Mylotarg FDA ODAC Briefing Document 11 July 2017 WYETH PHARMACEUTICALS INC., A SUBSIDIARY OF PFIZER INC MYLOTARG (gemtuzumab ozogamicin; PF-05208747) In combination with chemotherapy for the treatment of previously untreated de novo CD33-positive acute myeloid leukemia and as monotherapy for the treatment of CD33-positive acute myeloid leukemia in first relapse FDA ONCOLOGIC DRUGS ADVISORY COMMITTEE BRIEFING DOCUMENT (BLA 761060) Meeting Date: 11 July 2017 ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE 090177e18c1aa788\Approved\Approved On: 12-Jun-2017 13:05 (GMT) Page 1 Mylotarg FDA ODAC Briefing Document 11 July 2017 TABLE OF CONTENTS TABLE OF CONTENTS...........................................................................................................2 LIST OF TABLES.....................................................................................................................5 LIST OF FIGURES ...................................................................................................................6 1. EXECUTIVE SUMMARY .................................................................................................7 1.1. Introduction..............................................................................................................7 1.2. Rationale for Mylotarg Dosing Regimens ...............................................................8 1.3. Mylotarg in Patients With Previously Untreated De Novo AML............................9 1.4. Mylotarg in Patients With AML in First Relapse..................................................11 1.5. Summary................................................................................................................12 2. BACKGROUND AND TREATMENT LANDSCAPE....................................................12 2.1. Regulatory History.................................................................................................15 2.2. Mylotarg Clinical Trial Experience .......................................................................16 3. CLINICAL PHARMACOLOGY OF MYLOTARG ........................................................17 3.1. Dose/Pharmacodynamic Relationships..................................................................18 4. PHARMACOKINETIC AND EXPOSURE-RESPONSE MODELING..........................18 4.1. Pharmacokinetic Modeling ....................................................................................18 4.2. Exposure-Response Modeling ...............................................................................18 4.2.1. Effect of Dose on Efficacy........................................................................18 4.2.2. Effect of Dose on Hepatotoxicity and VOD .............................................19 4.2.3. Effect of Dose on Myelosuppression ........................................................20 4.2.4. Exposure-Response Model Summary.......................................................21 5. MYLOTARG IN PATIENTS WITH PREVIOUSLY UNTREATED AML....................21 5.1. Efficacy in Patients With Previously Untreated AML ..........................................21 5.1.1. Study SWOG S0106 .................................................................................21 5.1.2. ALFA-0701 Study.....................................................................................22 5.1.2.1. Study Objectives and Design ..................................................22 5.1.2.2. Appropriateness of EFS as the Primary Efficacy Endpoint in AML Studies .......................................................23 5.1.2.3. Study Population .....................................................................24 5.1.2.4. Primary Efficacy Endpoint (Event-Free Survival by Investigator Assessment) ........................................................25 5.1.2.5. Secondary Efficacy Endpoints (Relapse-Free Survival, Overall Survival, Overall Response Rate) ..............................29 5.1.2.6. Efficacy Conclusions from the ALFA-0701 Study.................32 090177e18c1aa788\Approved\Approved On: 12-Jun-2017 13:05 (GMT) Page 2 Mylotarg FDA ODAC Briefing Document 11 July 2017 5.1.2.7. Differences in Design and Outcome Between the ALFA- 0701 and SWOG S0106 Studies .............................................32 5.1.3. Individual Patient Data Meta-Analysis .....................................................32 5.1.3.1. Objectives and Design.............................................................32 5.1.3.2. Primary Efficacy Endpoint: Overall Survival .........................35 5.1.3.3. Secondary Efficacy Endpoints ................................................38 5.1.3.4. Efficacy Conclusions from the Individual Patient Data MA ..........................................................................................38 5.1.4. Correlation Between EFS and OS.............................................................39 5.2. Safety in Patients With Previously Untreated AML..............................................40 5.2.1. SWOG S0106 Study .................................................................................40 5.2.2. ALFA-0701 Study.....................................................................................40 5.2.3. Individual Patient Data Meta-Analysis .....................................................45 6. MYLOTARG IN PATIENTS WITH RELAPSED AML .................................................47 6.1. Efficacy in Patients With Relapsed AML..............................................................47 6.1.1. Studies 201, 202, and 203 .........................................................................47 6.1.2. Rationale for Lower Dose Fractionated Regimen.....................................48 6.1.3. MyloFrance 1 ............................................................................................48 6.2. Safety in Patients With Relapsed AML.................................................................49 6.2.1. Studies 201, 202, and 203 .........................................................................49 6.2.2. Myelosuppression (Including Neutropenia and Thrombocytopenia) With Mylotarg Monotherapy ....................................................................50 6.2.3. Veno-Occlusive Disease With Mylotarg Monotherapy............................50 6.2.4. MyloFrance 1 ............................................................................................53 7. RATIONALE FOR PROPOSED DOSING REGIMENS.................................................53 7.1. Rationale for Proposed Dosing Regimen in Patients With Previously Untreated De Novo CD33-Positive AML..............................................................54 7.2. Rationale for Proposed Dosing Regimen in Patients With CD33-Positive AML in First Relapse.............................................................................................54 7.2.1. Dosing Regimen Adjustment for Patients With CD33-Positive AML in First Relapse who Undergo HSCT........................................................55 8. DISCUSSION....................................................................................................................56 8.1. Advantages of the Lower Dose Fractionated Regimen of Mylotarg .....................56 8.2. Benefit/Risk Assessment of the Lower Dose Fractionated Mylotarg Regimen in Previously Untreated De Novo CD33-Positive AML........................56 8.3. Benefit/Risk Assessment of Mylotarg Dosing for the Treatment of CD33- Positive AML in First Relapse...............................................................................57 090177e18c1aa788\Approved\Approved On: 12-Jun-2017 13:05 (GMT) Page 3 Mylotarg FDA ODAC Briefing Document 11 July 2017 9. OVERALL CONCLUSION ..............................................................................................58 10. APPENDICES ...................................................................................................................59 10.1. Abbreviations and Definitions ...............................................................................59 10.2. Overview of the Clinical Studies Included in the BLA .........................................61 10.3. Mylotarg Clinical Trial Experience in Relapsed/Refractory AML .......................64 10.4. Patient Treatment Summary – ALFA-0701...........................................................65 10.5. References..............................................................................................................66 090177e18c1aa788\Approved\Approved On: 12-Jun-2017 13:05 (GMT) Page 4 Mylotarg FDA ODAC Briefing Document 11 July 2017 LIST OF TABLES Table 1. Mylotarg Clinical Trial Experience in Previously Untreated AML .....................17 Table 2. Treatment Outcomes After Induction Chemotherapy – SWOG S0106 ...............22 Table 3. Demographic and Baseline Characteristics (mITT Population) – ALFA-0701...........................................................................................................24 Table 4. Patient Treatment Summary (All Patients) – ALFA-0701...................................25 Table 5. Primary Event-Free Survival Endpoint (mITT Population) – ALFA-0701 .........26 Table 6. Studies Included in the Individual Patient Data Meta-Analysis...........................34 Table 7. Overall Survival – Individual Patient Data Meta-Analysis ..................................35 Table 8. Adverse Events of Special Interest by MedDRA SOC and PT (As-Treated Population) – ALFA-0701....................................................................................41