Emergent Adverse Events In the pooled analyses of total non-TGCT solid tumor patients treated at any dose of pexidartinib (200 to 600 mg/day or 900 to 1200 mg/day), 97.6% of patients experienced one or more TEAEs (Table 7.11); 83.3% of patients experienced treatment-related TEAEs. The frequency of Grade 3 or 4 TEAEs was 48.2%. There were 3 (1.8%) patients with Grade 5 TEAEs, of which 1 (0.6%) was treatment related. The frequency of TEAEs leading to discontinuation of pexidartinib was 14.3% and the incidence of pexidartinib-treated patients with TEAEs leading to dose reduction or interruption was 33.3%. Treatment-emergent SAEs were reported in 25.0% of patients; 7.7% had treatment-related events. Adverse events of special interest were myelosuppression (20.8%), hepatic disorders (19.0%), and cognitive disorders (11.3%). For the AML patients treated with pexidartinib, all 90 patients (100%) experienced TEAEs (Table 7.11); 84.4% of patients experienced treatment-related TEAEs. The incidence of Grade 3 or 4 TEAEs was 76.7%. There were 12 (13.3%) patients with Grade 5 TEAEs, of which 1 (1.1%) was treatment related. The frequency of TEAEs leading to discontinuation of pexidartinib was 20.0%, and the incidence of TEAEs leading to dose reduction or interruption in pexidartinib-treated patients was 45.6%. Treatment-emergent SAEs were reported in 70.0% of patients; 17.8% of patients had treatment-related events.

Page 87 of 108

Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

8 RATIONALE FOR PROPOSED DOSING REGIMEN

The proposed dose regimen of 800 mg/day (400 mg BID) is revised from the dose regimen of 1000 mg/day for 2 weeks followed by 800 mg/day (400 mg BID) used in Part 1 of ENLIVEN. A lower starting dose will reduce the dose-dependent aminotransferase elevations but will not alter the risk for idiosyncratic hepatotoxicity. However, it is unlikely that a starting dose of 800 mg/day versus 1000 mg/day for the first 2 weeks of treatment will substantively reduce the overall efficacy, given the long-term duration of therapy for most patients, the slow growth dynamics of TGCT, the time to maximum treatment effect that spans many months, and the clinical activity observed in the crossover cohort of 30 patients who began treatment with pexidartinib at 800 mg/day (Table 6.8). With this in mind, and the serious nature of the hepatotoxicity primarily observed in the first 8 weeks of therapy, the initial 2-week treatment with the higher (1000 mg/day) dose of pexidartinib is not justifiable. The proposed pexidartinib dose regimen of 400 mg (2 × 200-mg capsules) BID is also supported by exposure-response modeling of efficacy and safety.

Page 91 of 108

Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

completed and validated by the REMS administrator before the healthcare provider can prescribe pexidartinib. Prescribers are also responsible for using the patient guide to counsel patients on the risk of liver toxicity, the need for liver tests, and the importance of reporting any signs or symptoms of hepatotoxicity to their physician. During treatment, prescribers must assess patients’ liver tests and make dose modifications, in accordance with the prescribing information. No more than a 30-day supply of pexidartinib is permitted for the first 3 months of treatment. Together, these REMS requirements for prescribers support the appropriate use of pexidartinib in the intended patient population.

9.2.2 REMS Requirements for Patients Patients must review the patient guide. This guide will communicate the risk of hepatotoxicity, the requirements for frequent liver monitoring, and the need to stop treatment and immediately report to their physician if they experience jaundice or dark urine. It also includes a description of other signs and symptoms of hepatotoxicity, such as gastrointestinal symptoms or rash and itching, which must be reported immediately to their physician.

9.2.3 REMS Requirements for Wholesalers and Pharmacies Wholesalers are only permitted to distribute to certified pharmacies. Wholesalers are required to train their staff on the REMS requirements, to establish processes and procedures that ensure pexidartinib is only distributed to certified pharmacies, and to maintain proper distribution records. Wholesalers will be audited and are required to comply with these audits. Pexidartinib will not be available at all pharmacies. To dispense pexidartinib, the pharmacy must become certified. An authorized representative at the pharmacy must review the REMS overview and then complete and submit the pharmacy certification form to the REMS administrator. The pharmacy must obtain authorization to dispense each prescription by contacting the REMS administrator to verify that the prescriber of pexidartinib is certified. To maintain certification, pharmacies are only permitted to dispense a 30-day supply of pexidartinib.

