Zilovertamab Vedotin Monotherapy for Patients with Relapsed or Refractory Mantle Cell Lymphoma: Cohort a of the Multicenter, Open-Label, Phase 2 Waveline-006 Study

Background: Mantle cell lymphoma (MCL) is a rare, aggressive, and incurable form of non-Hodgkin lymphoma with poor prognosis. Bruton tyrosine kinase inhibitors (BTKis) are a standard-of-care option for relapsed/refractory (R/R) MCL; however, effective treatments are limited for patients (pts) whose disease progresses during or after BTKi therapy. Zilovertamab vedotin is a ROR1-targeting antibody-drug conjugate with a monomethyl auristatin E payload that has shown antitumor activity in pts with R/R MCL in the phase 1 waveLINE-001 study. The phase 2, multicohort, waveLINE-006 study (NCT05458297) was designed to assess the efficacy and safety of zilovertamab vedotin as monotherapy and in combination with the BTKi nemtabrutinib in R/R aggressive and indolent B-cell malignancies. We present results from cohort A, which evaluated zilovertamab vedotin monotherapy for pts with R/R MCL.

Methods: In cohort A, eligible pts were aged ≥18 years who had histologically confirmed MCL per 2016 WHO classification of neoplasms of the hematopoietic and lymphoid tissues, R/R disease after ≥2 prior systemic therapies including a BTKi, and progressive disease (PD) after or were ineligible for chimeric antigen receptor (CAR) T-cell therapy. Eligible pts had PET-positive disease by blinded independent central review (BICR) at screening (defined as 4-5 on the Lugano 5-point scale), measurable disease per Lugano criteria, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2. Pts received zilovertamab vedotin 2.5 mg/kg IV every 3 weeks until PD, unacceptable toxicity, or withdrawal. Primary prophylaxis with growth factors was not permitted. The primary end point was objective response rate (ORR) per Lugano criteria by investigator review. Secondary end points were duration of response (DOR) per Lugano criteria by investigator review and safety and tolerability. Exploratory end points included progression-free survival (PFS) per Lugano criteria by investigator review and overall survival (OS). The data cutoff date was May 1, 2024.

Results: Cohort A included 40 pts. The median age was 68 years (range, 42-86), 28 pts (70%) were male, 19 (48%) had an ECOG PS of 0 or 1, 16 (40%) had high-risk disease per the mantle cell lymphoma prognostic index, 7 (18%) were positive for TP53 mutation, 22 (55%) had a KI67 proliferation fraction ≥30%, and the median number of prior lines of therapy was 4 (range, 2-9). All patients received a covalent or noncovalent BTKi. Eleven pts (28%) had undergone prior autologous stem cell transplant, and 6 (15%) received prior CAR T-cell therapy. At data cutoff, 37 pts (93%) had discontinued treatment (17 PD, 8 adverse event [AE], 5 patient withdrawal, 4 clinical progression, 2 physician decision, 1 nonstudy anticancer therapy), and 3 pts (8%) were ongoing on treatment. Median time from first dose to data cutofff was 11.9 months (range, 6.5-19.6). ORR was 40% (95% CI, 25-57); 5 pts (13%) had a complete response and 11 (28%) had a partial response. Of 28 pts with ≥1 postbaseline target lesion, 16 (57%) had ≥50% reduction in target lesion size; 3 additional pts had a reduction in target lesion size and a best response of stable disease. Median DOR was 3.0 months (range, 0.0+ to 8.8+); 2 responders had a response duration ≥6 months. Median PFS was 3.4 months (95% CI, 2.6-5.3); the 6-month PFS rate was 26%. Median OS was 9.0 months (95% CI, 6.6-not reached); the 6-month OS rate was 67%. Treatment-related AEs occurred in 36 pts (90%), of which the most common (≥25%) were neutropenia (58%), peripheral neuropathy (43%; defined as peripheral neuropathy, paresthesia, peripheral sensory neuropathy, and polyneuropathy), and diarrhea (28%). Grade 3 or 4 treatment-related AEs occurred in 32 pts (80%); most commonly (≥10%) neutropenia (50%) and peripheral neuropathy (18%). Median time to onset of first peripheral neuropathy was 61 days (range, 3-207). One pt (3%) had grade 3 tumor lysis syndrome, and no pts experienced infusion reactions. Treatment-related AEs led to discontinuation in 7 pts (18%). No pts died due to treatment-related AEs.

Conclusions: Zilovertamab vedotin monotherapy demonstrated antitumor activity and manageable safety in heavily pretreated pts with R/R MCL in cohort A of waveLINE-006. Further investigation is warranted to better understand the efficacy of zilovertamab vedotin for R/R MCL.