Zilovertamab Vedotin Plus Chemo Combo Shows Responses in R/R DLBCL

Among patients with with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), zilovertamab vedotin, a ROR1-targeted antibody-drug conjugate, plus Rituxan (rituximab) and gemcitabine-oxaliplatin (R-GemOx) elicited an objective response rate of 56.3%, according to findings from the phase 2/3 waveLINE-003 study which were shared at the 2025 ASCO Annual Meeting.

At the recommend phase 2 dose of 1.75 milligrams per kilogram (mg/kg) for zilovertamab vedotin plus standard R-GemOx, the complete response rate was 50% in the study. After a median of 9.9 months of follow-up, the median duration of response was 8.7 months, with 28.6% of patients continuing to respond at nine months. The median overall survival was not yet reached, with a 12-month estimated overall survival rate of 68.9% at the RP2D.

"This combination had a manageable safety profile, and the objective and complete response rate of 56% and 50% of the zilovertamab vedotin plus R-GemOx combination at the recommended phase 2 dose suggest improved activity in relapsed/refractory DLBCL," said principal investigator Dr. Philippe Armand, from Dana-Farber Cancer Institute. "The study is currently enrolling the phase 3 portion."

The phase 2 portion of the study enrolled 40 participants with relapsed/refractory DLBCL. R-GemOx was administered at standard doses in each group, with zilovertamab escalated across three dose levels. There were 17 patients who received 1.5 mg/kg, 16 receiving 1.75 mg/kg, and seven who received 2.0 mg/kg. Across all groups, the median number of prior therapies was two, with two specifically having received the CD79b-directed Polivy (polatuzumab vedotin). Armand noted this agent specifically, as it carries the same cytotoxic payload as zilovertamab vedotin; however, data were not shown for this subgroup during the presentation.

Across all patients enrolled, the median age was 66.5 years, with 55% being 65 years or older. ECOG performance status was zero (43%), one (48%), and two (10%) and nearly half of patients had Ann Arbor stage IV disease (53%). The DLBCL cell of origin was most commonly GCB (45%).

At the 1.5 mg/kg dose, the overall response rate was 26.7% with a complete response rate of 20.0%. The median duration of response in this group was 14.4 months, with a 9-month duration of response rate of 100%. The median overall survival was 11.5 months in this group, with a 12-month overall survival rate of 40.8%. The median follow-up for this dose level was 18.1 months.

In the 2.0 mg/kg group, the overall response rate was 57.1%, with a complete response rate of 42.9%. The median duration of response in this group was not yet reached. The median overall survival in this group was 7.4 months, with a 12-month overall survival rate that was not yet reached. The median follow-up in this cohort was 9.3 months.

"The obvious caveat here are the few patients and still limited duration of follow up. So, the estimates are not very stable," Armand cautioned regarding the response duration data.

There was a total of 7 dose limiting toxicities observed across the three dose levels. At the 2.0-mg/kg dose, there were four, compared with one in the 1.5-mg/kg group and two at the recommended phase 2 dose group. In the 2.0-mg/kg dose level, there was one treatment-related death from sepsis.

Other dose limiting toxicities in this group included grade 3 diarrhea, grade 4 neutrophil count decrease, grade 4 thrombocytopenia, grade 3 febrile neutropenia, and grade 4 neutrophil count decrease. To address these side effects, midway through the trial the protocol was adapted to included mandatory prophylaxis with G-CSF. In the recommended phase 2 dose arm, the dose limiting toxicities were grade 3 alanine aminotransferase increase and intestinal obstruction.

This combination had a manageable safety profile, and the objective and complete response rate of 56% and 50% of the zilovertamab vedotin plus R-GemOx combination at the recommended phase 2 dose suggest improved activity in relapsed/refractory DLBCL.

Zilovertamab vedotin-related side effects of grade 3 (severe)/4 (life threatening) in severity were experienced by 63% of patients in the recommended phase 2 dose group. This compared with 86% of those in the largest dose and for 53% of those in the lowest dose. Two patients discontinued the drug in the highest dose group, related to sepsis and respiratory fatigue. There were no discontinuations at the other dose levels. Serious drug-related side effects were experienced by 24% of those in the low dose group, by 31% at the recommended phase 2 dose group, and for 57% of those at the 2.0 mg/kg dose.

Several studies continue to explore zilovertamab vedotin for patients with DLBCL, including the phase 3 portion of the waveLINE-003 study. Armand also drew attention to studies looking at zilovertamab vedotin as a first-line treatment for DLBCL in combination with chemotherapy compared with chemo alone. Additionally, waveLINE-011 is investigating zilovertamab vedotin with chemo as a first-line therapy for the GCB subtype of DLBCL compared with Polivy plus chemo.

Reference:

“WaveLINE-003: Phase 2/3 trial of zilovertamab vedotin plus standard of care in relapsed/refractory diffuse large B-cell lymphoma” by Dr. Philippe Armand, et al., American Society of Clinical Oncology Annual Meeting.