FDA Grants Breakthrough Therapy Designation to Zenocutuzumab for Patients With Advanced NRG1-Positive Cholangiocarcinoma

On October 23, 2025, the US Food and Drug Administration (FDA) granted Breakthrough Therapy designation to zenocutuzumab for the treatment of patients with advanced unresectable or metastatic cholangiocarcinoma harboring a neuregulin 1 (NRG1) gene fusion. This designation was supported by updated results from the phase 2 eNRGy trial. 

These data were first presented by principal investigator Alison Scram, MD, Memorial Sloan Kettering Cancer Center, New York, New York, at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston, Massachusetts. 

In this open-label study, 204 patients with advanced NRG1-positive solid tumors across 12 tumor types were enrolled to receive 750 mg of intravenous zenocutuzumab once every 2 weeks. The primary end point was overall response rate (ORR). Key secondary end points included duration of response, progression-free survival (PFS), and safety. 

Among 19 evaluable patients in the cholangiocarcinoma cohort, zenocutuzumab demonstrated an ORR of 37%. Median time to response was 1.9 months and median duration of response was 7.4 months. Median PFS was 9.2 months, and the clinical benefit rate was 58%. For patients with evaluable CA 19-9 data, all showed a decline in serum levels, including a >50% reduction in 69% of patients. The safety profile was consistent with prior findings and most adverse events were grade 1 or 2. Serious adverse events occurred in 23% of patients and were deemed not to be treatment-related. No discontinuations due to treatment-related toxicities were reported.

“NRG1 fusions represent a rare but actionable driver in cholangiocarcinoma, and the data from the eNRGy trial continue to highlight the potential of zenocutuzumab to offer meaningful clinical benefit for these patients,” stated Dr Schram. 

Sources: 

Partner Therapeutics, Inc. Zenocutuzumab-zbco granted FDA breakthrough therapy designation for NRG1+ cholangiocarcinoma; Data highlighting potential of zenocutuzumab-zbco in NRG1+ cholangiocarcinoma to be presented at AACR-NCI-EORTC. Press Release. Published October 23, 2025. Accessed October 29, 2025. https://www.prnewswire.com/news-releases/zenocutuzumab-zbco-granted-fda-breakthrough-therapy-designation-for-nrg1-cholangiocarcinoma-data-highlighting-potential-of-zenocutuzumab-zbco-in-nrg1-cholangiocarcinoma-to-be-presented-at-aacr-nci-eortc-302593179.html 

Schram AM, Goto K, Kim DW, et al. Efficacy of zenocutuzumab in NRG1 fusion–positive cancer. N Engl J Med. Published online: February 5, 2025. doi: 10.1056/NEJMoa2405008