9.2.4 Pexidartinib REMS and Benefit:Risk Ratio The Sponsor is proactively proposing a REMS to ensure that prescribers and patients have adequate information to make an informed decision concerning the use of pexidartinib. The REMS is designed to ensure that stakeholders understand the indicated population, risks associated with pexidartinib, and the required monitoring and dose modifications. It also aims to ensure that distribution is limited to those wholesalers and pharmacies that have been trained and certified to provide pexidartinib. The proposed REMS supports the important safety information communicated in the labeling, which includes a black-box warning and medication guide. These labeling and education materials support the positive benefit:risk ratio of pexidartinib in a select population of TGCT patients according to the proposed indication. The Sponsor is committed to working with the Agency to optimize the elements of the REMS, labeling, and medication guide, as appropriate.

Page 94 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

10 BENEFIT:RISK SUMMARY

The potential for meaningful clinical benefit of pexidartinib for patients with TGCT is well established and defined by the Phase 3 ENLIVEN study. The safety profile of pexidartinib is also well defined by this double-blind, randomized, placebo-controlled study with additional information on the risk of mixed or cholestatic hepatotoxicity coming from the rest of the clinical program. The most important risk for pexidartinib is the hepatotoxicity, which may be fatal. The target indication of TGCT is not a life-threatening disease, but it is debilitating in many patients. To maintain a favorable benefit:risk assessment, we are proposing an indication that is restricted to those patients for whom the potential for benefit is high relative to the risk, and a REMS program (as detailed in Section 9).

10.1 Benefits of Pexidartinib The efficacy of pexidartinib is clearly established in TGCT. ENLIVEN demonstrated that pexidartinib achieved a tumor response rate of 39% at Week 25 compared with 0 in placebo- treated patients. With continued pexidartinib treatment, the tumor response rate increased to 53% according to RECIST, and the tumor volume decreased by 50% or more in 64% of patients. Tumor reduction was associated with clinically meaningful improvement in function and disease symptoms, as assessed by a wide range of relevant quality-of-life endpoints. Pexidartinib’s duration of benefit is prolonged, with 61 (47%) of 130 TGCT patients treated with pexidartinib remaining on treatment as of the 31 Jan 2018 data cutoff, at which time the median follow-up from first dose was 23 months (range: 16 to 67 months). A median duration of response had still not been reached, demonstrating that responses are durable. Few of these patients discontinued due to progressive disease and 30 (23%) discontinued due to an AE. In ENLIVEN, the risk of postoperative morbidity was assessed as severe in 62 (54%) patients, 63 (53%) patients had prior surgery, median pain and stiffness scores were 5.8 and 6.0, respectively, and median ROM was 63% of normal, indicating that many patients had severe morbidity or functional limitations, and their disease was not amenable to improvement with surgery. Substantial efficacy (>30% response rate) was observed across disease subgroups including disease location, joint size, and type of TGCT (diffuse or localized). These data show that efficacy is observed across the studied TGCT population including those with disease consistent with the proposed restricted indication.

10.2 Risks of Pexidartinib The safety profile of pexidartinib is also clearly established. In the randomized Part 1 of ENLIVEN, the most common adverse reactions (>20%), including worsened laboratory abnormalities, were AST increased (87%), hair color changes (67%), fatigue (64%), ALT increased (64%), ALP increased (39%), nausea (38%), eye edema (30%), rash (28%), and dysgeusia (26%). The safety data reported from ENLIVEN were generally consistent with the results from the Phase 1 extension TGCT cohort. Long-term safety follow-up in the Phase 1 extension TGCT cohort and the updated safety from ENLIVEN did not reveal any new, concerning safety findings, and there were no new cases of mixed or cholestatic hepatotoxicity. Most adverse reactions were manageable with dose interruptions and reductions, but some resulted in discontinuation. The important exception is mixed or cholestatic hepatotoxicity.

