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LBA-4 Efficacy and Safety Results from ASCEMBL, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, vs Bosutinib (BOS) in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Previously Treated with ≥2 Tyrosine Kinase Inhibitors (TKIs

Program: General Sessions
Session: Late-Breaking Abstracts Session
Hematology Disease Topics & Pathways:
Adult, Diseases, CML, Study Population, Myeloid Malignancies, Clinically relevant
Tuesday, December 8, 2020, 7:00 AM-9:00 AM

Andreas Hochhaus, MD1, Carla Boquimpani, MD2*, Delphine Rea, MD, PhD3, Yosuke Minami, MD, PhD4, Elza Lomaia, MD, PhD5*, Sergey Voloshin, MD, PhD6*, Anna G. Turkina, Prof., MD7, Dong-Wook Kim, MD8, Jane Apperley, FRCP, FRCPath, MB 9, Jorge E. Cortes, MD10, Andre Abdo, MD11*, Laura Maria Fogliatto, MD, PhD12, Dennis Dong Hwan Kim, MD, PhD13*, Philipp D le Coutre, MD14, Susanne Saussele, MD15, Mario Annunziata, MD16*, Timothy P. Hughes, MD, MBBS, FRACP, FRCPA17, Naeem A. Chaudhri, MD18, Lynette C.Y. Chee, MBBS, PhD, FRACP, FRCPA19, Valentín García Gutiérrez, MD, PhD20, Koji Sasaki, MD21, Paola Aimone, MD22*, Alex Allepuz, MD, MPH23*, Sarah Quenet24*, Véronique Bédoucha24* and Michael J. Mauro, MD25

1Klinik für Innere Medizin II, Jena, Germany
2HEMORIO, State Institute of Hematology Arthur de Siquiera Cavalcanti, Rio de Janeiro, Brazil
3Hopital Saint Louis, Paris, France
4National Cancer Center Hospital East, Kashiwa, Japan
5Institute of Hematology, Almazov National Medical Research Centre, St. Petersburg, Russian Federation
6Russian Research Institute of Hematology and Transfusiology, Saint Petersburg, Russian Federation
7National Research Center for Hematology, Moscow, Russian Federation
8Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of (South)
9Centre for Haematology, Department of Medicine, Hammersmith Hospital, Imperial College, London, United Kingdom
10Georgia Cancer Center Augusta University, Augusta, GA
11Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
12Serviço Hematologia e Transplante de Medula Ossea, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
13Princess Margaret Cancer Centre, University of Toronto, Messner Allogeneic Blood and Marrow Transplantation Program, Toronto, ON, Canada
14Charité – Universitätsmedizin Berlin, Berlin, Berlin, Germany
15Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg, Germany
16Hematology Unit, Cardarelli Hospital, Naples, Italy
17Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
18Oncology center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
19Clinical Haematology and Bone Marrow Transplant Service, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, VIC, Australia
20Hematology and Hemotherapy Department, Hospital Universitario Ramón y Cajal, Madrid, Spain
21Department of Leukemia, MD Anderson Cancer Center, Houston, TX
22Novartis Pharma AG, Basel, Switzerland
23Novartis Pharma AG, Basil, NJ, Switzerland
24Novartis Pharma AG, Basil, Switzerland
25Memorial Sloan-Kettering Cancer Center, New York, NY

Introduction: Asciminib, unlike all approved TKIs that bind to the ATP site of the BCR-ABL1 oncoprotein, is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with a new mechanism of action. BOS, an ATP-competitive TKI, has shown clinical efficacy in pts who received ≥2 TKIs and in newly diagnosed CML, in prospective clinical trials. We asked if asciminib could provide superior efficacy to BOS beyond 2nd line, based on the clinical activity of asciminib monotherapy in heavily pretreated pts with CML in a phase 1 study.

Methods: Adults with CML-CP previously treated with ≥2 TKIs were randomized 2:1 to asciminib 40 mg twice daily (BID) or BOS 500 mg once daily (QD). Randomization was stratified by major cytogenetic response (MCyR; Ph+ metaphases ≤35%) status at baseline. Pts intolerant of their most recent TKI were eligible if they had BCR-ABL1IS >0.1% at screening (19 pts with BCR-ABL1IS <1% enrolled). Pts with treatment failure (per 2013 European LeukemiaNet recommendations) on BOS are permitted to switch to asciminib per investigator judgement. Pts with known bosutinib-resistant T315I or V299L mutations were excluded. The primary endpoint was major molecular response (MMR) rate at 24 wks. We report primary efficacy and safety results from ASCEMBL (cutoff: May 25, 2020).

