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