Page 95 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

The dose regimens used in ENLIVEN (1000 mg/day decreasing to 800 mg/day after 14 days or starting at 800 mg/day) were tolerated better than the 1000-mg/day continuous dose used in Phase 1. In the Phase 1 extension TGCT cohort, 31 (80%) patients had a TEAE leading to dose reduction or interruption, and many of these occurred during the first few months of therapy. Accordingly, ENLIVEN was designed with a lower pexidartinib dose either after 14 days or from the start. The frequency of dose reduction or interruption was relatively lower for the pexidartinib cohort in ENLIVEN, with 23 (38%) patients experiencing a TEAE leading to a dose reduction or interruption in Part 1. Based on the exposure-response analysis, a dose lower than 800 mg/day is predicted to cause fewer aminotransferase elevations but is also predicted to be less effective. As stated above, pexidartinib can cause hepatic adverse reactions, including aminotransferase elevations or mixed or cholestatic hepatotoxicity. Serious and prolonged hepatotoxicity with ductopenia and/or cholestasis has been observed in patients treated with pexidartinib. All cases started within the first 8 weeks of treatment, which defines a period of high risk. One death of a cancer (non-TGCT) patient has been observed in the context of cholestatic hepatotoxicity. Another patient, receiving pexidartinib in combination with paclitaxel, experienced cholestatic hepatotoxicity that did not recover after 20 months and resulted in a liver transplant. In ENLIVEN, 3 of 61 (4.9%) TGCT patients randomized to pexidartinib experienced ALT and AST ≥3 × ULN with TBIL and ALP ≥2 × ULN. The hepatotoxicity resolved upon treatment discontinuation, and the duration of hyperbilirubinemia was 1 to 7 months. The mechanism of cholestatic hepatotoxicity is unknown and its occurrence cannot be predicted. In clinical studies of pexidartinib, patients with elevations of serum transaminases or bilirubin, or active liver or biliary tract disease, are excluded. In addition, weekly monitoring of liver tests was implemented with strict dose interruption, dose reduction, and dose discontinuation criteria. There is no evidence that these risk management procedures have prevented cases of cholestatic hepatotoxicity. However, prompt interruption of pexidartinib might help to reduce the severity and duration of ductopenia and/or cholestasis. For an event that cannot be predicted and thus prevented, weekly monitoring with prompt discontinuation and effective risk communication are the best risk mitigation procedures available.

10.3 Benefit:Risk Conclusion For some patients with diffuse TGCT, the tumor results in severe pain, stiffness, swelling, and reduced ROM, resulting in debilitating functional limitations and reduced quality of life. No systemic therapies are approved for TGCT, and pexidartinib is the only one that has demonstrated a high tumor response rate with improved clinical outcomes. When considering the totality of the data and the significant unmet medical need in TGCT, the Sponsor concluded that the clear and durable benefits afforded by pexidartinib offer an important treatment option for carefully selected TGCT patients who are suffering from severe morbidity or functional limitations and for whom no proven treatment options exist. The proposed pexidartinib labeling, REMS, and required laboratory monitoring will provide physicians and patients with the requisite information for a robust benefit:risk assessment on an individual patient basis.

Page 96 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

11 REFERENCES

1. Mastboom MJL, Hoek DM, Bovee J, van de Sande MAJ, Szuhai K. Does CSF1 overexpression or rearrangement influence biological behaviour in tenosynovial giant cell tumours of the knee? Histopathology 2019;74:332-40. 2. Staals EL, Ferrari S, Donati DM, Palmerini E. Diffuse-type tenosynovial giant cell tumour: Current treatment concepts and future perspectives. Eur J Cancer 2016;63:34-40. 3. Ehrenstein V, Andersen SL, Qazi I, et al. Tenosynovial Giant Cell Tumor: Incidence, Prevalence, Patient Characteristics, and Recurrence. A Registry-based Cohort Study in Denmark. J Rheumatol 2017;44:1476-83. 4. Mastboom MJL, Verspoor FGM, Gelderblom H, van de Sande MAJ. Limb Amputation after Multiple Treatments of Tenosynovial Giant Cell Tumour: Series of 4 Dutch Cases. Case Rep Orthop 2017;2017:7402570. 5. Myers BW, Masi AT. Pigmented villonodular synovitis and tenosynovitis: a clinical epidemiologic study of 166 cases and literature review. Medicine (Baltimore) 1980;59:223-38. 6. US Census Bureau. Projected Population by Single Year of Age, Sex, Race, and Hispanic Origin for the United States: 2016 to 2060. Available at: https://www.census.gov/data/datasets/2017/demo/popproj/2017-popproj.html. Accessed March 25, 2019. 7. Brahmi M, Vinceneux A, Cassier PA. Current Systemic Treatment Options for Tenosynovial Giant Cell Tumor/Pigmented Villonodular Synovitis: Targeting the CSF1/CSF1R Axis. Curr Treat Options Oncol 2016;17:10. 8. Cassier PA, Gelderblom H, Stacchiotti S, et al. Efficacy of imatinib mesylate for the treatment of locally advanced and/or metastatic tenosynovial giant cell tumor/pigmented villonodular synovitis. Cancer 2012;118:1649-55. 9. Gelderblom H, Cropet C, Chevreau C, et al. Nilotinib in locally advanced pigmented villonodular synovitis: a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 2018;19:639-48. 10. Molena B, Sfriso P, Oliviero F, et al. Synovial colony-stimulating factor-1 mRNA expression in diffuse pigmented villonodular synovitis. Clin Exp Rheumatol 2011;29:547-50. 11. West RB, Rubin BP, Miller MA, et al. A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. Proc Natl Acad Sci U S A 2006;103:690-5. 12. Sankhala K, Blay JY, Ganjoo K, et al. A phase 1/2 dose escalation and expansion study of cabiralizumab (FPA008), an anti-CSF1R antibody, in tenosynovial giant cell tumor (TGCT, diffuse pigmented villonodular synovitis D-PVNS. Poster presented at: 2017 ASCO Annual Meeting. Abstract 11078. 13. Tap WD, Wainberg ZA, Anthony SP, et al. Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor. N Engl J Med 2015;373:428-37.

