waveLINE-011: Zilovertamab vedotin plus R-CHP versus polatuzumab vedotin plus R-CHP as first-line therapy in germinal center B-cell–like (GCB) diffuse large B-cell lymphoma (DLBCL).

TPS7104 Background: DLBCL is a heterogeneous malignancy broadly categorized into 3 subtypes: activated B-cell–like (ABC) DLBCL, GCB DLBCL, and unclassified DLBCL. The standard-of-care first-line treatment option for DLBCL regardless of subtype is polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP). However, while polatuzumab plus R-CHP prolongs PFS compared with R-CHOP in ABC DLBCL, it provides no benefit over R-CHOP in GCB DLBCL. Alternative first-line treatment options for GCB DLBCL are needed. Receptor tyrosine kinase–like orphan receptor 1 (ROR1) is an oncofetal transmembrane protein that is overexpressed in DLBCL, making it an attractive therapeutic target. Zilovertamab vedotin is an antibody-drug conjugate comprising an anti-ROR1 antibody with a proteolytically cleavable linker and the cytotoxic antimicrotubule agent MMAE. In the phase 1 waveLINE-001 study, zilovertamab vedotin was shown to have antitumor activity in heavily pretreated lymphoid cancers and promising efficacy and manageable safety in combination with R-CHP as first-line treatment for DLBCL. The randomized, open-label, phase 2 waveLINE-011 study (NCT06890884) has been designed to evaluate the efficacy and safety of zilovertamab vedotin plus R-CHP versus polatuzumab vedotin plus R-CHP in participants with previously untreated GCB DLBCL. Methods: Key eligibility criteria include age ≥18 years, previously untreated histologically confirmed GCB DLBCL (including but not limited to: DLBCL not otherwise specified GCB type and high-grade B-cell lymphoma HGBL GCB subtype), PET-positive disease at screening, an ECOG performance status score of 0 to 2, and an International Prognostic Index (IPI) score of 2 to 5. Participants with a history of transformation of indolent disease to DLBCL or with primary mediastinal B-cell lymphoma or gray zone lymphoma are excluded. All participants will be randomly assigned (1:1) to zilovertamab vedotin 1.75 mg/kg plus R-CHP or polatuzumab vedotin 1.8 mg/kg plus R-CHP on day 1 of every 3-week cycle for 6 cycles. Randomization will be stratified by geographic region (Western Europe vs US vs rest of world), IPI score (2 vs 3-5), bulky disease (<7.5 cm vs ≥7.5 cm), and histopathology (HGBL vs others). The primary end point is CR rate at the end of therapy per Lugano criteria by BICR. Secondary end points include PFS, EFS, duration of CR, OS, safety, and change in PROs. Response assessments (CT/FDG-PET) will be performed after cycle 4 day 1 but on or before cycle 5 day 1, and at 12 weeks after the cycle 4 scan. Follow-up efficacy assessments will be completed every 24 weeks for 2 years from the end of treatment assessment, then every year for 3 years. Adverse events will be graded per NCI CTCAE v5.0. Approximately 594 participants will be enrolled. Recruitment is ongoing. Clinical trial information: NCT06890884 .