PTJA16 – Core Submission Dossier Venetoclax in combination with a hypomethylating agent for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy Submitted by: AbbVie Contact details for administrative purposes Name of contact person: Martha Skup Email address: [email protected] For agency completion Date of receipt: 26 April 2021 (initial dossier received on 9 December 2020). Telephone number: Version 2: Amended dossier after Grace Period to reflect changes Emailin CHMP address: opinion Identifier: PTJA16 Disclaimer: The sole responsibility for the content of this document lies with the submitting manufacturer and neither the European Commission nor EUnetHTA are responsible for any use that may be made of the information contained therein. PTJA16 – Core Submission Dossier for Venetoclax in combination w ith an hypomethylating agent for the treatment of adult patients w ith new ly diagnosed acute myeloid leukaemia (AML) w ho are ineligible for intensive chemotherapy Submitted by: AbbVie DOCUMENT HISTORY Version Date Description V0.1 08/12/20 Initial Core Submission Dossier V0.2 08/01/21 Updated Core Submission Dossier based on Missing Items V0.3 26/04/21 Amended Core Submission Dossier following CHMP opinion (grace period) V1.0 DD/MM/YY Publication of final version (editorial changes only) 2 © All Rights Reserved. PTJA16 – Core Submission Dossier for Venetoclax in combination w ith an hypomethylating agent for the treatment of adult patients w ith new ly diagnosed acute myeloid leukaemia (AML) w ho are ineligible for intensive chemotherapy Submitted by: AbbVie LIST OF ABBREVIATIONS AE Adverse event ALT Alanine aminotransferase AML Acute myeloid leukaemia ara-C Cytarabine ASCO American Society of Clinical Oncology ASH American Society of Hematology AST Aspartate transaminase BCL-2 B-cell lymphoma 2 BSC Best supportive care BSH British Society for Haematology CAG Cytarabine, aclarubicin, G-CSF CCR Conventional care regimens CDSR Cochrane Database of Systematic Reviews CENTRAL Cochrane Central Register of Controlled Trials CHF Congestive heart failure CHMP Committee for Medicinal Products for Human Use CI Confidence interval CLL Chronic lymphocytic leukaemia CML Chronic myeloid leukaemia CNS Central nervous system CONSORT Consolidated Standards of Reporting Trials CR Complete response CRD Centre for Reviews and Dissemination CRh Complete response with partial haematological recovery CRi Complete response with incomplete bone marrow recovery CT Computerised tomography CTCAE Common Terminology Criteria for Adverse Events DARE Database of Abstracts of Reviews of Effects DLCO Diffusing capacity of the lungs for carbon monoxide ECOG Eastern Cooperative Oncology Group EFS Event-free survival EHA European Haematology Association ELN European LeukemiaNet EMA European Medicines Agency EORTC QLQ-C30 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 EQ-5D-5L EuroQol 5-dimension 5-level questionnaire ESMO European Society for Medical Oncology EUnetHTA European Network for Health Technology Assessment FAB French-American-British system FDA Food and Drug Administration FEV1 Forced expiratory volume in one second GHS/QoL Global health status/quality of life 3 © All Rights Reserved. PTJA16 – Core Submission Dossier for Venetoclax in combination w ith an hypomethylating agent for the treatment of adult patients w ith new ly diagnosed acute myeloid leukaemia (AML) w ho are ineligible for intensive chemotherapy Submitted by: AbbVie HBV Hepatitis B virus HCV Hepatitis C virus HIV Human immunodeficiency virus HMA Hypomethylating agent HR Hazard ratio HRQL Health-related quality of life HSCT Hematopoietic stem cell transplant HTA Health technology assessment IC Intensive chemotherapy ICD-10 International Classification of Diseases Version 10 IPD Individual patient data IRC Independent review committee IRT Interactive response technology ITC Indirect treatment comparison ITT Intent to treat IV Intravenous IVRS Interactive voice response system IWG International Working Group LDAC Low-dose cytarabine MCL-1 Myeloid cell leukaemia 1 MDS Myelodysplastic syndrome MEC Mitoxantrone, etoposide, and cytarabine MedDRA Medical dictionary for regulatory activities MFC Multicolour flow cytometry MLFS Morphological leukaemia-free state MPN Myeloproliferative neoplasms MR Minor response MRC Myelodysplasia-related changes MRD Minimal/measurable residual disease NCCN National Comprehensive Cancer Network NCI National Cancer Institute NICE National Institute for Health and Care Excellence NMA Network meta-analysis OR Odds ratio OS Overall survival PD Progressive disease PFS Progression-free survival PICO Population, intervention, comparator, outcome PR Partial response PRISMA Preferred