Page 97 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

14. Monaghan H, Salter DM, Al-Nafussi A. Giant cell tumour of tendon sheath (localised nodular tenosynovitis): clinicopathological features of 71 cases. J Clin Pathol 2001;54:404-7. 15. Mastboom MJ, Planje R, van de Sande MA. The Patient Perspective on the Impact of Tenosynovial Giant Cell Tumors on Daily Living: Crowdsourcing Study on Physical Function and Quality of Life. Interact J Med Res 2018;7:e4. 16. van der Heijden L, Mastboom MJ, Dijkstra PD, van de Sande MA. Functional outcome and quality of life after the surgical treatment for diffuse-type giant-cell tumour around the knee: a retrospective analysis of 30 patients. Bone Joint J 2014;96-B:1111-8. 17. van der Heijden L, Piner SR, van de Sande MA. Pigmented villonodular synovitis: a crowdsourcing study of two hundred and seventy two patients. Int Orthop 2016;40:2459- 68. 18. Giustini N, Bernthal NM, Bukata SV, Singh AS. Tenosynovial giant cell tumor: case report of a patient effectively treated with pexidartinib (PLX3397) and review of the literature. Clin Sarcoma Res 2018;8:14. 19. Ushijima M, Hashimoto H, Tsuneyoshi M, Enjoji M. Giant cell tumor of the tendon sheath (nodular tenosynovitis). A study of 207 cases to compare the large joint group with the common digit group. Cancer 1986;57:875-84. 20. Nakayama R, Jagannathan JP, Ramaiya N, et al. Clinical characteristics and treatment outcomes in six cases of malignant tenosynovial giant cell tumor: initial experience of molecularly targeted therapy. BMC Cancer 2018;18:1296. 21. Mastboom MJL, Verspoor FGM, Hanff DF, et al. Severity classification of Tenosynovial Giant Cell Tumours on MR imaging. Surg Oncol 2018;27:544-50. 22. van der Heijden L, Gibbons CL, Hassan AB, et al. A multidisciplinary approach to giant cell tumors of tendon sheath and synovium--a critical appraisal of literature and treatment proposal. J Surg Oncol 2013;107:433-45. 23. Cassier PA, Italiano A, Gomez-Roca CA, et al. CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose- escalation and dose-expansion phase 1 study. Lancet Oncol 2015;16:949-56. 24. Genovese MC, Hsia E, Belkowski SM, et al. Results from a Phase IIA Parallel Group Study of JNJ-40346527, an Oral CSF-1R Inhibitor, in Patients with Active Rheumatoid Arthritis despite Disease-modifying Antirheumatic Drug Therapy. J Rheumatol 2015;42:1752-60. 25. Zhou L, Sikorski R, Rogers S, et al. A Phase 1 study of FPA008, an anti-colony stimulating factor 1 receptor (anti-CSF1R) antibody in patients (pts) with rheumatoid arthritis (RA): preliminary results [abstract]. Arthritis Rheumatol 2015;67(suppl 10):Abstract 2749.

