Phase 2 Study of Zilovertamab Vedotin in Participants with Metastatic Solid Tumors.

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.

Patients and methods: This phase 2, open-label, nonrandomized study (NCT04504916) enrolled participants with metastatic triple-negative breast cancer, hormone receptor-positive 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). The primary endpoint was objective response rate per RECIST version 1.1 by blinded independent central review. ROR1 protein expression was correlated with clinical outcomes.

Results: A total of 102 participants were enrolled (Q1/3W, n = 70; Q2/3W, n = 32). The objective response rate was 1% [95% confidence interval (CI), 0%-8%] with Q1/3W dosing (one partial response, hormone receptor-positive/HER2-negative breast cancer cohort) and 0% with Q2/3W dosing. The median progression-free survival (95% CI) was 2.3 (2.0-4.1) and 1.9 (1.7-2.1) months, respectively; the median overall survival (95% CI) was 8.3 (5.2-10.3) and 5.5 (4.4-11.0) months, respectively. Across dosing regimens, treatment-related adverse events were reported in 85 participants (83%), most commonly fatigue (29%) and nausea (28%). Treatment-related peripheral neuropathy occurred in 8%. Treatment-related adverse events led to dose interruption/reduction in 32 participants (31%) and permanent treatment discontinuation in 7 (7%). Tissue for ROR1 IHC 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.

Significance: Zilovertamab vedotin had minimal antitumor activity and manageable safety in participants with previously treated metastatic solid tumors of various histologic subtypes. The results suggest that further development of zilovertamab vedotin in these solid tumors is not warranted.