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

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.