Zenocutuzumab Demonstrates Durable Activity in NRG1 Fusion–Positive Cholangiocarcinoma

Clinical Summary: 

• Design/Population: The phase 2 eNRGy trial evaluated zenocutuzumab, a HER2 × HER3 bispecific antibody, in patients with advanced NRG1 fusion–positive cholangiocarcinoma who had received prior standard therapy or were considered unsuitable for standard treatment.
• Key Outcomes: Zenocutuzumab demonstrated durable antitumor activity with meaningful and sustained clinical benefit while maintaining a favorable safety profile. 
• Clinical Relevance: These findings support HER2/HER3-targeted therapy as a promising treatment strategy for patients with NRG1 fusion–positive cholangiocarcinoma and reinforce the importance of comprehensive molecular profiling to identify this rare but actionable genomic alteration.

Results from the phase 2 eNRGy trial demonstrated that zenocutuzumab produced durable responses and meaningful clinical activity in patients with advanced NRG1 fusion–positive cholangiocarcinoma, supporting HER2/HER3-targeted therapy as a potential treatment option for this rare molecular subtype.

“In the current treatment paradigm, first-line therapy for patients with advanced disease typically consists of gemcitabine/cisplatin chemotherapy in combination with PD-1 blockade,” stated James Cleary, MD, PhD, Dana-Farber Cancer Institute, Boston, Massachusetts, and coauthors. “Given the modest efficacy of second-line chemotherapy, a significant advance has been the development of targeted therapies for cholangiocarcinoma patients with tumors harboring actionable alterations such as FGFR2 rearrangements, IDH1 mutations, BRAF V600E mutations, and HER2 amplification.”

In this single-arm study, 22 patients with advanced NRG1 fusion–positive cholangiocarcinoma received 750 mg of zenocutuzumab intravenously once every 2 weeks. Eligible patients had received prior standard therapy or were considered unlikely to tolerate or derive meaningful benefit from available treatment options. The primary end point was investigator-assessed objective response rate (ORR). Secondary end points included duration of response, clinical benefit rate, progression-free survival (PFS), overall survival (OS), and safety. 

At the data cutoff point, 19 patients met the protocol-defined criteria for the primary efficacy analysis. The confirmed ORR was 36.8%, with all responses classified as partial responses by investigator assessment. Median duration of response was 7.4 months, median time to response was 1.9 months, and the clinical benefit rate was 57.9%. Tumor shrinkage was observed in 73.7% of evaluable patients.

Median PFS was 9.2 months. At the time of analysis, median OS had not been reached, with estimated OS rates of 82.6% at 12 months and 54.2% at 24 months. Responses were observed across multiple NRG1 fusion partners and among both previously treated and treatment-naïve patients.

Most treatment-related adverse events were grade 1/2, with diarrhea (27.3%), fatigue (18.2%), and nausea (13.6%) reported most frequently. One patient experienced a grade 3 treatment-related adverse event of anemia, and no patients discontinued treatment because of an adverse event. No treatment-related serious adverse events or treatment-related deaths were reported.

“Zenocutuzumab represents a promising targeted therapy for this rare, molecularly defined subset of cholangiocarcinoma with limited treatment options,” concluded Dr Cleary et al. 

“This less common mechanism of ligand blockade of a receptor tyrosine kinase is clinically relevant and opens new ways to treat this biologically unique solid tumor subtype,” added Journal of Clinical Oncology associate editor Robert Maki, MD, PhD, Memorial Sloan Kettering Cancer Center, New York, New York. 

Source:

Cleary JM, Springfeld C, Arnold D, et al. Efficacy and tolerability of zenocutuzumab in advanced NRG1 fusion–positive cholangiocarcinoma: Results from the eNRGy phase II trial. J Clin Oncol. Published online: July 1, 2026. doi: 10.1200/JCO-25-03128