CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 212608Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA/BLA Multi-disciplinary Review and Evaluation NDA 212608 AYVAKIT (avapritinib) NDA/BLA Multi-Disciplinary Review and Evaluation Application Type New Drug Application (NDA)/New Molecular Entity (NME) Application Number(s) 212608 Priority or Standard Priority Submit Date(s) June 14, 2019 Received Date(s) June 14, 2019 PDUFA Goal Date February 14, 2020 Division/Office DO3/OOD Established/Proper Name Avapritinib (Proposed) Trade Name AYVAKIT Pharmacologic Class Kinase inhibitor Code name BLU-285 Applicant Blueprint Medicines Corporation Dosage form 100 mg, 200 mg, and 300 mg tablets Applicant proposed Dosing 300 mg orally once daily Regimen Applicant Proposed For the treatment of adult patients with unresectable or Indication(s)/Population(s) metastatic gastrointestinal stromal tumor (GIST) who have a platelet-derived growth factor receptor alpha (PDGFA) exon 18 mutation, regardless of prior therapy Applicant Proposed SNOMED CT Indication Gastrointestinal Stromal Tumor Disease Term for each Proposed Indication Recommendation on Approval Regulatory Action Recommended For the treatment of adults with unresectable or metastatic Indication(s)/Population(s) GIST harboring a platelet-derived growth factor receptor alpha (if applicable) (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations Recommended SNOMED CT Indication Disease Gastrointestinal Stromal Tumor Term for each Indication (if applicable) Recommended Dosing 300 mg orally once daily Regimen 1 Version date: April 2, 2018 Reference ID: 4543562 NDA/BLA Multi-disciplinary Review and Evaluation NDA 212608 AYVAKIT (avapritinib) Table of Contents Table of Tables ................................................................................................................................ 5 Table of Figures ............................................................................................................................... 8 Reviewers of Multi-Disciplinary Review and Evaluation ................................................................ 9 Glossary ......................................................................................................................................... 10 1 Executive Summary ............................................................................................................... 11 Product Introduction ...................................................................................................... 11 Conclusions on the Substantial Evidence of Effectiveness ............................................ 12 Benefit-Risk Assessment ................................................................................................ 13 Patient Experience Data ................................................................................................. 17 2 Therapeutic Context .............................................................................................................. 18 Analysis of Condition ......................................................... 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Analysis of Current Treatment Options ......................................................................... 18 3 Regulatory Background ......................................................................................................... 19 U.S. Regulatory Actions and Marketing History ............................................................. 19 Summary of Presubmission/Submission Regulatory Activity ........................................ 19 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................. 22 Office of Scientific Investigations (OSI) .......................................................................... 22 Product Quality .............................................................................................................. 22 Clinical Microbiology ...................................................................................................... 23 Devices and Companion Diagnostic Issues .................................................................... 23 5 Nonclinical Pharmacology/Toxicology................................................................................... 25 Executive Summary ........................................................................................................ 25 Referenced NDAs, BLAs, DMFs ....................................................................................... 28 Pharmacology ................................................................................................................. 28 ADME/PK ........................................................................................................................ 35 Toxicology ....................................................................................................................... 39 General Toxicology .................................................................................................. 39 Genetic Toxicology .................................................................................................. 46 Carcinogenicity ........................................................................................................ 48 Reproductive and Developmental Toxicology ........................................................ 48 Other Toxicology Studies ........................................................................................ 51 6 Clinical Pharmacology ............................................................................................................ 53 Executive Summary ........................................................................................................ 53 2 Version date: April 2, 2018 Reference ID: 4543562 NDA/BLA Multi-disciplinary Review and Evaluation NDA 212608 AYVAKIT (avapritinib) Summary of Clinical Pharmacology Assessment ............................................................ 54 Pharmacology and Clinical Pharmacokinetics ........................................................ 54 General Dosing and Therapeutic Individualization ................................................. 55 Comprehensive Clinical Pharmacology Review ............................................................. 56 General Pharmacology and Pharmacokinetic Characteristics ................................ 56 Clinical Pharmacology Questions ............................................................................ 58 7 Sources of Clinical Data and Review Strategy ....................................................................... 64 Table of Clinical Studies .................................................................................................. 64 Review Strategy .............................................................................................................. 66 8 Statistical and Clinical and Evaluation ................................................................................... 67 Review of Relevant Individual Trials Used to Support Efficacy ...................................... 67 BLU-285-1101 (NAVIGATOR) .................................................................................. 67 Study Results ........................................................................................................... 74 8.1.3 Integrated Review of Effectiveness ........................................................................ 87 8.1.4 Integrated Assessment of Effectiveness ................................................................. 91 8.2 Review of Safety ................................................................ 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Bookmark not defined. 8.2.1 Safety Review Approach ......................................................................................... 92 8.2.2 Review of the Safety Database ............................................................................... 92 8.2.3 Adequacy of Applicant’s Clinical Safety Assessments ............................................ 96 8.2.4 Safety Results .......................................................................................................... 96 8.2.5 Analysis of Submission-Specific Safety Issues ....................................................... 126 8.2.6 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ...... 126 8.2.7 Safety Analyses by Demographic Subgroups ........................................................ 126 8.2.10 Safety in the Postmarket Setting ................................................................... 127 8.2.11 Integrated Assessment of Safety ................................................................... 128 8.3 Statistical Issues ........................................................................................................... 130 8.4 Conclusions and Recommendations ............................................................................ 130 9 Advisory Committee Meeting and Other External Consultations ....................................... 133 10 Pediatrics ............................................................................................................................. 134 11 Labeling Recommendations ...............................................................................................