Page 98 of 108

Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

12.2 Some Important Events of Mixed or Cholestatic Hepatotoxicity with Pexidartinib Seven cases of mixed or cholestatic hepatotoxicity are especially notable in the pexidartinib program: 5 in the TGCT population (4 in the Phase 3 ENLIVEN study and 1 in Study PL3397- A-U126) and 2 in the non-TGCT population.

12.2.1 TGCT Cases (b) (6) Case Report DSU-2016-125207 (PLX108-10 Subject ID ) (b) (6) Case Report DSU-2016-125207 (PLX108-10 Subject ID ) concerns a 75-year-old Caucasian female. The subject initiated pexidartinib 1000 mg/day on 13 Jun 2016 and per protocol the dose was reduced to 800 mg/day on 27 Jun 2016. The subject’s last dose of study drug was 13 Jul 2016. Total duration of therapy was 31 days. Medical history included thyroidectomy (1976) and hypothyroidism (1978 and ongoing) treated with a stable dose of l-thyroxine (100 mg/day) and hypercholesterolemia treated with atorvastatin 50 mg as needed started on study Day 1 and stopped on Day 3. This subject experienced fatigue, diarrhea, and nausea on Day 22 (04 Jun 2016). On Day 29 (11 Jul 2016), laboratory investigations noted ALT 5.7× ULN (231 U/L); AST 5.3× ULN (198 U/L); ALP 2× ULN (200 U/L); direct bilirubin (DBIL) 6.4× ULN (32 µmol/L); and TBIL 2.1× ULN (44 µmol/L). Treatment with pexidartinib was discontinued 13 Jul 2016 (Day 31). On (b) (6) laboratory values worsened without clinical symptoms and the subject was admitted to the hospital. At the time of admission, laboratory values were AST (281 U/L), ALT

Page 101 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

(376 U/L), TBIL (5.3 µmol/L), and ALP (231 U/L). Abdominal ultrasound showed there were no signs of pancreatitis, and hepatitis was ruled out. The subject initiated prednisone on (b) (6) With improving transaminases, but slow increasing bilirubin, the subject was (b) (6) (b) (6) discharged home Laboratory values at the time of discharge were ALT (137 U/L), AST (46 U/L), and ALP (167 U/L). TBIL at this time was 7.9× ULN (166 µmol/L) and DBIL was 22.8× ULN (114 µmol/L). Follow-up in outpatient setting noted ongoing improvement of transaminases, but bilirubin continued to rise with accompanying pruritus Grade 3. On Day 71, TBIL was 15× ULN (307.8 µmol/L) and DBIL was 84× ULN (b) (6) (287.3 µmol/L). The subject was admitted on for liver biopsy and bilirubin dialysis. Liver punch biopsy noted significant ductopenia and severe cholestasis; a mild fatty transformation (as seen with toxic liver damage) and ductopenia implicating specific (b) (6) damage of cholangioepithelium. Additional laboratory values postadmission ( were ALT(b) (51 (6) U/L), AST (66 U/L), and ALP (148 U/L). The subject was discharged on , and at the time of discharge, pruritus improved and laboratory results were ALT (b) (6) (55 U/L), AST (57 U/L), ALP (101 U/L), and TBIL (147.1 µmol/L). On (b) (6) , the subject was readmitted with elevated bilirubin and pruritus Grade 3 that required bilirubin dialysis. Laboratory results at the time of admission were ALT (70 U/L), AST (100 U/L), ALP (146 U/L), and TBIL (235.9 µmol/L). Two days later, laboratory results noted ALT (55 U/L), AST (71 U/L), ALP (129 U/L), and TBIL (193.2 µmol/L). The subject was discharged (b) (6) on . At the time of discharge (b) (6) laboratory results were ALT (66 U/L), AST (95 U/L), ALP (105 U/L), and TBIL (121.4 µmol/L). At Day 155 (14 Nov 2016), ALT was 5.8× ULN (191 U/L); TBIL 7.9× ULN (165 µmol/L), and DBIL 24× ULN (120.0 µmol/L). Ongoing laboratory analysis continued and on 08 Dec 2016 results were ALT (65 U/L), AST (51 U/L), ALP (212 U/L), and TBIL (106 µmol/L). The subject continued to improve and on 13 Feb 2017 laboratory results were ALT (35 U/L), AST (39 U/L), and TBIL (1.1 mg/dL) (Figure 12.1). (b) (6) Figure 12.1: Case Report DSU-2016-125207 (PLX108-10 Subject ID ): Hepatic Clinical Laboratory Results During Study Treatment

Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; d = day; LFT = liver function test; ULN = upper limit of normal.

