Phase 2 Study of Zilovertamab Vedotin in Participants With Metastatic Solid Tumors

Abstract Purpose: Zilovertamab vedotin, an antibody‒drug conjugate targeting receptor tyrosine kinase‒like orphan receptor 1 (ROR1), had manageable safety and promising antitumor activity in participants with relapsed or refractory non-Hodgkin lymphomas. We evaluated zilovertamab vedotin in participants with previously-treated metastatic solid tumors. Methods: This phase 2, open-label, nonrandomized study (NCT04504916) enrolled participants with metastatic triple-negative breast cancer, hormone receptor‒positive (HR+) breast cancer, nonsquamous non‒small-cell lung cancer, platinum-resistant ovarian cancer, or pancreatic cancer. Participants received zilovertamab vedotin ≤2.5 mg/kg once every 3 weeks (Q1/3W) or 1.75 mg/kg twice every 3 weeks (Q2/3W). Primary endpoint was objective response rate (ORR) per RECIST v1.1 by blinded independent central review. ROR1 protein expression was correlated with clinical outcomes. Results: 102 participants were enrolled (Q1/3W, n=70; Q2/3W, n=32). ORR was 1% (95% CI, 0%‒8%) with Q1/3W dosing (1 partial response, HR+/HER2− breast cancer cohort) and 0% with Q2/3W dosing. Median progression-free survival (95% CI) was 2.3 (2.0‒4.1) and 1.9 (1.7‒2.1) months, respectively; median overall survival (95% CI) was 8.3 (5.2‒10.3) and 5.5 (4.4‒11.0) months. Across dosing regimens, treatment-related adverse events (AEs) were reported in 85 participants (83%), most commonly fatigue (29%) and nausea (28%). Treatment-related peripheral neuropathy occurred in 8%. Treatment-related AEs led to dose interruption/reduction in 32 participants (31%) and permanent treatment discontinuation in 7 (7%). Tissue for ROR1 immunohistochemistry was available on 17 participants, with only 3 (all nonresponders) showing ROR1 expression. Conclusions: Zilovertamab vedotin had minimal antitumor activity, with only a single responder, and manageable safety in participants with previously-treated metastatic solid tumors.