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Multi-Discipline Review CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761139Orig1s000 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 {BLA 761139} ENHERTU (fam-trastuzumab deruxtecan-nxki) NDA/BLA Multi-disciplinary Review and Evaluation Disclaimer: In this document, the sections labeled as “The Applicant’s Position” are completed by the Applicant, which do not necessarily reflect the positions of the FDA. Application Type Biologics License Application (BLA) 351(a) Application Number BLA 761139 Priority or Standard Priority Submit Date(s) August 29, 2019 Received Date(s) August 29, 2019 PDUFA Goal Date April 29, 2020 Division/Office DO1/OOD/OND/CDER Review Completion Date Electronic Stamp Date Established Name fam-trastuzumab deruxtecan-nxki (Proposed) Trade Name ENHERTU Pharmacologic Class HER2-directed antibody and topoisomerase inhibitor conjugate Code name Applicant Daiichi Sankyo, Inc Formulation(s) 100 mg lyophilized powder Dosing Regimen 5.4 mg IV every 3 weeks (b) (4) Applicant Proposed Indication(s)/Population(s) Recommendation on Accelerated Approval Regulatory Action Recommended Treatment of adult patients with unresectable or metastatic Indication(s)/Population(s) HER2-positive breast cancer who have received two or more (if applicable) prior anti-HER2-based regimens in the metastatic setting. 1 Version date: June 11, 2019 (ALL NDA/BLA reviews) Disclaimer: In this document, the sections labeled as “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Reference ID: 4537638 NDA/BLA Multi-disciplinary Review and Evaluation {BLA 761139} ENHERTU (fam-trastuzumab deruxtecan-nxki) Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation .............................................................. 10 Additional Reviewers of Application ............................................................................................. 10 Glossary ......................................................................................................................................... 12 1 Executive Summary ............................................................................................................... 17 Product Introduction ...................................................................................................... 17 Conclusions on the Substantial Evidence of Effectiveness ............................................ 17 Benefit-Risk Assessment (BRA) ...................................................................................... 20 Patient Experience Data ................................................................................................. 23 2 Therapeutic Context .............................................................................................................. 26 Analysis of Condition ...................................................................................................... 26 Analysis of Current Treatment Options ......................................................................... 27 3 Regulatory Background ......................................................................................................... 33 U.S. Regulatory Actions and Marketing History ............................................................. 33 Summary of Presubmission/Submission Regulatory Activity ........................................ 33 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................. 35 Office of Scientific Investigations (OSI) .......................................................................... 35 Product Quality .............................................................................................................. 38 Clinical Microbiology ...................................................................................................... 39 Devices and Companion Diagnostic Issues .................................................................... 39 5 Nonclinical Pharmacology/Toxicology................................................................................... 40 Executive Summary ........................................................................................................ 40 Referenced NDAs, BLAs, DMFs ....................................................................................... 43 Pharmacology ................................................................................................................. 43 ADME/PK ........................................................................................................................ 48 Toxicology ....................................................................................................................... 53 General Toxicology .................................................................................................. 53 Genetic Toxicology .................................................................................................. 62 2 Version date: June 11, 2019 (ALL NDA/BLA reviews) Disclaimer: In this document, the sections labeled as “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Reference ID: 4537638 NDA/BLA Multi-disciplinary Review and Evaluation {BLA 761139} ENHERTU (fam-trastuzumab deruxtecan-nxki) Carcinogenicity ........................................................................................................ 65 Reproductive and Developmental Toxicology ........................................................ 66 Other Toxicology Studies ........................................................................................ 66 6 Clinical Pharmacology ............................................................................................................ 75 Executive Summary ........................................................................................................ 75 Summary of Clinical Pharmacology Assessment ............................................................ 76 Pharmacology and Clinical Pharmacokinetics ........................................................ 76 General Dosing and Therapeutic Individualization ................................................. 79 6.2.2.1. General Dosing ................................................................................................ 79 6.2.2.2. Therapeutic Individualization .......................................................................... 81 6.2.2.3. Outstanding Issues .......................................................................................... 82 Comprehensive Clinical Pharmacology Review ............................................................. 82 General Pharmacology and Pharmacokinetic Characteristics ................................ 82 Clinical Pharmacology Questions ............................................................................ 93 6.3.2.1. Does the clinical pharmacology program provide supportive evidence of effectiveness? ................................................................................................................... 93 6.3.2.2. Is the proposed dosing regimen appropriate for the general patient population for which the indication is being sought? ...................................................... 95 6.3.2.3. Is an alternative dosing regimen or management strategy required for subpopulations based on intrinsic patient factors? ......................................................... 96 6.3.2.4. Are there clinically relevant food-drug or drug-drug interactions, and what is the appropriate management strategy? .......................................................................... 98 7 Sources of Clinical Data ....................................................................................................... 101 Table of Clinical Studies ................................................................................................ 101 8 Statistical and Clinical Evaluation ........................................................................................ 109 Review of Relevant Individual Trials Used to Support Efficacy .................................... 109 Studies DS8201-A-U201 and DS8201-A-J101 ....................................................... 109 8.1.1.1. Study DS8201-A-U201 ................................................................................... 109 8.1.1.2. Study DS8201-A-J101 ..................................................................................... 123 8.1.1.3. Study DS8201-A-U201 ................................................................................... 126 8.1.1.4. Study DS8201-A-J101 ..................................................................................... 144 3 Version date: June 11, 2019 (ALL NDA/BLA reviews) Disclaimer: In this document, the sections labeled as “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Reference ID: 4537638 NDA/BLA Multi-disciplinary Review and Evaluation {BLA 761139} ENHERTU (fam-trastuzumab deruxtecan-nxki) Assessment of Efficacy Across Trials ..................................................................... 146 Integrated Assessment of
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