Phase 2 trial of zilovertamab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone plus rituximab in diffuse large B-cell lymphoma: Updated analysis of waveline-007

Abstract Background: Despite progress made with combination therapies that include cyclophosphamide, doxorubicin and prednisone plus rituximab (R-CHP) and polatuzomab vedotin, outcomes for patients with diffuse large B-cell lymphoma (DLBCL) leave room for improvement. 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 waveLINE-007 trial (NCT05406401) evaluated the safety and efficacy of ZV plus R-CHP in participants with untreated DLBCL. We previously reported results of waveLINE-007 with 36 participants and 10 months of follow up where the recommended phase 2 dose (RP2D) was determined to be ZV 1.75 mg/kg. All 15 (100%) participants receiving ZV 1.75 mg/kg plus R-CHP achieved complete response (CR) at end-of-treatment with an objective response rate (ORR) of 100% and median duration of response (DOR) not reached. We present an updated analysis of the waveLINE-007 trial with an additional 16 months of follow-up. Methods: Eligible participants were aged ≥18 years with DLBCL confirmed by positron emission tomography by BICR per Lugano criteria, no prior treatment for DLBCL, and ECOG performance score 0-1 to receive ZV (1.75, 2.0, 2.25 mg/kg) plus R-CHP Q3W for 6 or 8 cycles. Primary endpoints were safety, RP2D, and CR per Lugano 2014 response criteria by investigator. Secondary endpoints were ORR and DOR per Lugano criteria by investigator. Tertiary/Exploratory endpoints included overall survival (OS). Results: At data cut-off (May 6, 2025), the median follow-up was 26.6 months with 36 participants enrolled to receive ZV 1.75 mg/kg (n=15), 2.0 mg/kg (n=15), or 2.25 mg/kg (n=6) plus R-CHP. Overall, 34 (94%) participants completed the trial, and 2 (6%) discontinued treatment due to physician decision (ZV 2.0 mg/kg, n=1; ZV 2.25 mg/kg, n=1). Overall, 21 (58%) participants were female, 17 (47%) were ≥65 years old, 21 (58%) had ECOG performance score of 1, 18 (50%) had Ann Arbor stage IV disease, and 3 (8%) had a NCCN International Prognostic Index of high risk. Participants with germinal center B-cell (GCB) DLBCL were 15 (42%), with non-GCB were 16 (44%), and unknown 5 (14%). Treatment-related adverse events (AE) were reported in all 36 (100%) participants, the most common being neutropenia (n=15 [42%]), nausea (n=10 [28%]), anemia (n=9 [25%]), diarrhea (n=7 [19%]), peripheral sensory neuropathy (n=7 [19%]), and neutrophil count decreased (n=6 [17%]). Grade ≥3 treatment-related AEs were reported in 21 (58%) participants, the most common being neutropenia (n=13 [36%]), neutrophil count decreased (n=6 [17%]), and febrile neutropenia (n=5 [14%]). No treatment-related deaths were reported. Complete response was achieved in all 15 (100%) participants receiving ZV 1.75 mg/kg, 14 (93%) participants receiving ZV 2.0 mg/kg, and all 6 (100%) participants receiving ZV 2.25 mg/kg, for an overall CR rate of 97.2% (95% CI, 86-100). The ORR was 100%, 93%, and 100% for participants receiving ZV 1.75 mg/kg, 2.0 mg/kg, and 2.25 mg/kg, respectively. The median duration of CR was not reached (NR) for all participants, with 24-month CR rate of 84%. All participants with GCB (n=5) and non-GCB (n=7) DLBCL receiving ZV 1.75 mg/kg achieved complete response. An estimated 84% of participants overall had response duration ≥24 months. The 24-month PFS and OS rates were 84% and 94%, respectively, for all participants. For participants receiving ZV 1.75 mg/kg, the 24-month PFS and OS rates were 100% and 100%, respectively, for those with GCB DLBCL, and 83.3% and 100%, for those with non-GCB DLBCL. Conclusions: After approximately 27 months of follow-up, ZV plus R-CHP continues to demonstrate robust efficacy and acceptable safety as front-line treatment for participants with DLBCL regardless of cell of origin. No new safety concerns were reported.