Phase 2/3 trial of zilovertamab vedotin plus standard of care in relapsed/ refractory diffuse large B-cell lymphoma: Updated analysis of waveline-003

Abstract Background: Despite progress in the treatment of diffuse large B cell lymphoma (DLBCL),outcomes for patients with relapsed/refractory (R/R) DLBCL remain poor. The receptor tyrosine kinase-like orphan receptor 1 (ROR-1) is a cell-surface protein overexpressed in most lymphoid cancers including DLBCL (Daneshmanesh et al. 2014; Wang et al. 2022). Zilovertamab vedotin (ZV) is a novel ROR1-targeting antibody-drug conjugate that has shown promising efficacy in patients with DLBCL (Norasetthada et al. 2024). The phase 2/3 waveLINE-003 trial (NCT05139017) evaluated the safety and efficacy of ZV plus rituximab and gemcitabine-oxaliplatin (R-GemOx) in participants with R/R DLBCL. We previously reported results for the dose confirmation phase of waveLINE-003 with 40 participants and 9.8 months of follow up where the recommended phase 2 dose (RP2D) was determined to be ZV 1.75 mg/kg. In participants receiving ZV 1.75 mg/kg plus R-GemOx, the objective response rate (ORR) was 56% (8 CR, 1 PR) with median duration of response (DOR) of 8.7 months, and median overall survival (OS) not reached. We present an updated analysis of the waveLINE-003 dose confirmation phase with an additional 9 months of follow up. Methods Eligible participants were aged ≥18 years with confirmed R/R DLBCL after ≥1 lines of therapy who were ineligible for chimeric antigen receptor T-cell therapy (CAR-T), autologous stem-cell transplant (ASCT), or had failed such therapies. In the dose confirmation phase, eligible participants received ZV (1.5, 1.75, or 2.0 mg/kg) plus R-GemOx Q3W for ≥6 cycles. Primary endpoints were safety and RP2D. Tertiary/exploratory endpoints included ORR and DOR per Lugano 2014 response criteria by investigator, and OS. Results At data cut-off (May 5, 2025), the median follow-up was 18.9 months with 40 participants enrolled to receive ZV 1.5 mg/kg (n=17), 1.75 mg/kg (n=16), or 2.0 mg/kg (n=7) plus R-GemOx. A total of 22 (55%) participants were ≥65 years old, and 9 (23%) relapsed >12 months after completing first-line treatment. The median number of prior therapies was 2.0 with 7 (18%) pts receiving prior CAR-T, 7 (18%) receiving prior ASCT, and 2 (5%) received prior polatuzumab vedotin. Participants with germinal center B-cell (GCB) DLBCL were 18 (45%), with non-GCB were 19 (48%), and unknown 3 (8%). Treatment-related adverse events (AE) were reported in 39 (98%) participants; the most common being diarrhea (n=18 [45%]), nausea (n=15 [38%]), neutropenia (n=12 [30%]), neutrophil count decreased (n=12 [30%]), anemia (n=11 [28%]), and platelet count decrease (n=11 [28%]). Grade ≥3 treatment-related AEs were reported in 27 (68%) participants, the most common being neutropenia (n=11 [28%]), neutrophil count decreased (n=9 [23%]), platelet count decreased (n=9 [23%]), and anemia (n=8 [20%]). One treatment-related death due to sepsis occurred in the 2.0 mg/kg dose cohort. The ORR was 29.4% (4 CR, 1 PR [ZV 1.5 mg/kg]), 56.3% (8 CR, 1 PR [ZV 1.75 mg/kg]), and 42.9% (2 CR, 1 PR [ZV 2.0 mg/kg]), with median DOR of 14.4 months, 8.7 months and 10.6 months, respectively. The median OS was 11.5 months (ZV 1.5 mg/kg), 36.8 months (ZV 1.75 mg/kg), and 7.4 months (ZV 2.0 mg/kg), with 12-month OS rate of 43.6%, 65.8%, and 42.9%, respectively. Treatment responses were observed among both participants with GCB and non-GCB DLBCL. Conclusions After approximately 19 months of follow-up, ZV plus R-GemOX continues to demonstrate promising efficacy and acceptable safety in R/R DLBCL at the RP2D of ZV of 1.75 mg/kg plus R-GemOx. No new safety concerns were reported. The efficacy expansion phase of this trial randomizing participants to ZV plus R-GemOx versus R-GemOx is currently ongoing.