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3114 Efficacy and Safety of Nemtabrutinib, a Wild-Type and C481S-Mutated Bruton Tyrosine Kinase Inhibitor for B-Cell Malignancies: Updated Analysis of the Open-Label Phase 1/2 Dose-Expansion Bellwave-001 Study

Program: Oral and Poster Abstracts
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Research, Clinical Research, Diseases, Lymphoid Malignancies, Human, Study Population
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Jennifer A. Woyach, MD1, Ian W. Flinn, MD PhD2, Farrukh T. Awan, M.D.3, Herbert Eradat, MD4, Danielle Brander, MD5, Michael Tees, MD, MPH6, Sameer A. Parikh, MD7, Tycel J. Phillips, MD8, Razi Ghori9*, Nishitha M. Reddy, MD9*, Mohammed Z.H. Farooqui, DO9, John C. Byrd, MD10 and Deborah M. Stephens, DO11

1The Ohio State University, Columbus, OH
2Sarah Cannon Research Institute, Nashville, TN
3University of Texas Southwestern Medical Center, Dallas, TX
4David Geffen School of Medicine at UCLA, Los Angeles, CA
5Duke University, Duke PDC, Durham, NC
6Colorado Blood Cancer Institute, Denver, CO
7Mayo Clinic, Rochester, MN
8University of Michigan Rogel Cancer Center, Ann Arbor, MI
9Merck & Co., Inc., Rahway, NJ
10University of Cincinnati College of Medicine, Cincinnati, OH
11University of Utah Huntsman Cancer Institute, Salt Lake City, UT

Background: Bruton tyrosine kinase inhibitors (BTKis) have transformed the treatment landscapes of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and certain B-cell neoplasms. However, the most common mechanism of resistance is due to mutations to BTK at the cysteine binding site (C481). Nemtabrutinib (MK-1026, formerly ARQ-531) is a noncovalent, potent inhibitor of both wild-type and ibrutinib-resistant C481S-mutated BTK. Initial results from the phase 1/2 BELLWAVE-001 study (NCT03162536) showed nemtabrutinib had a manageable safety profile and promising antitumor activity in heavily pretreated patients (pts) with relapsed or refractory (R/R) CLL/SLL, including pts whose disease progressed after prior covalent BTKis (Woyach et al. Blood. 2021;138:392). We present updated efficacy for all pts with CLL/SLL treated with nemtabrutinib 65 mg and safety for all pts with hematological malignancies who were treated with nemtabrutinib at the 65-mg dose.

Methods: In this open-label, single-arm, phase 1/2 study, 9 expansion cohorts were initiated after determination of the preliminary nemtabrutinib recommended phase 2 dose (RP2D). Eligible pts with CLL/SLL were enrolled in cohort A (R/R CLL/SLL, with ≥2 prior therapies, including covalent BTKis, with documented C481 mutation), cohort B (R/R CLL/SLL with ≥2 prior therapies, intolerant to a BTKi, without C481 mutation), a dose-expansion group, or cohort I (food effect). Primary end points were ORR (per 2018 IWCLL criteria, by investigator), safety, and RP2D for pts with CLL/SLL. Secondary end points were DOR (including partial response [PR] with lymphocytosis), PFS, and safety. Efficacy analysis included CLL/SLL pts treated with nemtabrutinib 65-mg once-daily dose and safety included all pts with hematological malignancies who were treated with the nemtabrutinib 65-mg dose.

Results: A total of 112 pts were enrolled and were treated with nemtabrutinib 65 mg once daily: 57 had CLL/SLL, 46 had B-cell non-Hodgkin lymphoma (NHL), 6 had Waldenstrom’s macroglobulinemia, and 3 had a diagnosis of “other.” Among the 57 pts with CLL/SLL enrolled and treated with nemtabrutinib 65 mg (cohort A, n = 25; cohort B, n = 10; dose escalation, n = 13; cohort I, n = 9); median age was 66.0 years; 16 pts (28%) were female, and 50 (88%) had ECOG PS ≤1. Median (range) number of prior therapies was 4 (1-18); 54 pts (95%) had prior BTKi therapy; 24 (42%) had prior BTKi and BCL2i therapy. In addition, 36 pts (63%) had C481S-mutated BTK; 18 (32%) had TP53 mutation; 19 (33%) had del(17p); and 30 (53%) had unmutated IGHV. Of pts with CLL/SLL, 39 (68%) discontinued, most commonly because of clinical disease progression [PD] and “other” causes (10 [18%] each); 8 (14%) discontinued owing to adverse events (AEs). Among the 24 pts with CLL/SLL who received prior BTKis and BCL-2is, 19 (33%) discontinued, most commonly because of clinical PD and other causes (6 [11%] each) and AEs (4 [7%]).

At data cutoff (April 08, 2022), median (range) follow-up for pts with CLL/SLL was 8.1 months (0.1-38.8); 32 pts had objective response (ORR, 56% [95% CI, 42-69]; complete response, 2; PR, 15; PR with residual lymphocytosis, 15). Among the 32 pts who responded, median DOR was 24.4 months (95% CI, 13.9-not evaluable [NE]); median PFS was 26.3 months (95% CI, 10.1-NE). Efficacy by key subgroups is presented in the table. Among all pts with B-cell malignancies treated with nemtabrutinib at the 65-mg dose (N = 112) included in the safety analysis, 82 (73%) had any-grade treatment-related AEs (TRAEs), most common (≥10%) were dysgeusia (21%); decreased neutrophils (20%); fatigue (13%); nausea and decreased platelets (12%, each); and diarrhea and hypertension (10%, each). Grade 3 or 4 TRAEs occurred in 45 pts (40%); most common (≥5%) were decreased neutrophils (17%) and decreased platelets and lymphocytosis (5%, each). Treatment-related discontinuations occurred in 15 pts (13%). No deaths were attributed to treatment.

