Zilovertamab Vedotin (MK-2140) in Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL): Updated Results from the Phase 2 Waveline-004 Study
Authors: Ozcan Muhit , Lv Fangfang , Norasetthada Lalita , Paszkiewicz-Kozik Ewa , Díaz Schmidt Joaquin , Modi Dipenkumar , Fosså Alexander , Goyal Sagun , Kim Won Seog , Lee Seung Tae , Santoro Armando , Sonmez Mehmet , Pathiraja Kumudu , Reddy Nishitha , Marinello Patricia , Song Yuqin 
Published: December 2023

Background: DLBCL is an aggressive non-Hodgkin lymphoma (NHL) that is often curable with frontline therapy, but up to 50% of patients (pts) will develop relapsed or refractory (R/R) disease. Treatment options are limited for pts with R/R DLBCL who have progressed after or are ineligible for autologous stem cell transplant (ASCT) or chimeric antigen receptor (CAR) T-cell therapy. ROR1 is an oncofetal transmembrane protein that is expressed in DLBCL. Zilovertamab vedotin, an antibody-drug conjugate comprising a humanized monoclonal antibody against ROR1, a proteolytically cleavable linker, and the antimicrotubule agent monomethyl auristatin E (MMAE), initially demonstrated promising antitumor activity and manageable safety in R/R NHL in the phase 1 waveLINE-001 study. Early results from the single-arm, open-label, phase 2 waveLINE-004 study (NCT05144841) showed that zilovertamab vedotin had clinically meaningful antitumor activity and manageable safety in pts with R/R DLBCL who progressed after or were ineligible for ASCT and/or CAR T-cell therapy. We present updated results from waveLINE-004.

Methods: Eligible pts were ≥18 y, had histologically confirmed R/R DLBCL per WHO classification, measurable disease per Lugano 2014 criteria, PET-positive disease, and an ECOG performance status of 0 to 2. Pts were required to have disease progression after ≥2 prior lines of therapy including an alkylating agent, anthracycline, and an anti-CD20 antibody, and had progressed after or were ineligible for ASCT and CAR T-cell therapy. Pts received zilovertamab vedotin 2.5 mg/kg IV Q3W until disease progression, unacceptable toxicity, or withdrawal. Primary end point was ORR per Lugano 2014 criteria. Secondary end points were DOR and safety and tolerability. PFS and OS were exploratory. Efficacy is reported for pts who had ≥1 postbaseline assessment available. Safety is reported for all pts who received ≥1 dose of zilovertamab vedotin.

Results: At the data cutoff (April 26, 2023), 98 pts had been enrolled and received ≥1 dose of zilovertamab vedotin; 61 pts (62%) had discontinued treatment predominantly because of disease progression (38%); 37 pts (38%) were ongoing. Median age was 66 y (range, 19-88), 63 pts (64%) were male, and 86 (92%) had an ECOG performance status of 0 or 1. Most pts (n = 70; 71%) had received ≥3 prior lines of therapy. Forty-one (42%) and 13 pts (13%) had high-intermediate and high-risk NCCN-IPI scores, respectively. Fifteen pts (15%) had undergone prior ASCT, 18 (18%) had undergone prior CAR T-cell therapy, and 5 (5%) had undergone both ASCT and CAR T-cell therapy. Median time from first dose to data cutoff was 4.5 mo (range, 0.2-13.2) for pts who received ≥1 dose of zilovertamab vedotin, and 5.6 mo (range, 0.9-13.2) for the 79 pts who had ≥1 postbaseline scan (efficacy analysis population). ORR per investigator review was 29% (95% CI, 19.4-40.4), with 10 pts (13%) having a complete response and 13 (16%) a partial response; 10 pts (13%) had stable disease, for a disease control rate of 42% (95% CI, 30.8-53.4). Median DOR was 3.0 mo (range, 0.0+ to 8.8+). Median PFS was 2.5 mo (95% CI, 1.9-3.0); 6-mo PFS was 15%. Median OS for all 98 pts was 10.6 mo (95% CI, 5.1-NR); 6-mo OS was 62%. Treatment-related AEs occurred in 78 pts (80%), most commonly (≥20%) neutrophil count decreased (n = 47; 48%), anemia (n = 25; 26%), diarrhea (n = 23; 23%), and white blood cell count decreased (n = 20; 20%). Grade 3-5 treatment-related AEs occurred in 51 pts (52%), most commonly (≥10%) neutrophil count decreased (n = 38; 39%), anemia (n = 15; 15%), and white blood cell count decreased (n = 12; 12%). Two pts (2%) died because of treatment-related AEs (septic shock, acute kidney injury). Four pts (4%) discontinued zilovertamab vedotin because of treatment-related AEs (2 diabetic ketoacidosis, 1 septic shock, 1 acute kidney injury). Peripheral neuropathy occurred in 18 pts (18%), 2 (2%) of whom had a grade 3/4 event. Dose modification because of peripheral neuropathy was required for 10 pts (10%). One pt (1%) experienced a grade 2 treatment-related infusion reaction.

Conclusions: In this updated analysis of waveLINE-004, zilovertamab vedotin continued to demonstrate clinically meaningful antitumor activity in pts with R/R DLBCL who had progressed after or were ineligible for ASCT and/or CAR T-cell therapy. The safety profile of zilovertamab vedotin was manageable, and consistent with the known profile of MMAE-containing agents.