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210861Orig1s000 211710Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 210861Orig1s000 211710Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA Multidisciplinary Review and Evaluation NDA 210861 and NDA 211710 VITRAKVI (larotrectinib) NDA Multi-Disciplinary Review and Evaluation Application Type NDA Application Number(s) 210861 211710 Priority or Standard Priority Submit Date(s) First module: December 19, 2017; Final module: March 26, 2018 Received Date(s) March 26, 2018 PDUFA Goal Date November 26, 2018 Division/Office DOP 2/OCE Review Completion Date November 26, 2018 Established Name Larotrectinib (Proposed) Trade Name Vitrakvi Pharmacologic Class Kinase inhibitor Code name LOXO-101 Applicant Loxo Oncology, Inc. Formulation(s) Capsule: 25 mg, 100 mg; Solution: 20mg/mL Dosing Regimen Adults and pediatric patients with BSA ≥1 m2: 100 mg orally twice daily Pediatric patients with BSA < 1 m2: 100mg/m2 orally twice daily Applicant Proposed Treatment of adult and pediatric patients with locally advanced Indication(s)/Population(s) or metastatic solid tumors harboring an NTRK gene fusion. Recommendation on Accelerated Approval Regulatory Action Recommended Treatment of adult and pediatric patients with solid tumors Indication(s)/Population(s) that have a neurotrophic receptor tyrosine kinase (NTRK) gene (if applicable) fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity and have no satisfactory alternative treatment options or whose cancer has progressed following treatment. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. 1 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4354090 NDA Multidisciplinary Review and Evaluation NDA 210861 and NDA 211710 VITRAKVI (larotrectinib) Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation ................................................................ 8 Additional Reviewers of Application ............................................................................................... 8 Glossary ......................................................................................................................................... 10 1 Executive Summary ............................................................................................................... 13 Product Introduction ...................................................................................................... 13 Conclusions on the Substantial Evidence of Effectiveness ............................................ 14 Benefit-Risk Assessment ................................................................................................ 15 Patient Experience Data ................................................................................................. 23 2 Therapeutic Context .............................................................................................................. 25 Analysis of Condition ...................................................................................................... 25 Analysis of Current Treatment Options ......................................................................... 29 3 Regulatory Background ......................................................................................................... 34 U.S. Regulatory Actions and Marketing History ............................................................. 34 Summary of Presubmission/Submission Regulatory Activity ........................................ 34 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 37 Office of Scientific Investigations (OSI) .......................................................................... 37 Product Quality .............................................................................................................. 37 Clinical Microbiology ...................................................................................................... 40 Devices and Companion Diagnostic Issues .................................................................... 40 5 Nonclinical Pharmacology/Toxicology................................................................................... 42 Executive Summary ........................................................................................................ 42 Referenced NDAs, BLAs, DMFs ....................................................................................... 46 Pharmacology ................................................................................................................. 46 ADME/PK ........................................................................................................................ 52 Toxicology ....................................................................................................................... 55 General Toxicology .................................................................................................. 55 2 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4354090 NDA Multidisciplinary Review and Evaluation NDA 210861 and NDA 211710 VITRAKVI (larotrectinib) Genetic Toxicology .................................................................................................. 64 Reproductive and Developmental Toxicology ........................................................ 65 Other Toxicology Studies ........................................................................................ 84 6 Clinical Pharmacology ............................................................................................................ 85 Executive Summary ........................................................................................................ 85 Recommendations ............................................................................................................ 85 Summary of Clinical Pharmacology Assessment ............................................................ 87 Pharmacology and Clinical Pharmacokinetics ........................................................ 87 General Dosing and Therapeutic Individualization ................................................. 89 Comprehensive Clinical Pharmacology Review ............................................................. 90 General Pharmacology and Pharmacokinetic Characteristics ................................ 90 Clinical Pharmacology Questions ............................................................................ 94 7 Sources of Clinical Data and Review Strategy ..................................................................... 108 Table of Clinical Studies ................................................................................................ 108 Review Strategy ............................................................................................................ 111 8 Statistical and Clinical Evaluation ........................................................................................ 113 Review of Relevant Individual Trials Used to Support Efficacy .................................... 113 LOXO-TRK-14001 (Version 5) ................................................................................ 113 LOXO-TRK-15002 (Version 7.0) ............................................................................. 118 LOXO-TRK 15003 (Version 8) ................................................................................ 126 Pooled Study Results ............................................................................................. 134 Assessment of Efficacy Across Trials ..................................................................... 149 Integrated Assessment of Effectiveness ............................................................... 153 Review of Safety ........................................................................................................... 154 Safety Review Approach ....................................................................................... 154 Review of the Safety Database ............................................................................. 155 Adequacy of Applicant’s Clinical Safety Assessments .......................................... 159 Safety Results ........................................................................................................ 161 Analysis of Submission-Specific Safety Issues ....................................................... 182 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ...... 184 Safety Analyses by Demographic Subgroups ........................................................ 184 3 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4354090 NDA Multidisciplinary Review and Evaluation NDA 210861 and NDA 211710 VITRAKVI (larotrectinib) Specific Safety Studies/Clinical Trials .................................................................... 185 Additional Safety Explorations .............................................................................
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