DOI: 10.1200/jco-25-03128 ISSN: 0732-183X

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

James M. Cleary, Christoph Springfeld, Dirk Arnold, Antoine Hollebecque, Olumide Gbolahan, Misako Nagasaka, Salvatore Siena, Frans Opdam, Yu Sunakawa, Philippe A. Cassier, Gaurav Trikha, Eelke H. Gort, Vaia Florou, Richard Greil, Paul F. La Porte, Pritesh J. Gandhi, Fiona Garner, Ernesto Wasserman, Shola Adeyemi, Alison M. Schram
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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.

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