Page 102 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

(b) (6) Case Report DSU-2016-129240 (PLX108-10 Subject ID ) (b) (6) Case Report DSU-2016-129240 (PLX108-10 Subject ID ) concerns a 52-year-old Caucasian male. The subject initiated pexidartinib 1000 mg/day on 19 Jul 2016 and per protocol the dose was reduced to 800 mg/day on 02 Aug 2016. Study drug was discontinued with the last dose on 23 Aug 2016 (Day 36). Medical history included gastroesophageal reflux disease, colitis, and diverticulitis since January 2014. On Day 29 (16 Aug 2016), ALT was 3.4× ULN (b) (6) (140 U/L), AST was 3.8× ULN (141 U/L), bilirubin unreported. On the subject went to the emergency room for nausea and vomiting. At that time, the subject had an

increased bilirubin of(b) (6)4.0 (units not available), and was jaundiced, but declined admission. On study staff was notified that the subject was symptomatic with jaundice, pruritus, nausea, and had had one episode of vomiting earlier that morning. The subject was (b) (6) admitted for a Grade 3 blood bilirubin increase. Laboratory testing on noted elevations in ALT 9.3× ULN (382 U/L), AST 4.8× ULN (176 U/L), TBIL 6.5× ULN (136 µmol/L), and (b) (6) DBIL 18.8× ULN (94 µmol/L). An abdominal ultrasound on noted no intrahepatic or extrahepatic ductal dilation, and computed tomography (CT) abdomen/pelvis the following (b) (6) day was unremarkable. Hepatitis panel was also negative. On liver function studies were trending down and the subject was discharged. Values at discharge were ALT (283 U/L), AST (130 U/L), and TBIL (107.7 µmol/L). The study drug was discontinued with the last dose on 23 Aug 2016 (Day 36). Final laboratory results provided on Day 75 noted ALT (39 U/L), AST (32 U/L), and TBIL (0.5 mg/dL) (Figure 12.2). (b) (6) Figure 12.2: Case Report DSU-2016-129240 (PLX108-10 Subject ID : Hepatic Clinical Laboratory Results During Study Treatment

Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; d = day; LFT = liver function test; ULN = upper limit of normal.

(b) (6) Case Report DSU-2016-133478 (PLX108-10 Subject ID ) (b) (6) Case Report DSU-2016-133478 (PLX108-10 Subject ID concerns a 67-year-old Caucasian female. The subject initiated pexidartinib 1000 mg/day (400 mg AM/600 mg PM) on 21 Jul 2016 to 03 Aug 2016. Per protocol the dose was reduced to 800 mg/day from

Page 103 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

04 Aug 2016 to 14 Sep 2016. The subject’s last dose prior to the event onset was 14 Sep 2016 (Day 56). The subject was discontinued from the study 29 Sep 2016 due to the event. On 01 Sep 2016 (Day 43), laboratory analysis noted transaminitis with GGT 10.4× ULN (449 U/L) and ALP 1.5× ULN (171 U/L). Additional investigations noted elevation in AST at 4.2× ULN (140 U/L). On 14 Sep 2016 (Day 56), laboratory results showed GGT 17.9× ULN (772 U/L) and ALP 2.1× ULN (228 U/L), and pexidartinib was discontinued. Additional laboratory findings at this time noted ALT 7.9× ULN (244 U/L), AST 4.7× ULN (145 U/L), and (b) (6) TBIL (14 µmol; normal). On the subject presented with ongoing transaminitis with clinical symptoms of acute cholangitis and was hospitalized. Laboratory findings at the time of admission were GGT 23× ULN (992 U/L), ALP 3.9× ULN (408 IU/L), ALT 7.9× ULN (262 U/L), AST 3.5× ULN (107 U/L), TBIL 2.5× ULN (52 µmol/L), and DBIL (b) (6) 7.2× ULN (36 µmol/L). On laboratory values were trending down and showed GGT (608 U/L), ALT (84 U/L), AST (53 U/L), ALP (360 U/L), and TBIL (28 µmol). The (b) (6) subject was discharged on while laboratory results continued to return to normal, and final analysis on 15 Nov 2016 (Day 116) showed ALT (21 U/L), AST (19 U/L), ALP (55 U/L), and TBIL (5 µmol) (Figure 12.3). (b) (6) Figure 12.3: Case Report DSU-2016-133478 (PLX108-10 Subject ID ): Hepatic Clinical Laboratory Results During Study Treatment

Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; d = day; LFT = liver function test; ULN = upper limit of normal.

