Zilovertamab Vedotin Plus R-GemOx Shows Activity in R/R DLBCL

The combination was generally well tolerated, with most adverse events manageable and low grade.

Zilovertamab vedotin, a ROR1-targeted antibody-drug conjugate (ADC), achieved a 56.3% objective response rate (ORR) when combined with gemcitabine-oxaliplatin (R-GemOx) in relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to data from the dose-confirmation portion of the phase 2/3 waveLINE-003 trial (NCT05139017) presented at the 2025 ASCO Annual Meeting.

At the recommend phase 2 dose (RP2D) of 1.75 mg/kg for zilovertamab vedotin plus standard R-GemOx, the complete response (CR) 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 9 months. The median overall survival (OS) was not yet reached, with a 12-month estimated OS 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 diffuse large B cell lymphoma," said principal investigator Philippe Armand, MD, PhD, 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 3 dose levels. There were 17 patients who received 1.5 mg/kg, 16 receiving 1.75 mg/kg, and 7 who received 2.0 mg/kg. Across all groups, the median number of prior therapies was 2, with 2 specifically having received the CD79b-directed ADC polatuzumab vedotin (Polivy). 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 0 (43%), 1 (48%), and 2 (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 ORR was 26.7% with a CR 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 OS was 11.5 months in this group, with a 12-month OS rate of 40.8%. The median follow-up for this dose level was 18.1 months.

In the 2.0 mg/kg group, the ORR was 57.1%, with a CR rate of 42.9%. The median duration of response in this group was not yet reached. The median OS in this group was 7.4 months, with a 12-month OS 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 (DLT) observed across the 3 dose levels. At the 2.0-mg/kg dose, there were 4, compared with 1 in the 1.5-mg/kg group and 2 at the RP2D group. In the 2.0-mg/kg dose level, there was 1 treatment-related death from sepsis. Other DLTs 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 adverse events (AEs), midway through the trial the protocol was adapted to included mandatory prophylaxis with G-CSF. In the RP2D arm, the DLTs were grade 3 alanine aminotransferase increase and intestinal obstruction.

Zilovertamab vedotin-related AEs of grade 3/4 in severity were experienced by 63% of patients in the RP2D 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 AEs were experienced by 24% of those in the low dose group, by 31% at the RP2D, 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 (NCT05139017). Armand also drew attention to studies looking at zilovertamab vedotin as a first-line treatment for DLBCL in combination with R-CHP compared with R-CHOP (waveLINE-010; NCT06717347). Additionally, waveLINE-011 (NCT06890884) is investigating zilovertamab vedotin with R-CHP as a first-line therapy for the GCB subtype of DLBCL compared with polatuzumab vedotin plus R-CHP.

Reference

Armand P, Lee ST, Jurczak W, et al. WaveLINE-003: Phase 2/3 trial of zilovertamab vedotin plus standard of care in relapsed/refractory diffuse large B-cell lymphoma. J Clin Oncol. 2025;43 (suppl 17; abstr 7005). doi:10.1200/JCO.2025.43.16_suppl.7005.