WaveLINE-003: Phase 2/3 Trial of Zilovertamab Vedotin Plus Standard of Care in Relapsed/Refractory Diffuse Large B-cell Lymphoma 

Philippe Armand

Introduction

ROR-1 (Receptor Tyrosine kinase like Orphan Receptor-1) is a cell surface receptor re-expressed in many cancers, including relapsed/refractory diffuse large-cell B-lymphoma (R/R DLBCL), but not in normal adult tissues. Zilovertamab vedotin (ZV) is a novel antibody-drug conjugate targeting ROR1, carrying an MMAE microtubule toxin payload. Early phase studies of ZV monotherapy in R/R DLBCL showed a response rate of 29%. Rituximab, gemcitabine, and oxaliplatin (R-GemOx) is a standard second-line chemotherapy, especially for transplant-ineligible patients.

Study Objective

• Evaluate safety, tolerability, and preliminary efficacy of ZV + R-GemOx
• Determine the recommended phase 2 and 3 dose (RP2D) of ZV.

Methods

• Study Design
  1. Phase 2/3, open-label, multicenter, dose confirmation trial (WAVELINE-003) in 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.
  2. Three dose cohorts of ZV: 1.5, 1.75 (intermediate), and 2.0 mg/kg.
  3. Administered with fixed-dose R-GemOx every 3 weeks for up to 6 cycles.
• Inclusion Criteria
  1. Age and performance status allowing for outpatient chemotherapy.
  2. Confirmed R/R DLBCL, including:
     • High-grade B-cell lymphoma.
     • Double-hit lymphoma.
  3. ≥1 prior line of therapy.
  4. Transplant-ineligible or relapsed/refractory post-transplant.
• Exclusion Criteria
  1. Primary mediastinal B-cell lymphoma.
  2. Significant comorbidities that would preclude chemotherapy.
• Endpoints
  1. Primary: Safety, dose limiting toxicities (DLTs), and RP2D determination.
  2. Secondary:
     • Objective response rate (ORR) and complete response (CR) by independent central review (Lugano criteria)
     • Duration of response (DoR)
     • Overall survival (OS)

Baseline Characteristics

• Total participants: 40
  1. 1.5 mg/kg: 17
  2. 1.75 mg/kg: 16
  3. 2.0 mg/kg: 7
• Median prior lines of therapy: 2 overall; 3 in high-dose cohort.
• Range: 1–7 prior therapies.
• Only 2 patients had prior exposure to polatuzumab vedotin (same payload as ZV).

Results

Safety

• Common DLTs: Febrile neutropenia, ALT elevation, diarrhea, cytopenias.
• Peripheral neuropathy (expected due to ZV + oxaliplatin): low and no ≥ grade 3 events.
• Mandatory G-CSF added mid-study after protocol amendment.

Efficacy

• Median follow-up: ~10 months (longer for low-dose group).
• Higher response rates seen with 1.75 mg/kg, supporting its selection as RP2D.

Conclusion

Zilovertamab vedotin 1.75 mg/kg + R-GemOx demonstrated

• Promising efficacy (ORR 56%, CR 50%)
• Manageable safety profile
• Improved activity over historical R-GemOx alone
• Selected as the recommended Phase 2 and Phase 3 dose (RP2D)
• Study enrolling Phase 3 portion randomizing patients to receive ZV ± R-GemOx.

ASCO 2025, May 30 – June 3, Chicago