Results: A total of 233 pts with CML-CP was randomized to receive asciminib 40 mg BID (n=157) or BOS 500 mg QD (n=76). Fewer pts on asciminib discontinued their last TKI due to lack of efficacy and fewer received ≥3 prior lines of TKI therapy (Table 1). At cutoff, treatment was ongoing in 97 (61.8%) and 23 (30.3%) pts, respectively; the most common reason for treatment discontinuation was lack of efficacy (asciminib, 33 [21.0%] pts; BOS, 24 [31.6%]) (Table 1). Lack of efficacy was most frequently BCR-ABL1 >10% or Ph+ >65% after 6 months of therapy (asciminib 10.8%, BOS 25.0%). Among the 24 pts who discontinued BOS due to lack of efficacy, 22 switched to asciminib. At baseline, ≥1 BCR-ABL1 mutation was present in 12.7% pts on asciminib (most common: F359C/V) and 17.1% on BOS (most common: M244V, F317L). Median duration of follow-up was 14.9 months from randomization to cutoff. Median duration of exposure was 43.4 wks (range, 0.1-129.9) for asciminib and 29.2 wks (range, 1.0-117.0) for BOS; median relative dose intensity was 99.7% (87-100) and 95.4% (74-100).

MMR rate at 24 wks was 25.5% with asciminib and 13.2% with BOS, meeting the primary objective. The between-arm common treatment difference for MMR at 24 wks, after adjustment for MCyR status at baseline, was 12.2% (95% CI, 2.19-22.3: 2-sided P=.029). Among those pts who achieved MMR, median time to MMR was 12.7 wks and 14.3 wks with asciminib and BOS, respectively. At 24 wks, more pts on asciminib (17 [10.8%] and 14 [8.9%]) than on BOS (4 [5.3%] and 1 [1.3%]) achieved deep molecular response (MR4 and MR4.5, respectively). CCyR rate at 24 wks was 40.8% with asciminib vs 24.2% with BOS. Preplanned subgroup analysis showed that the MMR rate at 24 wks was superior with asciminib than BOS across most major demographic and prognostic subgroups, including in pts who received ≥3 prior TKIs, in those who discontinued the prior TKI due to treatment failure, and regardless of baseline cytogenetic response (Figure).

Grade ≥3 adverse events (AEs) occurred in 50.6% and 60.5% of pts receiving asciminib and BOS, respectively. The proportion of pts who discontinued treatment due to AEs was lower with asciminib (5.8%) than BOS (21.1%). Grade ≥3 AEs and AEs requiring dose interruption and/or adjustments were reported less frequently with asciminib than BOS (Table 2). Most frequent grade ≥3 AEs (occurring in >10% of pts in any treatment arm) with asciminib vs BOS were thrombocytopenia (17.3%; 6.6%), neutropenia (14.7%; 11.8%), diarrhea (0%, 10.5%), and increased alanine aminotransferase (0.6%, 14.5%). On-treatment deaths occurred in 2 pts (1.3%) on asciminib (ischemic stroke and arterial embolism, 1 pt each) and 1 pt (1.3%) on BOS (septic shock).

Conclusions: In this first controlled study comparing treatments for resistant/intolerant (R/I) pts with CML, asciminib, a first-in-class STAMP inhibitor, demonstrated statistically significant and clinically meaningful superiority in efficacy compared with BOS (primary objective), deeper MR rates, and a favorable safety profile. These results support the use of asciminib as a new treatment option in CML, particularly in R/I pts who received ≥2 prior TKIs.

Disclosures: Hochhaus: Novartis: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding. Boquimpani: Novartis: Speakers Bureau. Rea: BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Minami: Pfizer Japan Inc.: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria. Lomaia: Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Voloshin: Novartis: Honoraria, Speakers Bureau. Turkina: Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria. Kim: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Sun Pharma.: Research Funding. Apperley: Bristol Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Cortes: Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Immunogen: Research Funding; Merus: Research Funding; Sun Pharma: Research Funding. Abdo: Novartis: Honoraria; Takeda: Honoraria. Kim: Paladin: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Research Funding. le Coutre: Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Saussele: Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria. Hughes: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chee: Novartis: Other: Travel support for attendance at investigator meeting. García Gutiérrez: Novartis Pharma AG: Consultancy, Honoraria, Other: travel/accommodations/expenses, Research Funding; Pfizer: Honoraria, Other: travel/accommodations/expenses, Research Funding; Incyte: Consultancy, Honoraria, Other: travel/accommodations/expenses, Research Funding. Sasaki: Pfizer Japan: Consultancy; Otsuka: Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Aimone: Novartis: Current Employment. Allepuz: Novartis: Current Employment. Quenet: Novartis: Current Employment. Bédoucha: Novartis: Current Employment. Mauro: Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Sun Pharma/SPARC: Research Funding.