Reporting Items for Systematic Reviews and Meta-analyses PRO Patient-reported outcome PROMIS Patient-reported Outcomes Measurement Information System PSW Propensity score weighting RAEB-t Refractory anaemia with excess blasts in transformation 4 © All Rights Reserved. PTJA16 – Core Submission Dossier for Venetoclax in combination w ith an hypomethylating agent for the treatment of adult patients w ith new ly diagnosed acute myeloid leukaemia (AML) w ho are ineligible for intensive chemotherapy Submitted by: AbbVie RBC Red blood cells RCT Randomised-controlled trial RFS Relapse-free survival R/R Relapsed/refractory SAE Serious adverse event SC Subcutaneous SD Stable disease SLL Small lymphocytic leukaemia SLR Systematic literature review SMC Scottish Medicines Consortium TC Treatment choice TLS Tumour lysis syndrome TTD Time to deterioration ULN Upper limit of normal WHO World Health Organization 5 © All Rights Reserved. PTJA16 – Core Submission Dossier for Venetoclax in combination w ith an hypomethylating agent for the treatment of adult patients w ith new ly diagnosed acute myeloid leukaemia (AML) w ho are ineligible for intensive chemotherapy Submitted by: AbbVie TABLE OF CONTENTS DOCUMENT HISTORY ..................................................................................................................2 LIST OF ABBREVIATIONS ............................................................................................................3 TABLE OF CONTENTS .................................................................................................................6 LIST OF TABLES ..........................................................................................................................8 LIST OF FIGURES....................................................................................................................... 10 EXECUTIVE SUMMARY .............................................................................................................. 11 1 DESCRIPTION AND TECHNICAL CHARACTERISTICS OF THE TECHNOLOGY .................... 15 1.1 SUMMARY OF THE CHARACTERISTICS OF THE TECHNOLOGY ....................................................... 15 1.2 CHARACTERISTICS OF THE TECHNOLOGY ................................................................................ 15 1.3 REGULATORY STATUS OF THE TECHNOLOGY ............................................................................ 17 2 HEALTH PROBLEM AND CURRENT CLINICAL PRACTICE .................................................. 19 2.1 SUMMARY OF ISSUES RELATING TO THE HEALTH PROBLEM AND CURRENT CLINICAL PRACTICE .......... 19 2.2 OVERVIEW OF THE DISEASE OR HEALTH CONDITION .................................................................. 19 2.3 TARGET POPULATION........................................................................................................... 25 2.4 CLINICAL MANAGEMENT OF THE DISEASE OR HEALTH CONDITION ................................................. 27 3 COMPARATORS IN THE ASSESSMENT ............................................................................... 34 3.1 CHOICE OF COMPARATORS ................................................................................................... 34 3.2 COMPARATOR PIVOTAL TRIALS .............................................................................................. 34 3.3 LIMITATIONS OF CLINICAL EVIDENCE FOR COMPARATORS ........................................................... 36 4 CURRENT USE OF THE TECHNOLOGY................................................................................ 37 4.1 SUMMARY OF ISSUES RELATING TO CURRENT USE OF THE TECHNOLOGY ...................................... 37 4.2 CURRENT USE OF THE TECHNOLOGY IN EUNETHTA COUNTRIES ................................................. 37 4.3 REIMBURSEMENT AND ASSESSMENT STATUS OF THE TECHNOLOGY ............................................. 38 5 INVESTMENTS AND TOOLS REQUIRED............................................................................... 39 5.1 SUMMARY OF ISSUES RELATING TO THE INVESTMENTS AND TOOLS REQUIRED TO INTRODUCE THE TECHNOLOGY ..................................................................................................................... 39 6 REQUIREMENTS TO USE THE TECHNOLOGY ..................................................................... 40 6.1 ADDITIONAL EQUIPMENT ....................................................................................................... 40 6.2 SUPPLIES REQUIRED TO USE THE TECHNOLOGY ....................................................................... 41 7 CLINICAL EFFECTIVENESS AND SAFETY ..........................................................................