Updated follow‐up of BELLWAVE‐001: an open‐label, single‐arm, phase 1/2 study of the efficacy and safety of nemtabrutinib for the treatment of B‐cell malignancies

Background: Bruton tyrosine kinase inhibitors (BTKis) are standard of care for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but resistance can develop, most commonly because of BTK mutations. Nemtabrutinib inhibits both wild-type and C481S-mutant BTK. Initial results from the phase 1/2 BELLWAVE-001 study (NCT03162536) showed that the recommended phase 2 dose (RP2D) of nemtabrutinib (65 mg QD) 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. We present updated analyses on the efficacy and safety of the RP2D of nemtabrutinib in pts with hematologic malignancies. Methods: Pts with CLL/SLL were enrolled in cohort A (R/R CLL/SLL with ≥2 prior therapies, including a covalent BTKi, with C481-mutated BTK) or cohort B (R/R CLL/SLL with ≥2 prior therapies, intolerant to a BTKi, without C481-mutated BTK) and pts with B-cell non-Hodgkin lymphoma were enrolled in cohorts C-I. Pts received nemtabrutinib 65 mg QD until unacceptable toxicity, disease progression, or other discontinuation criteria were met. Primary end points were ORR (for CLL/SLL pts, per 2018 iwCLL criteria by investigator), and RP2D. Secondary end points were DOR and safety. Efficacy and safety analyses included all pts who received ≥1 dose of nemtabrutinib. Results: 112 pts were enrolled and treated with nemtabrutinib 65 mg; 57 had CLL/SLL. Among pts with CLL/SLL, median age was 66 years (range, 45–86), 16 (28%) were female, and 51 (89%) had ECOG PS ≤1. Among pts with CLL/SLL, the median number of prior lines of therapy was 4 (range, 2–18), all pts received prior BTKi therapy, 27 (47%) received prior BTKi and BCL2i therapy, and 36 (63%) had C481S-mutated BTK. At data cutoff (October 28, 2022), median follow-up for pts with CLL/SLL treated with nemtabrutinib 65 mg was 9.4 months (range, 0.1–45.5). Among pts with CLL/SLL treated with nemtabrutinib 65 mg, 32 had an objective response (ORR, 56% [95% CI, 42–69]; 2 CR; 15 PR; 15 PR with residual lymphocytosis [PR-L]); median DOR was 26.0 months (95% CI, 13.9-not reached [NR]). ORR for pts in cohorts A (n = 25) and B (n = 10) were 56% (95% CI, 35–76; 4 PR; 10 PR-L) and 40% (95% CI, 12–74; 1 CR; 2 PR; 1 PR-L), respectively; median DOR was 16.6 months (95% CI, 5.7–26.0) and NR, respectively. Among all pts with hematological malignancies treated with nemtabrutinib 65 mg, 82 (73%) had any-grade treatment-related AEs, most common (≥15%) were dysgeusia (21%) and decreased neutrophil count (20%). Grade 3 or 4 treatment-related AEs occurred in 47 pts (42%); most commonly (≥5%) decreased neutrophil count (17%) and decreased platelet count (7%). No deaths were attributed to treatment. Conclusion: With ∼9 months of follow-up, nemtabrutinib 65 mg QD continued to show antitumor activity with manageable safety in pts with R/R CLL/SLL. The research was funded by: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA Keywords: Aggressive B-cell non-Hodgkin lymphoma, Chronic Lymphocytic Leukemia (CLL), Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. H. Eradat Consultant or advisory role: Abbvie, Genentech, Morphosys, Incyte, Beigene Honoraria: Abbvie, Morphosys, Incyte, Beigene, Genentech, Pharmacyclics Research funding: Abbvie, Genentech, Incyte, Morphosys, Beigene, ATARA, Juno, BMS, Celgene, Pharmacyclics, AstaZeneca, Kite, Gilead Other remuneration: Speaker