Conclusion: Nemtabrutinib 65 mg continued to show promising and durable antitumor activity with a manageable safety profile in a highly relapsed/refractory population who had prior therapy with novel agents.

Disclosures: Woyach: AbbVie: Consultancy, Research Funding; Loxo@Lilly: Research Funding; Karyopharm Therapeutics: Research Funding; AstraZeneca: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Newave: Consultancy; MorphoSys: Consultancy, Research Funding; Schrodinger: Research Funding; ArQule: Consultancy; Pharmacyclics: Consultancy; BeiGene: Consultancy. Flinn: Genmab: Consultancy; Janssen: Consultancy, Research Funding; InnoCare Pharma: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Bristol Myers Squibb: Research Funding; CALIBR: Research Funding; CALGB: Research Funding; Gilead Sciences: Research Funding; Pfizer: Research Funding; Portola Pharmaceuticals: Research Funding; Merck: Research Funding; Loxo@Lilly: Research Funding; Infinity Pharmaceuticals: Research Funding; Incyte: Research Funding; Roche: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Nurix Therapeutics: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Biopath: Research Funding; Rhizen Pharmaceuticals: Research Funding; Trillium Therapeutics: Research Funding; Kite Pharma: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Myeloid Therapeutics: Research Funding; Secura Bio: Consultancy; Xencor: Consultancy; Hutchison MediPharma: Consultancy; 2seventy bio: Research Funding; Triphase Research & Development Corp: Research Funding; TCR2 Therapeutics: Research Funding; Tessa Therapeutics: Research Funding; Millenium Pharmaceuticals: Research Funding; Fate Therapeutics: Research Funding; Epizyme: Research Funding; CTI Biopharma: Research Funding; City of Hope National Medical Center: Research Funding; ArQule: Research Funding; Agios: Research Funding; Verastem: Consultancy, Research Funding; Vincerx Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; Curis: Research Funding; Forma Therapeutics: Research Funding; Servier Pharmaceuticals: Consultancy; Takeda: Consultancy; TG Therapeutics: Consultancy, Research Funding; Unum Therapeutics: Research Funding; Forty Seven: Research Funding; IGM Biosciences: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Constellation Pharmaceuticals: Research Funding; Genentech: Consultancy, Research Funding; Century Therapeutics: Consultancy; BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. Awan: Verastem: Consultancy; Kite Pharma: Consultancy; Karyopharm: Consultancy; MEI Pharma: Consultancy; Celgene: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy, Research Funding; Incyte: Consultancy; BeiGene: Consultancy; Johnson and Johnson: Consultancy; Dava Oncology: Consultancy; BMS: Consultancy; Merck: Consultancy; Cardinal Health: Consultancy; ADCT Therapeutics: Consultancy; Epizyme: Consultancy; Caribou Biosciences: Consultancy; Cellecter Bisosciences: Consultancy; Janssen: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy. Eradat: AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Morphosys: Consultancy, Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; Beigene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; ATARA: Research Funding; Juno: Research Funding; BMS: Research Funding; Celgene: Research Funding; AstraZeneca: Research Funding; Kite: Research Funding; Gilead: Research Funding. Brander: Ascentage (transitioning): Research Funding; Juno/Celgene/BMS: Research Funding; AstraZeneca/Acerta: Research Funding; CATO/SMS Catapult: Research Funding; NeWave: Research Funding; DTRM: Research Funding; Pfizer: Consultancy; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; BeiGene: Research Funding; MEI Pharma: Research Funding; TG Therapeutics: Consultancy, Research Funding; ArQule/Merck: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. Parikh: Adaptive Biotehcnologies: Consultancy; Phamacyclics: Consultancy, Research Funding; Janssen: Research Funding; AstraZeneca: Consultancy, Research Funding; TG Therapeutics: Research Funding; Merck: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Ascentage Pharma: Research Funding; Genetech: Consultancy; GlaxoSmithKline: Consultancy. Phillips: AstraZeneca: Consultancy; Gilead: Consultancy; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Xencor: Consultancy; ADC Therapeutics: Consultancy; Beigene: Consultancy; Incyte: Consultancy, Other: Travel Expenses ; Bayer: Consultancy; Genmab: Consultancy; Eli Lilly: Consultancy; Pharmacyclics: Consultancy; Epizyme: Consultancy. Ghori: Merck & Co., Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Reddy: Merck & Co., Inc.: Current Employment. Farooqui: Merck & Co., Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Byrd: Syndax: Consultancy; Janssen: Consultancy; Novartis: Consultancy; AstraZeneca: Consultancy; Newave: Consultancy; Zencor: Research Funding; Pharmacyclics: Research Funding; Trillium: Consultancy; Ohio State University: Patents & Royalties; AbbVie: Consultancy; Kura: Consultancy; Vincerx: Consultancy, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Stephens: Newave: Research Funding; Epizyme: Consultancy; TG Therapeutics: Consultancy; Lilly: Consultancy; Genentech: Consultancy; Celgene: Consultancy; Acerta: Research Funding; Arqule: Research Funding; JUNO: Research Funding; Karyopharm: Research Funding; Mingsight: Research Funding; Novartis: Research Funding; AbbVie: Consultancy; AstraZeneca: Consultancy; CSL Behring: Consultancy; Beigene: Consultancy.

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