(b) (6) Case Report DSU-2016-130954 (PLX108-10 Subject ID ) (b) (6) Case Report DSU-2016-130954 (Subject ID concerns a 39-year-old Caucasian female. Medical history reported alcohol use but no other significant medical history. The subject initiated pexidartinib at 1000 mg daily from 21 Jul 2016 to 04 Aug 2016. On 04 Aug 2016 (Day 15), the patient experienced fatigue and nausea (both Grade 1), and hepatic evaluation revealed ALT 8.3× ULN (275 U/L), AST 7.6× ULN (235 U/L), and ALP 1.9× ULN (201 IU/L); pexidartinib was interrupted. Treatment was restarted at 800 mg daily from 18 Aug 2016 (Day 29). On 24 Aug 2016 (Day 35), hepatic evaluations revealed AST 3.3× ULN (101 U/L),

Page 104 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

ALT 8.6× ULN (285 U/L) and ALP 6.2× ULN (642 U/L), and treatment was interrupted. On 08 Sep 2016 (Day 50), AST and ALT were normal, and ALP was 1.9× ULN (208 IU/L), and pexidartinib was reintroduced at 600 mg daily. The patient took the evening dose of 400 mg and awoke with nausea, crampy abdominal pain, hot and cold flushes, and vomiting. The subject did not take the next morning 200-mg dose on 09 Sep 2016 (Day 51); laboratory values showed ALT 4.1× ULN (138 U/L), AST 6.4× ULN (192 U/L), ALP 1.7× ULN (220 U/L) and normal TBIL. Study therapy was held until 26 Sep 2016 (Day 68), when pexidartinib was restarted at a reduced dose of 400 mg/day. The patient took the evening 200-mg dose and awoke with stomach cramps, hot and cold flashes, and nausea. On 28 Sep 2016 (Day 70), the hepatic evaluations revealed ALP 2.9× ULN (314 IU/L), ALT 7.9× ULN (433 U/L), AST 6.7× ULN (369 U/L), total bilirubin 1.4× ULN (29 μmol/L), and GGT 6.4× ULN (224 U/L). Pexidartinib was permanently discontinued with the last dose taken on 27 Sep 2016 (Day 69). The event of elevated LFTs was reported as recovered on 27 Oct 2016 (Day 99) (Figure 12.4).

(b) (6) Figure 12.4: Case Report DSU-2016-130954 (PLX108-10 Subject ID : Hepatic Clinical Laboratory Results During Study Treatment

Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; d = day; LFT = liver function test; ULN = upper limit of normal.

(b) (6) Case Report DSU-2018-140587 (PL3397-A-U126 Subject ID (b) (6) Case Report DSU-2018-140587 (PL3397-A-U126 Subject ID ) concerns a 43-year- old Asian female enrolled in an open-label, single sequence, crossover study assessing the effect of pexidartinib on the PK of CYP3A4 and CYP2C9 substrates. On 15 Aug 2018 (Day 1), the subject received midazolam (2 mg) and tolbutamide (500 mg). On 17 Aug 2018 (Cycle 1 Day 1), the subject started pexidartinib at 400 mg twice daily. Midazolam and tolbutamide were given again with the first pexidartinib dose and on 27 Aug 2018 (Cycle 1 Day 11). On 31 Aug 2018, 14 days after the start of pexidartinib, hepatic evaluation noted ALT 1.7× ULN (54 U/L) and AST 1.9× ULN (79 U/L) (Figure 12.5). On 06 Sep 2018, 20 days after the start of pexidartinib, the subject was tired and vomited once. The following day hepatic evaluation