bureau: Abbvie, Genentech, Morphosys, Incyte, Beigene J. Woyach Consultant or advisory role: AbbVie, ArQule, AstraZeneca, BeiGene, Genentech, Janssen, MorphoSys, Newave, and Pharmacyclics Research funding: AbbVie, Karyopharm, Loxo Oncology, MorphoSys, and Schrodinger I. W. Flinn Consultant or advisory role: Consultancy: All payments made to Sarah Cannon Research Institute, not to the physician. AbbVie, AstraZeneca, BeiGene, Century Therapeutics, Genentech, Genmab, Hutchison MediPharma, Iksuda Therapeutics, InnoCare Pharma, Janssen, Kite Pharma, MorphoSys, Myeloid Therapeutics, Novartis, Nurix Therapeutics, Pharmacyclics, Roche, Secura Bio, Servier Pharmaceuticals, Takeda, TG Therapeutics, Verastem, Vincerx Pharma, Xencor Research funding: Research Grants: All payments made to Sarah Cannon Research Institute, not to the physician. AbbVie, Acerta Pharma, Agios, ArQule, AstraZeneca, BeiGene, Biopath, Bristol Myers Squibb, CALIBR, CALGB, Celgene, City of Hope National Medical Center, Constellation Pharmaceuticals, Curis, CTI Biopharma, Epizyme, Fate Therapeutics, Forma Therapeutics, Forty Seven, Genentech, Gilead Sciences, InnoCare Pharma, IGM Biosciences, Incyte, Infinity Pharmaceuticals, Janssen, Kite Pharma, Loxo, Merck, Millennium Pharmaceuticals, MorphoSys, Myeloid Therapeutics, Novartis, Nurix, Pfizer, Pharmacyclics, Portola Pharmaceuticals, Rhizen Pharmaceuticals, Roche, Seattle Genetics, Tessa Therapeutics, TCR2 Therapeutics, TG Therapeutics, Trillium Therapeutics, Triphase Research & Development Corp., Unum Therapeutics, Verastem, 2 seventy bio F. T. Awan Consultant or advisory role: Genentech, Astrazeneca, Abbvie, Janssen, Pharmacyclics, Gilead sciences, Kite pharma, Celgene, Karyopharm, MEI Pharma, Verastem, Incyte, Beigene, Johnson and Johnson, Dava Oncology, BMS, Merck, Cardinal Health, ADCT therapeutics, Epizyme, Caribou Biosciences, Cellecter Bisosciences Research funding: Pharmacyclics D. Brander Consultant or advisory role: Abbvie, ArQule/Merck, Pfizer, Genentech, Pharmacyclics, TG Therapeutics Research funding: Abbvie, ArQule,/Merck, Ascentage, Astra Zeneca/Acerta, Beigene, CATO/SMS Catapult, DTRM, Genentech, Juno/Celgene/Bms, MEI Pharma, NeWave, Novartis, Pharmacyclics, TG Therapeutics-Grants paid to institution S. A. Parikh Consultant or advisory role: Pharmacyclics, Merck, AstraZeneca, Genentech, GlaxoSmithKline, Adaptive Biotechnologies, Amgen, and AbbVie Research funding: Pharmacyclics, Janssen, AstraZeneca, TG Therapeutics, Merck, AbbVie, and Ascentage Pharma T. Phillips Consultant or advisory role: Abbvie, ADC Therapuetics, AstraZeneca, Bayer, Beigene, Eli Lily, Epizyme, Genentech, Genmab, Gilead, Incyte, Pharmacyclics, Xencor Research funding: Abbvie, Incyte, Genentech R. Ghori Employment or leadership position: Merck & Co., Inc. Stock ownership: Merck & Co., Inc. I. Paydar Employment or leadership position: Merck & Co., Inc. Stock ownership: Merck & Co., Inc. M. Z. H. Farooqui Employment or leadership position: Merck & Co., Inc. Stock ownership: Merck & Co., Inc. J. C. Byrd Consultant or advisory role: Abbvie; Astra Zeneca; Janssen, Kura, Newave, Novartis, Syndax, Trillium, Vincerx Stock ownership: Vincerx Research funding: Zencor; Pharmacyclics Other remuneration: Patents/Royalties: OSU D. M. Stephens Consultant or advisory role: AstraZeneca, Abbvie, Genentech, Epizyme, Beigene, TG Therapeutics, Lilly, CSL Behring, Celgene Research funding: Acerta, Novartis, Karyopharm, Mingsight, Arqule, JUNO, Newave