Updated Results from the Phase 2 Waveline-004 Study of Zilovertamab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Background: Up to 50% of patients with diffuse large B-cell lymphoma (DLBCL) will develop relapsed or refractory (R/R) disease, and treatment options are limited for patients whose disease has progressed after or were ineligible for autologous stem cell transplantation (ASCT) or chimeric antigen receptor T-cell (CAR-T) therapy. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed in various hematological malignancies such as DLBCL. Zilovertamab vedotin is a ROR1-targeting antibody-drug conjugate that has demonstrated clinically meaningful antitumor activity and manageable safety in early results of the phase 2 waveLINE-004 study (NCT05144841) for patients with R/R DLBCL whose disease progressed after or were ineligible for ASCT and/or CAR-T therapy. We present updated results from waveLINE-004. Methods: Eligible patients ≥18 years of age with histologically confirmed R/R DLBCL per WHO classification whose disease progressed after ≥2 lines of therapy including an alkylating agent, anthracycline, and an anti-CD20 antibody and whose disease had progressed after or were ineligible for ASCT and CAR-T therapy. Additionally, patients had to have had measurable disease per Lugano 2014 criteria, PET-positive disease, and an ECOG PS of 0-2. Patients received zilovertamab vedotin 2.5 mg/kg IV until disease progression or until any other discontinuation criteria were met. ORR per Lugano 2014 criteria by investigator review was the primary end point. DOR per Lugano 2014 criteria by investigator review and safety/tolerability were secondary end points. DCR (CR + PR + SD) and PFS per Lugano 2014 criteria by investigator review and OS were exploratory end points. Efficacy is reported for patients with ≥1 postbaseline assessment. Safety is reported for all patients who received ≥1 dose of zilovertamab vedotin. All patients provided written informed consent. The data cutoff date was April 26, 2023. Results: A total of 98 patients were enrolled and received ≥1 dose of zilovertamab vedotin. The median age was 66 years (range, 19-88), 63 patients (64%) were male, 86 (92%) had an ECOG PS of 0 or 1, and 70 (71%) had received ≥3 prior lines of therapy. Of these 98 patients, 57 (58%) were ineligible for ASCT or CAR-T therapy. At data cutoff, 61 patients (62%) had discontinued treatment, most commonly due to progressive disease (37 [38%]), and treatment was ongoing for 37 patients (38%). Median time from first dose to data cutoff was 4.5 months (range, 0.2-13.2) for patients who received ≥1 dose of zilovertamab vedotin (all-patients-as-treated population; N = 98) and 5.6 months (range, 0.9-13.2) for patients who had ≥1 postbaseline scan (efficacy analysis population; n = 79). ORR was 29% (95% CI, 19-40); 10 patients (13%) had a CR, 13 (16%) had a PR, and 10 (13%) had SD; DCR was 42% (95% CI, 31-53). Median DOR was 3.0 months (range, 0.0+ to 8.8+); an estimated 40% of responders had a response duration ≥6 months. Median PFS was 2.5 months (95% CI, 1.9-3.0); the 6-month PFS rate was 15%. Median OS for all 98 patients was 10.6 months (95% CI, 5.1-NR); the 6-month OS rate was 62%. Treatment-related adverse events (AEs) occurred in 78 patients (80%), of which the most common (≥25%) were neutrophil count decreased (48%) and anemia (26%). Grade 3-5 treatment-related AEs occurred in 51 patients (52%); most commonly (≥15%) neutrophil count decreased (39%) and anemia (15%). One patient (1%) experienced a grade 2 treatment-related infusion reaction. Eighteen patients (18%) experienced peripheral neuropathy regardless of treatment of whom 2 (2%) had a grade 3 or 4 event. Median time to onset of first peripheral neuropathy was 29.5 days (range, 3-284). Dose modification because of peripheral neuropathy was required for 10 patients (10%); 6 (6%) experienced dose reduction and 4 (4%) experienced dose interruption. Treatment-related AEs led to discontinuation in 4 patients (4%; 2 diabetic ketoacidosis, 1 septic shock, and 1 acute kidney injury). Two patients (2%) died because of treatment-related AEs (1 septic shock, 1 acute kidney injury). Summary/Conclusion: After additional follow-up, zilovertamab vedotin continued to demonstrate sustained antitumor activity and manageable safety in patients with R/R DLBCL whose disease progressed after or were ineligible for ASCT and/or CAR-T therapy. These results support the continued investigation of zilovertamab vedotin in patients with R/R DLBCL.