Zilovertamab Vedotin Produces Activity in Heavily Pretreated R/R Mantle Cell Lymphoma

Treatment with the ROR1-targeted antibody-drug conjugate (ADC) zilovertamab vedotin (MK 2140) produced antitumor activity and displayed a manageable safety profile in heavily pretreated patients with relapsed/refractory mantle cell lymphoma (MCL), according to data from cohort A of the phase 2 waveLINE-006 trial (NCT05458297) presented at the 2024 ASH Annual Meeting.

Findings showed that patients treated with the ADC (n = 40) achieved an overall response rate (ORR) of 40% (95% CI, 25%-57%), which included a complete response rate of 13% and a partial response rate of 28%. The rates of stable disease and progressive disease were 10% and 28%, respectively. One patient (3%) was not evaluable for response, and 20% of patients were not assessed for response.

Treatment-related adverse effects (TRAEs) occurred at any grade in 90% of patients and at grade 3/4 in 80% of patients. TRAEs led to treatment discontinuation in 18% of patients; however, no TRAEs led to death.

“Future analyses will evaluate the role of zilovertamab vedotin for the treatment of MCL, particularly with the recent [approvals] of bispecific antibodies,” lead study author Ingrid Glimelius, MD, PhD, of the Department of Immunology, Genetics and Pathology, at Uppsala University in Sweden, and colleagues wrote in a poster presentation of the data.

Background and Design of waveLINE-006

Cohort A of the phase 2 study enrolled patients at least 18 years of age with relapsed/refractory MCL who had received at least 2 prior lines of therapy including a BTK inhibitor. Prior treatment with CAR T-cell therapy was required unless patients were ineligible. Patients needed to have PET-positive disease with a score of 4 or 5 on the Lugano scale per blinded independent central review.

Other key inclusion criteria consisted of an ECOG performance status of 0 to 2; measurable disease per Lugano 2014 criteria; and adequate organ function.

All patients were treated with zilovertamab vedotin at 2.5 mg/kg once every 3 weeks, and treatment continued until disease progression, patient withdrawal, initiation of another anticancer treatment, or when other discontinuation criteria were met.

Investigator-assessed ORR per Lugano 2014 criteria served as the trial’s primary end point. Secondary end points comprised duration of response (DOR), safety, and tolerability. Exploratory end points included progression-free survival (PFS) and overall survival (OS).

Enrolled patients had a median age of 68 years (range, 42-86), and 55% were at least 65 years of age. Most patients were male (70%), White (70%), and not Hispanic or Latino (85%). A baseline ECOG performance status of 0 or 1 were both reported in 48% of patients, and 5% of patients had an ECOG performance status of 2.

Ninety-three percent of patients had refractory disease, 5% of patients had relapsed disease, and 3% of patients had an unknown relapsed/refractory status. Lugano clinical stages included II (5%), III (13%), IV (80%), or missing (3%). MCL International Prognostic Index scores included low risk (30%), intermediate risk (30%), and high risk (40%).

TP53 mutation status was missing for 63% of patients; 13% of patients did not harbor TP53 mutations, 18% of patients were positive for TP53 mutations, and TP53 mutation status was undetermined in 8% of patients. Fifty-five percent of patients had a Ki-67 proliferation fraction of at least 30%; this level was below 30% in 10% of patients, and data were missing for 35% of patients.

Enrolled patients had received a median of 4 prior lines of therapy (range, 2-9). Most patients (65%) had not received a prior stem cell transplant (SCT). Autologous SCT and allogeneic SCT were previously received by 28% and 8% of patients, respectively. All patients had received a prior BTK inhibitor. Fifteen percent of patients underwent prior CAR T-cell therapy, and the remaining 85% of patients were ineligible for CAR T-cell therapy.

Diving Deeper into Efficacy and Safety Data

Additional data showed that 68% of patients experienced any reduction in the size of target lesions, and at least a 50% reduction was observed in 57% of patients.

The median time to response was 2.8 months (range, 1.9-3.0), and the median DOR was 3.0 months (range, 0.0+ to 8.8+).

The median PFS was 3.4 months (95% CI, 2.6-5.3), and the median OS was 9.0 months (95% CI, 6.6-not reached).

At the May 1, 2024, data cutoff, the median time from first dose of study drug to data cutoff was 11.9 months (range, 6.5-19.6), and patients received a median of 6 doses of zilovertamab vedotin (range, 1-14). At data cutoff, 37 patients had discontinued treatment due to progressive disease (n = 17), AEs (n = 8), patient withdrawal (n = 5), clinical progression (n = 4), physician decision (n = 2), and nonstudy anticancer therapy (n = 1).

TRAEs reported in at least 10% of patients included neutropenia (any-grade, 58%; grade 3/4, 50%), peripheral neuropathy (43%; 18%), diarrhea (28%; 5%), thrombocytopenia (23%; 5%), decreased white blood cell count (20%; 8%), anemia (18%; 5%), increased alanine aminotransferase levels (15%; 0%), increased aspartate aminotransferase levels (15%; 0%), constipation (13%; 3%), nausea (13%; 0%), decreased appetite (10%; 0%), fatigue (10%; 0%), decreased lymphocyte count (10%; 3%), and pruritus (10%; 0%).

Notably, the median time to onset of first peripheral neuropathy was 61 days (range, 3-207), and this AE led to dose reductions in 8% of patients.

Reference

Glimelius I, Kim WS, Paszkiewicz-Kozik E, et al. Zilovertamab vedotin monotherapy for patients with relapsed or refractory mantle cell lymphoma: cohort A of the multicenter, open-label, phase 2 waveLINE-006 study. Blood. 2024;144(suppl 1):4405. doi:10.1182/blood-2024-205897