Session: 623. Mantle Cell, Follicular, Waldenstrom’s, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Research, Clinical trials, Adult, Lymphomas, Non-Hodgkin lymphoma, Clinical Research, Diseases, Aggressive lymphoma, Lymphoid Malignancies, Study Population, Human
Methods: In cohort C, eligible pts were aged ≥18 y who had histologically confirmed MCL according to the 2016 WHO Classification of Neoplasms of the Hematopoietic and Lymphoid Tissues, at least 1 prior systemic therapy, and no prior exposure to a noncovalent BTKi. Eligible pts had PET-positive disease by blinded independent central review (BICR) at screening (4-5 on the Lugano 5-point scale), measurable disease per Lugano criteria, and an ECOG PS of 0 to 2. Dose finding (escalation and de-escalation) was conducted using the mTPI design with 3 prespecified dose levels combining different ZV doses with nemtabrutinib at a fixed 65 mg dose (DL-1: ZV at 2.00 mg/kg ZV; DL0: ZV at 2.25 mg/kg; and DL1: ZV at 2.50 mg/kg). ZV was given IV every 3 weeks and nemtabrutinib by mouth once daily until PD or discontinuation to determine the recommended phase 2 dose (RP2D). Primary prophylaxis with growth factors was not permitted. Each dose level required 3-15 pts. The dose-limiting toxicity (DLT)–evaluable population comprised the all-patients-as-treated population who finished the DLT evaluation period regardless of experiencing a DLT. Primary end points were safety and tolerability and objective response rate (ORR) per Lugano criteria by investigator review.
Results: At the data cutoff date (May 1, 2024), 28 pts had been enrolled in cohort C. Median age was 70 y (range, 45-78), 18 pts (64%) had an ECOG PS of 0, 6 (21%) had high-risk disease per the mantle cell lymphoma prognostic index, 6 (21%) were positive for TP53 mutation, 16 (57%) had a Ki67 index ≥30%, and the median number of prior lines of therapy was 2.5 (range, 1-6). Twelve pts (43%) had undergone prior autologous stem cell transplant, and 7 (25%) had undergone prior chimeric antigen receptor T-cell therapy. Of the overall 28 pts, 12 pts received ZV at DL0, 8 at DL1, and 8 at DL-1. Median time from first dose to data cutoff was 7.3 mo (range, 0.9-14.0). Of the 24 pts evaluable for DLTs, 3 of 12 pts who received ZV at DL0 experienced a DLT (1 asthenia, 1 peripheral neuropathy [PN], and 1 maculopapular rash), 2 of 7 at DL1 (1 fatigue; 1 neutropenia), and 0 of 5 at DL-1. At data cutoff, 11 pts (39%) had discontinued treatment (4 PD, 3 adverse event [AE], 3 patient withdrawal, 1 nonstudy anticancer therapy) and 17 (61%) remained on treatment. Treatment-related AEs (TRAEs) occurred in 26 pts (93%), most commonly (≥35%) neutropenia (57%). Grade 3 or 4 TRAEs occurred in 22 pts (79%); most commonly (≥20%) neutropenia (grade 3 [29%] and grade 4 [25%]). One patient (4%) had grade 3 tumor lysis syndrome, and 1 (4%) had a grade 2 infusion-related reaction. Nineteen pts (68%) had PN regardless of treatment based on the following terms: gait disturbance, muscular weakness, peripheral neuropathy, paresthesia, peripheral sensory neuropathy, polyneuropathy; 3 pts (11%) had grade 3 or 4 events. TRAEs led to discontinuation in 5 pts (18%). No pts died due to TRAEs. The ORR was 64% (95% CI, 44-81); complete and partial responses occurred in 9 pts (32%) each. Of 22 pts with ≥1 postbaseline target lesion, 21 (96%) had any reduction in target lesion size, of whom 14 (64%) had a ≥50% reduction.
Conclusions: ZV in combination with nemtabrutinib showed clinically meaningful antitumor activity and manageable safety in pts with R/R MCL. Further investigation into efficacy of this combination is warranted for pts with R/R MCL. The study is ongoing and the RP2D is yet to be determined.
Disclosures: Paszkiewicz-Kozik: Roche, Takeda, Abbvie: Honoraria; Takeda, Roche: Consultancy; Incyte, Beigene: Speakers Bureau; Roche, Takeda, Beigene: Other: Travel/Accommodations/Expenses. Garrido: Bayer, Novartis, MSD, BMS, Pfizer, Macrogenic, Merck: Consultancy; Novartis, Pfizer, Bayer, BMS, MSD, GBT Biotoscana, Lilly: Speakers Bureau; MSD, BMS, Novartis, Roche,Astellas, Deciphera, PPD, IQVIA, Bayer, Principia, Covance, Daiichi-Sankyo, Basilea, PRA-Exelisis, Syneos, Zimeworks: Other: Leadership Role; Grant from ANID, Chile. grants n° 1221499: Research Funding; Medical Director, Precision Oncology Center, Universidad Mayor, Santiago de Chile: Membership on an entity's Board of Directors or advisory committees. Glimelius: Janssen: Speakers Bureau; Takeda: Honoraria, Other: Research Grant/Funding; AstraZeneca: Consultancy. Sawalha: AbbVie: Research Funding; ADC: Consultancy; Beigene: Research Funding; Genmab: Honoraria, Research Funding. Ren: Merck: Current Employment, Current holder of stock options in a privately-held company. Ryland: Merck & Co., Inc., Rahway, NJ, USA: Current Employment, Current holder of stock options in a privately-held company. Ogbu: Merck & Co., Inc. & Roche: Current holder of stock options in a privately-held company; Merck & Co., Inc.: Current Employment. Villa: Merck, Abbvie, Roche, AstraZeneca, BeiGene, Janssen, BMS/Celgene, Kite/Gilead, InCyte: Consultancy; Roche, AstraZeneca: Research Funding; Merck, Abbvie, Roche, AstraZeneca, BeiGene, Janssen, BMS/Celgene, Kite/Gilead, InCyte: Honoraria.