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475 Asciminib (ASC) Demonstrates Favorable Safety and Tolerability Compared with Each Investigator-Selected Tyrosine Kinase Inhibitor (IS TKI) in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) in the Pivotal Phase 3 ASC4FIRST Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia: Novel Molecules in Clinical Practice
Hematology Disease Topics & Pathways:
Clinical trials, Research, Adult, Clinical Research, CML, Chronic Myeloid Malignancies, Diseases, Myeloid Malignancies, Study Population, Human
Sunday, December 8, 2024: 9:30 AM

Jorge E. Cortes, MD1, Andreas Hochhaus, MD2, Timothy P Hughes, MD, MBBS, FRACP, FRCPA3, Jianxiang Wang, MD4, Dong-Wook Kim, MD, PhD5, Dennis Dong Hwan Kim, MD, PhD6, Jiri Mayer, MD7, Yeow Tee Goh, MD8, Philipp le Coutre, MD9*, Gabriel Etienne, MD, PhD10*, Naoto Takahashi, MD, PhD11, Inho Kim, MD, PhD12*, David Andorsky, MD13, Ghayas C. Issa, MD14, Felice Bombaci15*, Shruti Kapoor16*, Rajendra Jinwal, MD17*, Lillian Yau, PhD18* and Richard Larson, MD19*

1Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA
2Hematology and Medical Oncology, Universitätsklinikum Jena, Jena, Germany
3Precision Cancer Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, Australia
4State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
5Uijeongbu Eulji Medical Center, Geumo-dong, Uijeongbu, Korea, Republic of (South)
6Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
7Internal Medicine Hematology and Oncology, University Hospital Brno and Masaryk University, Brno, Czech Republic
8Department of Haematology, Singapore General Hospital, Singapore, Singapore
9Department of Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany
10Hematology, Institut Bergonié, Bordeaux, France
11Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
12Internal Medicine, Seoul National University Hospital, Seoul, Korea, Republic of (South)
13Rocky Mountain Cancer Centers, Boulder, CO
14Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
15CML Patients Group, CML Advocates Network, Turin, Italy
16Novartis, East Hanover, NJ
17Novartis Healthcare Private Limited, Hyderabad, India
18Novartis Pharma AG, Basel, Switzerland
19University of Chicago, Chicago, IL

Introduction: About 1/3rd of patients (pts) with newly diagnosed CML discontinue/switch treatments (Tx) regardless of TKI (imatinib [IMA], nilotinib [NIL], dasatinib [DAS], or bosutinib [BOS]). Many pts have poor quality of life on existing therapies. Tx-free remission is a key Tx goal, but only 30%-40% pts on IMA and 40%-50% on 2nd-generation (2G) TKIs meet discontinuation criteria. A frontline agent with a superior benefit-risk profile is needed. ASC is the first BCR::ABL1 inhibitor to Specifically Target the ABL Myristoyl Pocket. ASC4FIRST is a randomized phase 3 study of ASC vs all standard-of-care TKIs in newly diagnosed CML-CP. We present primary efficacy results and additional safety/tolerability data for ASC vs each IS TKI from the primary analysis (wk 48) data cutoff. Key secondary results from the wk 96 cutoff (Oct 21, 2024) will be presented at the 2024 ASH Meeting.

Methods: Adults with newly diagnosed CML-CP were stratified by ELTS risk category and TKI (IMA/2G TKIs [NIL, DAS, or BOS]) selected by investigators before randomization, accounting for pt preference. Pts were randomized 1:1 to receive either ASC 80 mg once daily or an IS TKI at label doses. The 2 primary and 2 key secondary efficacy endpoints are major molecular response (MMR) rate at wk 48 and 96, respectively, with ASC vs IS TKI and with ASC vs IS TKI in the IMA stratum; time to Tx discontinuation due to adverse events (AEs) is a secondary safety endpoint.

Results: In ASC4FIRST, 201 pts randomized to ASC and 204 to IS TKIs (IMA/2G TKIs) were included in efficacy analyses. Safety analyses were done in pts who received ASC (n=200), IMA (n=99), and 2G TKIs (NIL, n=49; DAS, n=42; BOS, n=11). At the wk 48 cutoff, after a median duration of follow-up of ≈16 months across study arms, Tx was ongoing in 86%, 62%, and 75% of pts on ASC, IMA, and 2G TKIs, respectively. Both primary objectives were met: MMR rate at wk 48 was superior with ASC (67.7%) vs IS TKIs (49.0%) (difference, 18.9%; 95% CI, 9.6%-28.2%; adjusted 2-sided P<.001) and with ASC (69.3%) vs IMA (40.2%) in the IMA stratum (difference, 29.6%; 95% CI, 16.9%-42.2%; adjusted 2-sided P<.001).

The rates of optimal responses at wk 12 (BCR::ABL1IS ≤10%) and wk 24 (BCR::ABL1IS ≤1%), respectively, were higher with ASC vs IS TKIs (89.6% vs 70.1%; 88.6% vs 63.7%), ASC vs IS TKI in the IMA stratum (88.1% vs 59.8%; 88.1% vs 52.9%), and ASC vs IS TKI in the 2G TKI stratum (91.0% vs 80.4%; 89.0% vs 74.5%).