Page 105 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

noted ALT 8.7× ULN (271 U/L), AST 8.8× ULN (363 U/L) and GGT 3.9× ULN (253 U/L); pexidartinib was discontinued. On 11 Sep 2018, 25 days after start of pexidartinib treatment, total bilirubin was elevated 3× ULN (3.1 mg/dL) and direct bilirubin was 2.3× ULN (2.3 mg/dL). Other laboratory investigations included ALT 7.1× ULN (221 U/L), AST 5.2× ULN (215 U/L), ALP 5.3× ULN (555 U/L) and GGT 5.5× ULN (350 U/L). Hepatitis B and hepatitis C testing were negative. On 17 Sep 2018, 31 days after start of pexidartinib, an abdominal ultrasound noted two hepatic hemangiomas and left hepatic cyst that were considered clinically insignificant. On 09 Nov 2018, 84 days after start of pexidartinib, ALT and AST increases were resolved, and increased total bilirubin was considered resolved on 15 Nov 2018, 90 days after start of pexidartinib. (b) (6) Figure 12.5: Case Report DSU-2018-140587 (PLX3397-A-U126 Subject ID ): Hepatic Clinical Laboratory Results During Study Treatment

Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; d = day; Dbil = direct bilirubin; Tbil = total bilirubin; ULN = upper limit of normal.

12.2.2 Non-TGCT Cases (b) (6) Case Report DSU-2017-118366, Serial No 0127 (PLX108-13 Subject ID (b) (6) Case Report DSU-2017-118366, Serial No 0127 (PLX108-13 Subject ID ) occurred in the Phase 2 study, PLX108-13 (Open-label, Multicenter Study of PLX3397 in Patients with Unresectable or Metastatic KIT-mutated Melanoma in Asia). The subject had Stage 3C vaginal mucosal melanoma and had resection of the primary tumor with bladder fistula. At screening, her target lesion was a tumor mass in the vaginal stump (47 × 24 mm) and the nontarget lesions were inguinal lymph nodes. She had a mild increase in ALT/AST <2× ULN, attributed to quinolone antibiotic treatment, with normal bilirubin. This subject was started on pexidartinib 1000 mg/day and liver function tests were monitored weekly from the start of treatment. On Day 21, Grade 3 transaminitis was observed with doubling of bilirubin from baseline, which was considered a dose-limiting toxicity. Four days later, bilirubin increased to 3× ULN with decreasing transaminitis. She was diagnosed with drug-induced hepatitis. Day 28 CT scans

Page 106 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

showed a tumor reduction without liver metastasis. Day 40 pelvic CT showed irregular thickening of the posterior bladder wall (18 mm) and multiple lesions in the bilateral inguinal lymph nodes that were interpreted as possible metastasis. On Day 58, she presented in the emergency room with a diagnosis of hematuria. On Day 60, the subject underwent bilirubin adsorption and received transfusion for anemia. A thoracic and abdominal CT on Day 77 showed no evidence of metastasis. She remained jaundiced until her death on Day 124. Based on the death certificate, the cause of death was melanoma and cachexia. Hepatic laboratory parameters for this subject are shown in Figure 12.6. (b) (6) Figure 12.6: Case Report DSU-2017-118366 (PLX108-13 Subject ID ): Hepatic Laboratory Parameters by Day

Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; d = day; LFT = liver function test; ULN = upper limit of normal.

(b) (6) Case Report DSU-2015-135086 (IST3397-006 Subject ID The other suspected unexpected serious adverse reaction concerns a 60-year-old female with metastatic breast cancer (b)(DSU (6) -2015-135086, Investigator-initiated study IST3397-006 [ISPY2- 097517], Subject ID . Medical history included hysterectomy, mastectomy, alcohol use, and migraine. She received pexidartinib 1200 mg/day in combination with weekly paclitaxel. On Day 18, transaminases were increasing with fever (Figure 12.7) and study treatment was withheld. On Day 19, transaminases and bilirubin were noted to be increasing. On Day 22, MRI suggested cholestasis and she received a cholecystectomy. On Day 26, liver function tests continued to elevate. Endoscopic retrograde cholangiopancreatography showed no biliary duct obstruction. On the next day, a liver biopsy showed cholestasis and severe steatosis with duct damage and duct loss. On 07 Dec 2016 (14 months after the last dose), her ALT/AST remained above ULN and TBIL was 20× ULN. In June 2017 (20 months after the last dose), she received a liver transplant. In September 2017, her ALT/AST and TBIL returned to normal range.

Page 107 of 108 Pexidartinib NDA 211810 FDA Advisory Committee Briefing Document Daiichi Sankyo April 11, 2019

(b) (6) Figure 12.7: Case Report DSU-2015-135086 (IST3397-006 Subject ID : Hepatic Laboratory Parameters by Day

Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; LFT = liver function test; ULN = upper limit of normal.

Page 108 of 108