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3025 Zilovertamab Vedotin in Combination with Nemtabrutinib for Patients with Relapsed or Refractory Mantle Cell Lymphoma: Cohort C of the Open-Label, Phase 2 Waveline-006 Study

Program: Oral and Poster Abstracts
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
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Ewa Paszkiewicz-Kozik1*, Claudia Moreira2*, Mehmet Turgut, MD3*, Marcelo Garrido4*, Ingrid Glimelius, MD, PhD5,6, Seung Tae Lee, MD, PhD7, Yazeed Sawalha, MD8, Yixin Ren9*, Katherine Ryland, PhD9, Uzor C. Ogbu, MBBS, PhD9 and Diego Villa, MD10

1Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
2Instituto Português de Oncologia do Porto Francisco Gentil Epe, Porto, Portugal
3Department of Hematology, Mayis University Medical School, Samsun, Turkey
4SAGA Clinical Trial Center, Universidad Mayor, Santiago, Chile
5Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
6Akademiska sjukhuset-Blod-och tumorsjukdomar, Uppsala, Sweden
7University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD
8The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Columbus, OH
9Merck & Co., Inc., Rahway, NJ
10Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada

Background: Covalent Bruton tyrosine kinase inhibitors (BTKis) are a standard-of-care option for relapsed or refractory (R/R) mantle cell lymphoma (MCL); however, patients (pts) discontinue therapy because of resistance or intolerance. Patients who discontinue BTKis, especially those with progressive disease (PD), have a poor prognosis and an overall survival between 6-10 months. Thus, an unmet need exists for more effective treatments. Zilovertamab vedotin (ZV) is a ROR1-targeted antibody-drug conjugate with a monomethyl auristatin E payload that has shown antitumor activity in pts with MCL in the waveLINE-001 study. Nemtabrutinib is a novel noncovalent BTKi that has showed antitumor activity in pts with hematologic malignancies. The phase 2 waveLINE-006 study (NCT05458297) was designed to assess efficacy and safety of ZV as monotherapy and in combination with nemtabrutinib in R/R aggressive and indolent B-cell malignancies. We present preliminary results from cohort C, which evaluated ZV in combination with nemtabrutinib in pts with R/R MCL.

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.

*signifies non-member of ASH