CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761121Orig1s000 CLINICAL REVIEW(S) CLINICAL REVIEW Application Type Original BLA Application Number 761121 Priority or Standard Priority Submit Dates 11/21/2018, 12/19/2018 Received Dates 11/21/2018, 12/19/2018 PDUFA Goal Date 8/19/2019 Division/Office DHP / OHOP Reviewer Names Yvette Kasamon, M.D. (primary clinical reviewer) R. Angelo de Claro, M.D. (team leader) Review Completion Date 5/28/2019 Established/Proper Name Polatuzumab vedotin-piiq (DCDS4501A) (Proposed) Trade Name Polivy Applicant Genentech, Inc. Dosage Form For injection: 140 mg of polatuzumab vedotin-piiq as a lyophilized powder in a single-dose vial Applicant Proposed 1.8 mg/kg IV infusion every 21 days for 6 cycles, in combination with Dosing Regimen bendamustine (90 mg/m2/day for 2 days) and rituximab (b) (4) Applicant Proposed Indication/Population Recommendation on Accelerated approval Regulatory Action Recommended In combination with bendamustine and a rituximab product for the Indication/Population treatment of adult patients with relapsed or refractory diffuse large B- cell lymphoma, not otherwise specified, after at least two prior therapies Reference ID: 44400814446194 BLA 761121 Clinical Review Yvette Kasamon, MD Polivy (polatuzumab vedotin-piiq) Table of Contents Glossary ........................................................................................................................................... 6 1. Executive Summary ................................................................................................................. 8 Product Introduction ........................................................................................................ 8 Conclusions on the Substantial Evidence of Effectiveness .............................................. 8 Benefit-Risk Assessment .................................................................................................. 8 Patient Experience Data ................................................................................................. 12 2. Therapeutic Context .............................................................................................................. 13 Analysis of Condition ...................................................................................................... 13 Analysis of Current Treatment Options ......................................................................... 13 3. Regulatory Background ......................................................................................................... 14 U.S. Regulatory Actions and Marketing History ............................................................. 14 Summary of Presubmission/Submission Regulatory Activity ........................................ 14 Foreign Regulatory Actions and Marketing History ....................................................... 15 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................. 15 Office of Scientific Investigations (OSI) .......................................................................... 15 Product Quality .............................................................................................................. 15 Nonclinical Pharmacology/Toxicology ........................................................................... 15 Clinical Pharmacology .................................................................................................... 15 Devices and Companion Diagnostic Issues .................................................................... 16 5. Sources of Clinical Data and Review Strategy ....................................................................... 17 Table of Clinical Studies .................................................................................................. 17 Review Strategy .............................................................................................................. 19 6. Review of Relevant Individual Trials Used to Support Efficacy ............................................. 21 GO29365 ......................................................................................................................... 21 Study Design ........................................................................................................... 21 Study Results ........................................................................................................... 25 7. Integrated Review of Effectiveness ....................................................................................... 39 2 Reference ID: 44400814446194 BLA 761121 Clinical Review Yvette Kasamon, MD Polivy (polatuzumab vedotin-piiq) Assessment of Efficacy Across Trials .............................................................................. 39 Integrated Assessment of Effectiveness ........................................................................ 40 8. Review of Safety .................................................................................................................... 41 Safety Review Approach ................................................................................................ 41 Review of the Safety Database ...................................................................................... 41 Overall Exposure ..................................................................................................... 41 Relevant Characteristics of the Safety Populations ................................................ 43 Adequacy of the Safety Database ........................................................................... 44 Adequacy of Applicant’s Clinical Safety Assessments .................................................... 44 Issues Regarding Data Integrity and Submission Quality ....................................... 44 Categorization of Adverse Events ........................................................................... 44 Routine Clinical Tests .............................................................................................. 44 Safety Results ................................................................................................................. 44 Deaths ..................................................................................................................... 44 Serious Adverse Events ........................................................................................... 47 Dropouts and/or Discontinuations Due to Adverse Effects ................................... 48 Significant Adverse Events ...................................................................................... 49 Treatment-Emergent Adverse Events and Adverse Reactions ............................... 49 Laboratory Findings ................................................................................................ 53 Vital Signs ................................................................................................................ 54 Electrocardiograms / QT ......................................................................................... 54 Immunogenicity ...................................................................................................... 54 Safety Analyses by Demographic Subgroups ................................................................. 55 Analysis of Submission-Specific Safety Issues ................................................................ 55 Peripheral Neuropathy ........................................................................................... 55 Neutropenia and Infections .................................................................................... 57 Other AESIs ............................................................................................................. 58 Specific Safety Studies / Clinical Trials ........................................................................... 61 Additional Safety Explorations ....................................................................................... 61 Human Carcinogenicity or Tumor Development .................................................... 61 Human Reproduction and Pregnancy ..................................................................... 61 3 Reference ID: 44400814446194 BLA 761121 Clinical Review Yvette Kasamon, MD Polivy (polatuzumab vedotin-piiq) Pediatrics and Assessment of Effects on Growth ................................................... 61 Overdose, Drug Abuse Potential, Withdrawal, and Rebound ................................ 62 Safety in the Postmarket Setting.................................................................................... 62 Safety Concerns Identified Through Postmarket Experience ................................. 62 Expectations on Safety in the Postmarket Setting ................................................. 62 Additional Safety Issues from Other Disciplines ..................................................... 62 Integrated Assessment of Safety ................................................................................ 62 9. Advisory Committee Meeting and Other External Consultations ......................................... 63 10. Labeling Recommendations .................................................................................................. 63 Prescription Drug Labeling ........................................................................................