FDA Briefing Document Cellular, Tissue, and Gene Therapies Advisory Committee and Oncologic Drugs Advisory Committee Meeting April 29, 2015 BLA 125518 talimogene laherparepvec (Amgen) BLA 125518 Talimogene laherparepvec CTGTAC / ODAC Briefing Document Amgen DISCLAIMER STATEMENT The attached package contains background information prepared by the Food and Drug Administration (FDA) for the members of the advisory committee. The FDA background package often contains assessments, conclusions, and recommendations written by individual FDA reviewers. Such conclusions and recommendations do not necessarily represent the final position of the individual reviewers, nor do they necessarily represent the final position of the Review Division or Office. We bring the talimogene laherparepvec BLA with the Applicant's proposed indication to this Advisory Committee to gain the Committee’s insights and opinions. The background package may not include all issues relevant to the final regulatory recommendation and instead is intended to focus on issues identified by the Agency for discussion by the Advisory Committee. The FDA will not issue a final determination on the issues at hand until input from the Advisory Committee process has been considered and all reviews have been finalized. The final determination may be affected by issues not discussed at the Advisory Committee meeting. Page 2 BLA 125518 Talimogene laherparepvec CTGTAC / ODAC Briefing Document Amgen Table of Contents Glossary ······················································································································································· 8 1 Purpose of Advisory Committee Meeting ·································································································· 11 1.1 Assessment of Benefits and Risks ··············································································································· 11 1.1.1 Benefits ·················································································································································· 11 1.1.2 Safety ····················································································································································· 12 1.1.3 Patient Population ·································································································································· 12 1.2 Dosing ························································································································································ 12 1.3 Shedding and Pharmacovigilance ·············································································································· 12 1.4 Overall benefit-risk profile ························································································································· 13 2 Melanoma ··················································································································································· 13 2.1 Melanoma Overview ·································································································································· 13 2.2 Treatment of Unresectable Stage III, Stage IV, and Recurrent Melanoma ················································ 14 3 Product Description ··································································································································· 16 3.1 Oncolytic HSV ············································································································································ 16 3.2 Talimogene Laherparepvec ························································································································ 17 3.3 Proposed Mechanism of Action (MOA) ····································································································· 18 3.4 Virus Biodistribution ·································································································································· 18 4 Study 005/05 ··············································································································································· 18 4.1 Trial Design ··············································································································································· 18 4.2 Objectives ··················································································································································· 19 4.3 Major Eligibility Criteria ··························································································································· 19 4.3.1 Inclusion Criteria: ·································································································································· 19 4.3.2 Exclusion Criteria: ································································································································· 20 4.4 Treatment and Study Drug Administration Schedule ················································································· 20 4.4.1 Talimogene Laherparepvec Treatment Group ······················································································· 20 4.4.2 Control (GM-CSF) Group ····················································································································· 21 4.4.3 Treatment in the Presence of New Lesions and Progressive Disease ···················································· 21 4.5 Study and Treatment Duration ··················································································································· 21 4.6 Trial Endpoints and Analyses ···················································································································· 22 4.6.1 Trial Endpoints ······································································································································ 24 4.6.2 Primary Endpoint Evaluation ················································································································· 24 4.6.2.1 Patient Assessments ······················································································································ 24 Page 3 BLA 125518 Talimogene laherparepvec CTGTAC / ODAC Briefing Document Amgen 4.6.2.2 Lesion Definition ··························································································································· 24 4.6.2.3 Lesion Assessments ······················································································································· 24 4.6.2.3.1 Measurable Lesions ················································································································· 27 4.6.2.3.2 Non-measurable Lesions ·········································································································· 27 4.6.2.4 Evaluation of Overall Melanoma Response to the Treatment ······················································· 28 4.6.3 Primary Endpoint: Durable Response Rate ··························································································· 28 4.6.4 Secondary Endpoint: Overall Survival ·································································································· 29 4.6.5 Additional Secondary and Exploratory Endpoints ················································································· 29 4.7 Statistical Considerations ·························································································································· 29 4.7.1 Randomization ······································································································································· 29 4.7.2 Sample Size ··········································································································································· 29 4.7.3 Analysis of Durable Response Rate (DRR), the Primary Endpoint ······················································· 30 4.7.4 Analysis of Overall Survival (OS) ········································································································· 30 4.7.5 Interim Analysis ····································································································································· 30 4.7.6 Analysis Population ······························································································································· 31 5 Study 005/05 Population and Subject Disposition ····················································································· 31 5.1 Study Populations ······································································································································ 31 5.2 Subject Characteristics ······························································································································ 32 5.3 Subject Disposition····································································································································· 34 5.4 Study Conduct ············································································································································ 35 5.4.1 Duration of Response Assessment ·········································································································