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

7005 Background: Outcomes for patients relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) remain poor. Zilovertamab vedotin (ZV) is a novel ROR1-targeting antibody-drug conjugate that has shown promising efficacy in patients with DLBCL. Here we present results of the dose confirmation part of the waveLINE-003 (NCT05139017) trial evaluating ZV plus rituximab and gemcitabine-oxaliplatin (R-GemOx) in pts with R/R DLBCL. Methods: The phase2/3 trialwaveLINE-003 enrolled adult participants (pts) with confirmed R/R DLBCL after ≥1 lines of therapy (LOT) who were ineligible for chimeric antigen receptor T-cell therapy (CAR-T), autologous stem-cell transplant (ASCT), or failed such therapies (cohort A). In the dose confirmation phase, eligible pts received ZV (1.5, 1.75, or 2.0 mg/kg) plus R-GemOx Q3W for ≥6 cycles. Primary endpoints were safety and recommended phase 2 dose (RP2D). Secondary endpoints were objective response rate (ORR) and duration of response (DOR) per Lugano 2014 response criteria by central review, and overall survival. Results: At data cut-off date (August 1, 2024),40 pts had been enrolled in cohort A to receive R-GemOx plus ZV 1.5 mg/kg (n=17), 1.75 mg/kg (n=16), or 2.0 mg/kg (n=7); 22 (55%) were ≥65 years old, and 8 (20%) relapsed >12 mo. Median number of prior LOTs was 2.0 with 7 (18%) pts receiving prior CAR-T, and 7 (18%) receiving prior ASCT. Median follow-up was 9.8 months (mo). Seven DLTs (1 for ZV [1.5 mg/kg], 2 for ZV [1.75 mg/kg], and 4 for ZV [2.0 mg/kg]) were reported. Treatment-related adverse events (AE) were reported in 39 (98%) pts; the most common being diarrhea (n=18 [45%]), nausea (n=15 [38%]), anemia (n=11 [28%]), and platelet count decrease (n=11 [28%]). Grade ≥3 treatment-related AEs were reported in 26 (65%) pts, the most common being neutropenia (n=9 [23%]), neutrophil count decreased (n=9 [23%]), platelet count decreased (n=9 [23%]), and anemia (n=8 [20%]). Two pts discontinued due to AE (sepsis and respiratory failure, both treatment-related), and 1 pt died due to sepsis (treatment related), all in the 2.0 mg/kg dose cohort. The RP2D was determined to be 1.75 mg/kg. ORR was 27% (3 CR, 1 PR [ZV 1.5 mg/kg]), 56% (8 CR, 1 PR [ZV 1.75 mg/kg]), and 57% (3 CR, 1 PR [ZV 2.0 mg/kg]), with median DOR of 14.4 mo, 8.7 mo and not reached (NR), respectively. Median overall survival was 11.5 mo (ZV 1.5 mg/kg), NR (ZV 1.75 mg/kg), and 7.4 mo (ZV 2.0 mg/kg), with 6-month OS rate of 70.0%, 78.8%, and 68.6%, respectively. Conclusions: Zilovertamab vedotin in combination with R-GemOx demonstrated promising efficacy and acceptable safety in R/R DLBCL at the RP2D of ZV of 1.75 mg/kg plus R-GemOx. The study is proceeding to the phase 3 portion randomizing patients to ZV-RGemOx versus RGemOx. Clinical trial information: NCT05139017 .