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

There are no approved targeted therapies for neuregulin 1 gene fusion-positive (NRG1+) cholangiocarcinoma. Zenocutuzumab, a HER2 x HER3 bispecific antibody, is approved for previously treate, advanced/metastatic NRG1+ non-small cell lung cancer and pancreatic adenocarcinoma. In the multinational phase 2 eNRGy trial, 22 adult patients with advanced NRG1+ cholangiocarcinoma received zenocutuzumab 750 mg intravenously once every 2 weeks. The median number of previous therapy lines was 1.0 (range 0-6). Among the 18 patients with tumor subtype data available, all had intrahepatic cholangiocarcinoma. The primary endpoint was investigator-assessed overall response rate (ORR). Three patients did not meet the protocol-defined criteria for inclusion in the efficacy analysis. Overall response was seen in 7 of 19 patients, for an ORR of 36.8% (95% CI 16.3-61.1). The median time to response was 1.9 months and the median duration of response was 7.4 months. The clinical benefit rate was 57.9% (95% CI 33.5-79.9), and the median progression-free survival was 9.2 months (3.9-11.1). Most treatment-related adverse events were grade 1 and 2. One patient had a grade 3 TRAE of anemia. No patients discontinued treatment due to an adverse event. The authors conclude that zenocutuzumab demonstrated clinically meaningful and durable antitumor activity with a favorable safety profile in patients with advanced NRG1+ cholangiocarcinoma.