A phase 2 study of zilovertamab vedotin as monotherapy or in combination in patients (pts) with aggressive and indolent B‐cell malignancies: waveLINE‐006

Background: The transmembrane protein ROR1 is overexpressed in hematologic malignancies. Additionally, targeting Bruton tyrosine kinase (BTK) has been found to be a viable therapeutic option. Zilovertamab vedotin (ZV) is a humanized IgG1 monoclonal anti-ROR1, with a proteolytically cleavable linker and the antimicrotubule agent monomethyl auristatin E. Nemtabrutinib is a reversible inhibitor of BTK. With different mechanisms of action and nonoverlapping toxicities, the combination of ZV and a BTKi has the potential for improved responses in B-cell malignancies. The waveLINE-006 study (NCT05458297) will be conducted to investigate safety and efficacy of ZV in pts with B-cell malignancies, as monotherapy or in combination with nemtabrutinib. Methods: Approximately 275 pts will be enrolled (cohorts A-F; see table). Pts ≥18 years old with biopsy-proven and/or histologically confirmed mantle cell lymphoma (MCL), Richter transformation (RT), chronic lymphocytic leukemia (CLL), or follicular lymphoma (FL), with relapsed or refractory (R/R) disease, ECOG performance status of 0 to 2, and adequate organ function are eligible. In cohorts A and B, patients will receive ZV 2.5 mg/kg IV Q3W. In cohort C, 30 patients will be enrolled in a safety run-in phase of ZV in combination with nemtabrutinib, then an additional 15 patients will receive the RP2D of the combination. Patients in cohort D (schedule optimization) will be randomly assigned 1:1 to receive ZV 2.5 mg/kg IV Q3W (arm 1) or ZV 2.0 mg/kg IV Q2/3W (arm 2). Patients in cohorts E and F (efficacy expansion) will receive the dose and schedule of ZV determined during schedule optimization. Each pt will receive ZV and/or nemtabrutinib until disease progression, unacceptable toxicity, or other discontinuation criteria are met. The primary end points are the safety and tolerability of ZV alone (cohort D) and in combination with nemtabrutinib (cohort C), and the objective response rate of ZV alone (cohorts A, B, D, E, and F) and in combination with nemtabrutinib (cohort C). The secondary end points are the duration of response of ZV alone (cohorts A, B, D, E, and F) and in combination with nemtabrutinib (cohort C) and the safety and tolerability of ZV alone (cohorts A, B, E, and F). Tumor scans will be performed at baseline, then Q12W up to week 108, and Q24W thereafter. Adverse events will be monitored and graded per NCI CTCAE v5. Enrollment is ongoing. Encore Abstract - previously submitted to ASCO 2023 The research was funded by: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA Keywords: Aggressive B-cell non-Hodgkin lymphoma, Indolent non-Hodgkin lymphoma, Ongoing Trials Conflicts of interests pertinent to the abstract. P. L. Zinzani Consultant or advisory role: Celltrion, Gilead Sciences, Janssen-Cilag, BMS, SERVIER, Sandoz, MSD, Roche, EUSA Pharma, Kyowa Kirin, Takeda, Secure BIO, TG Therapeutics, Novartis, ADC Therapeutics, Incyte, BeiGene Other remuneration: Speaker's Bureau: MSD, EUSA Pharma, Novartis J. Mayer Research funding: Merck & Co., Inc. O. Benjamini Consultant or advisory role: Janssen, AbbVie, AstraZeneca A. Berkovits Educational grants: Janssen Other remuneration: Speaker Bureau/Expert Testimony: Pfizer, Novartis I. Glimelius Other remuneration: Jansen Cilag I have helped as scientific board for a meeting and Takeda participate in a real world evidence collaboration. Funding to insitution. A. Chaudhry Employment or leadership position: American Oncology Network R. G. Sanz Consultant or advisory role: Janssen, BeiGene, Takeda Honoraria: Janssen, BeiGene, Takeda, Incyte, Novartis Research funding: Gilead, Takeda Educational grants: Janssen, BeiGene, Takeda Other remuneration: Patents, Royalties, other intellectual property: invivo scribe (IVS); Speaker's Bureau: Janssen, BeiGene, Takeda W. S. Kim Research funding: Sanofi, Beigene, Boryong, Roche, Kyowa-kirin, Donga A. Marin-Niebla Consultant or advisory role: Janssen, Gilead-Kite, AstraZeneca Honoraria: Janssen, Takeda, AstraZeneca, Gilead-Kite Educational grants: Janssen, Takeda, Gilead-Kite (congresses attendance) M. Ozcan Research funding: AbbVie, Bayer, Janssen, Roche, Takeda, MSD, Pfizer, Acerta E. Paszkiewicz-Kozik Consultant or advisory role: Takeda Educational grants: Roche Other remuneration: Speaker's Bureau: Roche, Takeda, Abbvie A. Santoro Consultant or advisory role: Arqule, Sanofi, Bristol Myers Squibb, Servier, Gilead, Pfizer, Eisai, Bayer, Merck Sharp & Dohme Other remuneration: Speaker's Bureau: Takeda, Bristol Myers Squibb, Roche, AbbVie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, Arqule, Lilly, Sandoz, Eisai, Novartis, Bayer, Merck Sharp & Dohme Y. Ren Employment or leadership position: Merck Stock ownership: Merck U. Ogbu Employment or leadership position: Merck P. Marinello Employment or leadership position: Merck Stock ownership: Merck W. Jurczak Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, Lilly, Roche, Takeda Research funding: AbbVie, AstraZeneca, BeiGene, Janssen, Lilly, Roche, Takeda