Abstract A102: Zenocutuzumab efficacy and safety in advanced NRG1+ cholangiocarcinoma: Analysis from the phase 2 eNRGy Trial

Abstract Background NRG1 gene fusions are rare oncogenic drivers in solid tumors including cholangiocarcinoma (∼0.5%), a disease with significant unmet need. No approved targeted therapy exists for NRG1+ cholangiocarcinoma. Zenocutuzumab, a HER2xHER3 bispecific antibody that blocks HER3-mediated NRG1 signaling and HER2/HER3 dimerization, recently received accelerated FDA approval for previously treated, advanced NRG1+ non-small cell lung cancer (NSCLC) and pancreatic adenocarcinoma based on results from the eNRGy phase 2 trial. We report an updated analysis of patients with NRG1+ cholangiocarcinoma enrolled in the eNRGy trial. Methods eNRGy is an ongoing, open-label, single-arm, phase 2 study of zenocutuzumab in advanced NRG1+ cancers. Patients are ≥18 y and previously treated with or not a candidate for other therapy and have measurable or evaluable disease per RECIST v1.1 and ECOG Performance Status ≤2. Zenocutuzumab (750 mg IV Q2W) is administered until disease progression or unacceptable toxicity. The primary endpoint is investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints include duration of response (DOR), progression-free survival (PFS), clinical benefit rate (CBR) (stable disease ≥24 weeks or partial/complete response), and safety. Results As of April 2025, 22 patients with advanced NRG1+ cholangiocarcinoma were enrolled. The median age was 57 years, 46% were male, and 64%/32%/5% had ECOG PS 0/1/2. The median time since diagnosis was 12.6 months and patients had a median of one prior systemic therapy (range 0-6). Three patients were excluded from efficacy analyses due to another driver mutation or prior anti-HER3 antibody therapy. The ORR was 37% (7/19) with a median DOR of 7.4 months (95% CI 4.6, NE), median time to response of 1.9 months, PFS of 9.2 months (95% CI 3.9, 11.4), and CBR of 58% (11/19). CA 19-9 declined in 100% of CA 19-9 evaluable patients (16/16) including >50% reduction in 69% (11/16). GGT declined in 84% (16/19) including >50% reduction in 74% (14/19). Most adverse events (AEs) were Grade 1/2. Grade 3+ AEs in ≥2 patients included anemia (14%), hypomagnesemia (9%), and GGT increase (9%). Conclusion Zenocutuzumab demonstrated clinically meaningful and durable efficacy with a favorable safety profile in patients with advanced NRG1+ cholangiocarcinoma, an aggressive disease with few treatment options. Citation Format: Alison M. Schram, James M. Cleary, Dirk Arnold, Antoine Hollebecque, Olumide Gbolahan, Misako Nagasaka, Salvatore Siena, Frans Opdam, Yu Sunakawa, Phillippe A. Cassier, Gaurav Trikha, Vaia Florou, Richard Greil, Paul F. La Porte, Pritesh Gandhi, Fiona Garner, Ernesto Wasserman, Shola Adeyemi, Christoph Springfeld. Zenocutuzumab efficacy and safety in advanced NRG1+ cholangiocarcinoma: Analysis from the phase 2 eNRGy Trial [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A102.