Multinational phase 2 trial of zenocutuzumab monotherapy for advanced NRG1 fusion-positive cancer

Dr. Alison Schram

Neuregulin 1 (NRG1) fusions are recurrent oncogenic drivers found in multiple solid tumors. NRG1 binds to human epidermal growth factor receptor 3 (HER3), leading to heterodimerization with HER2 and activation of downstream growth and proliferation pathways. Zenocutuzumab is a bispecific antibody against HER2 and HER3. The multinational phase 2 eNRGy trial evaluated zenocutuzumab in patients with advanced NRG1 fusion-positive solid cancer. The primary endpoint was overall response rate. Objective response occurred in 30% (95% CI 23-37) of patients, with a median duration of response of 11.1 months; 19% of responses were ongoing at the data-cutoff date. Responses were observed in multiple tumor types, including 29% of patients with non-small cell lung cancer and 42% of patients with pancreatic cancer. The median progression-free survival was 6.8 months (95% CI 5.5-9.1). Adverse events were primarily grade 1 or 2; one patient discontinued zenocutuzumab owing to a treatment-related adverse event. The authors conclude that zenocutuzumab showed efficacy in patients with advanced NRG1 fusion-positive cancer, notably NSCLC and pancreatic cancer, with mainly low-grade adverse events.