The Phase 3 waveLINE-010 Study Evaluating Zilovertamab Vedotin Plus R-CHP Versus R-CHOP in Participants With Untreated Diffuse Large B-Cell Lymphoma

Introduction/Background/Significance: The first-line standard-of-care for diffuse large B-cell lymphoma (DLBCL) is rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); however, more effective treatments are needed as 5-year survival rates for patients with DLBCL range from 60-80%. Zilovertamab vedotin (ZV) is a ROR1-targeting antibody-drug conjugate with a monomethyl auristatin E payload that has shown promising antitumor activity in patients with DLBCL. The randomized, open-label, phase 3 waveLINE-010 study (NCT06717347) will evaluate efficacy and safety of ZV in combination with rituximab plus cyclophosphamide, vincristine, and prednisone (R-CHP) versus R-CHOP in participants with treatment-naive DLBCL.

Materials and Methods/Case Presentation/Objective: Participants aged ≥18 years with histologically confirmed DLBCL per the World Health Organization classification of hematopoietic and lymphoid tissue neoplasms (including DLBCL, not otherwise specified [NOS]; DLBCL leg-type; Epstein-Barr virus–positive DLBCL; and T-cell histiocyte-rich DLBCL), positron emission tomography–positive disease (4-5 on the Lugano 5-point scale), an International Prognostic Index (IPI) score of 2-5, and an Eastern Cooperative Oncology Group performance status of 0-2 are eligible. Participants who received prior treatment for DLBCL will be excluded. Randomly assigned participants (1:1) will receive ZV 1.75 mg/kg plus R-CHP or R-CHOP every 3 weeks for ≤6 cycles. Participants with high-risk DLBCL and an IPI score of 3-5 will receive rituximab (or a rituximab biosimilar) for an additional 2 cycles. Randomization will be stratified by geographic region (Western Europe, United States, Canada, Australia vs Asia vs rest of world), IPI score (2 vs 3-5), and disease bulk (< 7.5 cm vs ≥7.5 cm). Response assessments, including computed tomography (CT) scans, will be performed after administration of study intervention on day 1 of cycle 4 and before day 1 of cycle 5. Subsequent CT scans will be performed 12 weeks after the cycle 4 scan (end of treatment [EOT] assessment). Efficacy follow-up CT scans will be performed every 24 weeks for 2 years from EOT assessment, then annually for 3 years (total of 5 years). Safety will be monitored throughout the study and for 30 days after treatment end (90 days for serious adverse events [AEs]) or 30 days if new anticancer therapy is initiated). AEs will be graded per National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. The primary end point is progression-free survival per Lugano response criteria by blinded independent central review (BICR). Secondary end points are complete response rate and duration of complete response per Lugano response criteria by BICR at EOT, event-free survival per Lugano criteria by BICR, overall survival, safety, and change from baseline in health-related quality of life.

Results/Description/Main Outcome Measures: Approximately 1046 participants will be enrolled. Recruitment is ongoing in Argentina, Belgium, Brazil, Chile, China, Colombia, Denmark, France, Greece, Guatemala, Hong Kong, Israel, Italy, Japan, Republic of Korea, Malaysia, Mexico, Netherlands, Peru, Poland, Portugal, Puerto Rico, Romania, Singapore, South Africa, Spain, Switzerland, Taiwan, Thailand, Ukraine, and the United States.

©2025 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2025 ASCO Annual Meeting. All rights reserved.