Zilovertamab vedotin plus R-CHP versus polatuzumab vedotin plus R-CHP as first-line therapy in participants with germinal center B-cell diffuse large B-cell lymphoma (DLBCL): The randomized, open-label, Phase 2 waveline-011 Study

Abstract Introduction: DLBCL is a genetically heterogeneous malignancy that can be broadly categorized into 3 subtypes: activated B-cell–like (ABC) DLBCL, germinal center B-cell–like (GCB) DLBCL, and unclassified DLBCL. Polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) is a standard-of-care option for the first-line treatment of DLBCL, regardless of subtype. However, clinical data have shown that while polatuzumab plus R-CHP prolongs progression-free survival (PFS) compared with R-CHOP in patients with ABC DLBCL, the combination provides no benefit over R-CHOP in patients with GCB DLBCL. Novel, first-line options for the treatment of GCB DLBCL are needed. Receptor tyrosine kinase–like orphan receptor 1 (ROR1) is an oncofetal transmembrane protein that is overexpressed in a number of hematologic and solid malignancies including DLBCL, making it an attractive therapeutic target. Zilovertamab vedotin is an antibody-drug conjugate comprising an anti-ROR1 monoclonal antibody with a proteolytically cleavable linker and the cytotoxic antimicrotubule agent monomethyl auristatin E. Zilovertamab vedotin showed evidence of antitumor activity in heavily pretreated lymphoid cancers in the phase 1 waveLINE-001 study and showed promising efficacy and manageable safety in combination with R-CHP as front-line treatment in DLBCL. Here, we describe the methodology of the randomized, open-label, phase 2 waveLINE-011 study (NCT06890884), which has been designed to evaluate the efficacy and safety of zilovertamab vedotin plus R-CHP versus polatuzumab vedotin plus R-CHP in previously untreated GCB DLBCL. Methods: Eligible participants are aged ≥18 years, have previously untreated histologically confirmed diagnosis of GCB DLBCL per WHO classification of neoplasms of the hematopoietic and lymphoid tissues (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 Eastern Cooperative Oncology Group performance status score of 0 to 2, an International Prognostic Index (IPI) score of 2 to 5, adequate organ function, and have provided a tissue biopsy. Participants with a history of transformation of indolent disease to DLBCL, primary mediastinal B-cell lymphoma or gray zone lymphoma, or clinically significant cardiovascular disease, pericardial effusion, or pleural effusion 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 up to 6 cycles. Randomization will be stratified by geographic region (Western Europe vs US vs rest of world), IPI score (2 vs 3 to 5), bulky disease (<7.5 cm vs ≥7.5 cm), and histopathology (HGBL vs others). The primary end point is complete response (CR) rate at the end of therapy per Lugano response criteria by blinded independent central review (BICR). Secondary end points include PFS, event-free survival, and duration of CR per Lugano response criteria by BICR, overall survival, safety, and change in patient-reported outcomes. Approximately 594 participants with GCB DLBCL will be enrolled. Recruitment for waveLINE-011 is currently underway.