CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 210496Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review Multi-Disciplinary Review and Evaluation NDA 210496 BRAFTOVI™ (encorafenib) NDA Multi-Disciplinary Review and Evaluation Application Type NDA (Original-1) Application Number 210496 Priority or Standard Standard Submit Date June 30, 2017 Received Date June 30, 2017 PDUFA Goal Date June 30, 2018 Division/Office DOP2/OHOP Established Name Encorafenib (Proposed) Trade Name BRAFTOVI™ Pharmacologic Class Kinase inhibitor Code Name LGX818 Applicant Array BioPharma Inc. Formulation 50 mg and 75 mg capsules Dosing Regimen 450 mg orally once daily in combination with binimetinib Applicant Proposed In combination with binimetinib, for the treatment of patients Indication/Population with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation as detected by an FDA-approved test Recommendation on Regular approval Regulatory Action Recommended In combination with binimetinib, for the treatment of patients Indication/Population with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test 1 Reference ID: 4282494 Multi-Disciplinary Review and Evaluation NDA 210496 BRAFTOVI™ (encorafenib) Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation...............................................................14 Additional Reviewers of Application ............................................................................................15 Glossary ........................................................................................................................................16 1 Executive Summary...............................................................................................................19 1.1. Product Introduction......................................................................................................19 1.2. Conclusions on the Substantial Evidence of Effectiveness.............................................19 1.3. Benefit-Risk Assessment ................................................................................................21 1.4. Patient Experience Data.................................................................................................24 2 Therapeutic Context..............................................................................................................25 2.1. Analysis of Condition......................................................................................................25 2.2. Analysis of Current Treatment Options .........................................................................25 3 Regulatory Background .........................................................................................................29 3.1. U.S. Regulatory Actions and Marketing History.............................................................29 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................29 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................32 4.1. Office of Scientific Investigations (OSI) ..........................................................................32 4.2. Product Quality ..............................................................................................................32 4.3. Clinical Microbiology......................................................................................................33 4.4. Devices and Companion Diagnostic Issues ....................................................................33 5 Nonclinical Pharmacology/Toxicology ..................................................................................34 5.1. Executive Summary........................................................................................................34 5.2. Referenced NDAs, BLAs, DMFs ......................................................................................36 5.3. Pharmacology ................................................................................................................36 5.4. ADME/PK........................................................................................................................45 5.5. Toxicology ......................................................................................................................47 5.5.1. General Toxicology .................................................................................................47 5.5.2. Genetic Toxicology..................................................................................................52 5.5.3. Carcinogenicity .......................................................................................................53 2 Reference ID: 4282494 Multi-Disciplinary Review and Evaluation NDA 210496 BRAFTOVI™ (encorafenib) 5.5.4. Reproductive and Developmental Toxicology ........................................................54 5.5.5. Other Toxicology Studies ........................................................................................63 6 Clinical Pharmacology ...........................................................................................................64 6.1. Executive Summary........................................................................................................64 6.2. Summary of Clinical Pharmacology Assessment............................................................67 6.2.1. Pharmacology and Clinical Pharmacokinetics.........................................................67 6.2.2. General Dosing and Therapeutic Individualization.................................................68 6.3. Comprehensive Clinical Pharmacology Review..............................................................71 6.3.1. General Pharmacology and Pharmacokinetic Characteristics ................................71 6.3.2. Clinical Pharmacology Questions............................................................................75 7 Sources of Clinical Data and Review Strategy .......................................................................87 7.1. Table of Clinical Studies .................................................................................................87 7.2. Review Strategy .............................................................................................................91 8 Statistical and Clinical and Evaluation...................................................................................92 8.1. Review of Relevant Individual Trials Used to Support Efficacy ......................................92 8.1.1. COLUMBUS – Trial Design.......................................................................................93 8.1.2. LOGIC2 – Trial Design............................................................................................103 8.1.3. COLUMBUS – Study Results..................................................................................105 8.1.4. LOGIC2 – Study Results.........................................................................................129 8.1.5. Assessment of Efficacy Across Trials.....................................................................133 8.1.6. Integrated Assessment of Effectiveness...............................................................137 8.2. Review of Safety...........................................................................................................139 8.2.1. Safety Review Approach .......................................................................................139 8.2.2. Adequacy of Applicant’s Clinical Safety Assessments...........................................144 8.2.3. Safety Results........................................................................................................146 8.2.4. Analysis of Submission-Specific Safety Issues.......................................................173 8.2.5. Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ......203 8.2.6. Safety Analyses by Demographic Subgroups........................................................203 8.2.7. Specific Safety Studies/Clinical Trials....................................................................205 8.2.8. Additional Safety Explorations..............................................................................205 8.2.9. Safety in the Postmarket Setting ..........................................................................206 8.2.10. Integrated Assessment of Safety...................................................................206 3 Reference ID: 4282494 Multi-Disciplinary Review and Evaluation NDA 210496 BRAFTOVI™ (encorafenib) SUMMARY AND CONCLUSIONS..................................................................................................208 8.3. Statistical Issues ...........................................................................................................208 8.4. Conclusions and Recommendations ............................................................................208 9 Advisory Committee Meeting and Other External Consultations .......................................210 10 Pediatrics.............................................................................................................................211