Safety/tolerability of ASC was more favorable vs IMA and individual 2G TKIs. Grade ≥3 AEs were lower with ASC (38.0%) vs IMA (44.4%), NIL (51.0%), DAS (54.8%), and BOS (72.7%). Any-grade AEs leading to Tx discontinuation were lower with ASC (4.5%) vs IMA (11.1%), NIL (8.2%), DAS (11.9%), and BOS (9.1%), the most frequent (≥2% in any arm) being generalized edema (BOS, 9.1%), pleural effusion (DAS, 4.8%), cardiac failure, colitis, hypersensitivity, and muscular weakness (DAS, 2.4% each), lymphopenia and diarrhea (IMA, 2.0% each), QT prolongation, rash, and maculopapular rash (NIL, 2.0% each), and thrombocytopenia (ASC, 1.0%; NIL, 2.0%). Any-grade AEs leading to dose adjustment and/or interruption were lower with ASC (30.0%) vs IMA (39.4%), NIL (49.0%), DAS (54.8%), and BOS (63.6%). Arterial occlusive events occurred in 2 (1.0%) pts with ASC (arteriosclerosis coronary artery, n=1; cerebrovascular accident, n=1), 1 (1.0%) with NIL (vertebral artery arteriosclerosis), and 1 (1.0%) with DAS (myocardial infarction and ischemia). Two pts had cardiac failure with DAS.

Any-grade AEs of special interest (≥5% in any arm), defined as serious or nonserious safety events of medical concern, were lower with ASC vs IMA and/or 2G TKIs and included gastrointestinal toxicity (34.5%, 42.4%, 48.0%), myelosuppression (43.0%, 51.5%, 62.7%), hypersensitivity (24.0%, 41.4%, 41.2%), hepatotoxicity (16.5%, 19.2%, 34.3%), acute pancreatitis (isolated enzyme elevations) (13.0%, 16.2%, 14.7%), hemorrhage (6.0%, 7.1%, 9.8%), edema and fluid retention (3.5%, 13.1%, 11.8%), and ischemic heart and CNS conditions (6.0%, 5.1%, 7.8%).

Conclusions: In ASC4FIRST, ASC had a better benefit-risk profile compared with IS TKIs. ASC’s superior efficacy vs all IS TKIs and more favorable safety/tolerability compared with each IS TKI (IMA, NIL, DAS, and BOS) suggests that ASC may transform the CML Tx paradigm. Key secondary endpoints, including MMR rate at wk 96, and other long-term secondary efficacy and safety/tolerability results, will be presented at ASH 2024.

Disclosures: Cortes: Biopath Holdings: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Ascentage: Research Funding; Rigel: Consultancy; Lilly: Consultancy; Nerviano: Consultancy; Syndax: Consultancy; AbbVie: Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding. Hochhaus: Terns: Honoraria, Other: Advisory Board; Novartis: Honoraria, Other: Advisory Board, Research Funding; Enliven: Honoraria, Other: Advisory Board. Hughes: Ariad: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Wang: AbbVie: Membership on an entity's Board of Directors or advisory committees. Kim: Korea Otsuka: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Enliven: Honoraria, Research Funding; Il-Yang: Honoraria, Research Funding, Speakers Bureau; Pharmaessencia: Research Funding; BMS: Honoraria, Research Funding, Speakers Bureau. Kim: Ascentage: Consultancy; Pfizer: Honoraria, Research Funding; Paladin: Honoraria, Research Funding; Novartis: Honoraria, Other: Advisory board, Research Funding. Mayer: Novartis: Research Funding; Merck & Co., Inc., Rahway, NJ, USA: Research Funding; AOP Health: Research Funding; AstraZeneca: Research Funding. Goh: Roche: Honoraria; Astellas: Honoraria; MSD: Honoraria; EUSA Pharma: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Johnson & Johnson: Consultancy, Honoraria; Antengene: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; AbbVie: Honoraria; NS Pharma: Consultancy. le Coutre: AOP: Honoraria; Novartis: Honoraria; Incyte: Honoraria; Blueprint: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Takahashi: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Otsuka: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas: Research Funding; Asahi Kasei: Research Funding; Ono: Research Funding. Andorsky: AbbVie: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; AstraZeneca: Research Funding; Novartis: Research Funding. Issa: Merck: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Astex: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; NuProbe: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Kura Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Celgene: Research Funding; Syndax Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees. Bombaci: MPN Advocates Network: Membership on an entity's Board of Directors or advisory committees, Other: Organizational grant funding; AIL – Associazione Italiana contro le Leucemie, i Linfomi e il Mieloma ONLUS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Organizational grant funding; Menarini Stemline: Other: Organizational grant funding; CLL Advocate Network: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Organizational grant funding; Novartis: Consultancy, Other: Organizational grant funding; Roche: Other: Organizational grant funding; Sanofi: Other: Organizational grant funding; GSK: Other: Organizational grant funding; CML Advocates Network: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Organizational grant funding; Astrazeneca: Other: Organizational grant funding; Takeda: Other: Organizational grant funding. Kapoor: Novartis: Current Employment. Jinwal: Novartis: Current Employment. Yau: Novartis Pharma AG: Current Employment. Larson: Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; CVS/Caremark: Consultancy; Gilead: Research Funding; Astellas: Consultancy, Research Funding; Epizyme: Consultancy; Rafael Pharmaceuticals: Research Funding; Cellectis: Research Funding.

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*signifies non-member of ASH