Efficacy and Tolerability of Zenocutuzumab in Advanced <i>NRG1</i> Fusion–Positive Cholangiocarcinoma: Results From the eNRGy Phase II Trial

PURPOSE Presently, to our knowledge, there are no approved targeted therapies for neuregulin 1 gene fusion–positive ( NRG1 +) cholangiocarcinoma. Zenocutuzumab, a HER2 × HER3 bispecific antibody, is approved for previously treated, advanced/metastatic NRG1 + non–small cell lung cancer and pancreatic adenocarcinoma. Here, we report results for 22 patients with NRG1 + cholangiocarcinoma in the eNRGy trial. METHODS eNRGy is a single-arm, phase II study of zenocutuzumab in advanced NRG1 + solid tumors. Patients were age 18 years and older and previously treated with or unsuitable for standard therapy. Zenocutuzumab 750 mg was administered intravenously once every 2 weeks. The primary end point was investigator-assessed overall response rate (ORR; RECIST v1.1). Secondary end points included duration of response (DOR), clinical benefit rate (CBR), progression-free survival (PFS), and safety. RESULTS As of July 31, 2025, 22 patients (median age 57.5 years) with advanced NRG1 + cholangiocarcinoma were enrolled and had received a median of 1.0 (range, 0-6) prior therapies. In the 18 patients with tumor subtype data available, all had intrahepatic cholangiocarcinoma. Three patients did not meet the protocol-defined criteria for inclusion in the efficacy analysis. Seven of 19 patients achieved a response, resulting in an ORR of 36.8% (95% CI, 16.3 to 61.6). The median DOR was 7.4 months and the median time to response was 1.9 months. The CBR was 57.9% (95% CI, 33.5 to 79.7). Median PFS was 9.2 months (95% CI, 3.9 to 11.1). Most treatment-related adverse events (TRAEs) were grade 1 and 2, and the most common were diarrhea (27.3%), fatigue (18.2%), and nausea (13.6%). One patient had a grade 3 TRAE of anemia. No patients discontinued treatment due to an AE. CONCLUSION Zenocutuzumab demonstrated clinically meaningful and durable antitumor activity with a favorable safety profile in patients with advanced NRG1+ cholangiocarcinoma.