Abstract Introduction: Diffuse large B-cell lymphoma (DLBCL) is associated with 5-year survival rates ranging from 53% to 70%, highlighting the need for more effective frontline therapies. The current standard of care for previously untreated DLBCL is rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Zilovertamab vedotin is an ROR1-targeting antibody-drug conjugate with a monomethyl auristatin E payload that has shown encouraging antitumor activity in patients with DLBCL. The waveLINE-010 study (NCT06717347) is a randomized, open-label, phase 3 study designed to assess the efficacy and safety of zilovertamab vedotin in combination with rituximab plus cyclophosphamide, vincristine, and prednisone (R-CHP) versus R-CHOP in participants with previously untreated DLBCL. Methods: Eligible participants are aged ≥18 years and have a confirmed diagnosis of DLBCL per the World Health Organization classification of hematopoietic and lymphoid tissue neoplasms. DLBCL subtypes that are eligible for enrollment include DLBCL, not otherwise specified (NOS); DLBCL leg-type; Epstein-Barr virus–positive DLBCL; and T-cell histiocyte-rich DLBCL. Additional inclusion criteria include disease confirmed by positron emission tomography (score of 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 score of 0-2. Participants who received prior treatment for DLBCL will be excluded. Approximately 1046 participants will be enrolled and randomly assigned 1:1 to receive zilovertamab vedotin 1.75 mg/kg plus R-CHP on day 1 of every 3-week cycle for 6 cycles or R-CHOP on day 1 of every 3-week cycle for 6 cycles. Participants with high-risk DLBCL, with 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). Imaging assessments using computed tomography (CT) will be conducted after administration of study intervention between cycles 4 and 5, with a follow-up scan 12 weeks later to mark the end of treatment (EOT) assessment. Post-treatment efficacy follow-up CT scans will be performed every 24 weeks for 2 years from the EOT assessment, followed by annual scans for 3 additional years (total, 5 years). Adverse events (AEs) will be monitored throughout the study and for 30 days after EOT (90 days for serious 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. Patient-reported outcomes measures will be administered before dosing on day 1 of every cycle, at the EOT visit, and at the 30-day safety follow-up visit. 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. Recruitment is ongoing. ©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.
Reddy et al. (Mon,) studied this question.