Zenocutuzumab Demonstrates Durable Responses in NRG1 Fusion-Positive Cholangiocarcinoma
Key Clinical Takeaways
- Design/Population: This phase 2 basket trial evaluated zenocutuzumab, a HER2/HER3 bispecific antibody, in patients with advanced NRG1 fusion–positive cholangiocarcinoma. Twenty-two patients were treated (19 evaluable), with a median age of 57 years and 95% presenting with stage IV disease; most had received prior systemic therapy.
- Key Outcomes: Zenocutuzumab achieved an overall response rate of 37% and a clinical benefit rate of 58%, with responses observed at a median of 1.9 months and a median duration of response of 7.4 months. Median progression-free survival was 9.2 months, and median overall survival was not yet reached at a 15.2-month follow-up.
- Safety: Treatment was well tolerated, with mostly grade 1–2 events such as anemia and diarrhea. Only one patient experienced a grade 3 treatment-related adverse event (anemia), and no discontinuations occurred due to toxicity.
- Clinical Relevance: Zenocutuzumab produced rapid and durable responses in patients with NRG1 fusion–positive cholangiocarcinoma, a population with limited therapeutic options. These results reinforce the agent’s activity across tumor types and support its role as a potential new targeted therapy for this rare molecular subset.
Alison Schram, MD, Memorial Sloan Kettering Cancer Center, New York, New York, discusses results from the phase 2 eNRGy trial evaluating zenocutuzumab, a HER2/HER3 bispecific antibody, in patients with advanced NRG1 fusion–positive cholangiocarcinoma.
Zenocutuzumab showed meaningful clinical activity, with an overall response rate of 37% and a clinical benefit rate of 58%. Responses were durable, and the treatment was well tolerated, with mostly grade 1/2, reversible adverse events. These findings support zenocutuzumab as a promising targeted therapy for patients with this rare and aggressive cancer.
These results were presented at the 2025 AACR-NCI EORTC International Conference on Molecular Targets and Cancer Therapeutics (TARGETs) in Boston, Massachusetts.
Transcript:
My name is Ali Schram from Memorial Sloan Kettering Cancer Center, and today I'll be talking about zenocutuzumab efficacy and safety in advanced NRG1 fusion–positive cholangiocarcinoma, analysis from the phase 2 NRG1 trial. This data was presented at the TRIPLE meeting in 2025.
As some background, zenocutuzumab is a HER2/HER3 bispecific antibody and it's being explored in patients who have NRG1 gene fusions. NRG1 is a rare oncogenic driver that's seen across different solid tumors. It is observed at about less than 1% frequency in patients with cholangiocarcinoma, in addition to other solid tumors.
This particular clinical trial was a basket trial, and I presented the data recently on the cholangiocarcinoma patients. Cholangiocarcinoma is a rare, aggressive gastrointestinal cancer with a poor prognosis. The median survival in advanced disease is about 1 year and there are no approved targeted therapies for patients with NRG1 fusion–positive cholangiocarcinoma so patients are typically treated with just palliative systemic therapy for their metastatic disease. Zenocutuzumab, as I mentioned, is a HER2/HER3 bispecific antibody that is being explored in patients with NRG1 fusions. NRG1 is the ligand for HER3, and it causes HER3 to heterodimerize with HER2, activating downstream HER2 signaling. Zenocutuzumab blocks NRG1 ligand binding to HER3 and blocks the subsequent dimerization of HER2 and HER3, thereby blocking the downstream signaling. Zenocutuzumab also causes antibody-dependent cellular cytotoxicity, so it allows the immune system to recognize the cancer and come in and help clear the cancer. Zenocutuzumab received accelerated FDA approval in December 2024 for patients with non-small cell lung cancer and pancreatic cancer that harbor NRG1 fusions but, as I mentioned, we are now focusing on cholangiocarcinoma patients with this rare alteration.
The clinical trial enrolled patients with advanced disease, at least 18 years of age or older, ECOG performance status of ≤ 2, and an NRG1 fusion as documented on local laboratory testing. Patients received zenocutuzumab 750 milligrams every 2 weeks and continued therapy until unacceptable toxicity or disease progression. Tumor assessments took place every 8 weeks, typically with CT scans. The primary end point was the overall response rate, using RECIST version 1.1 per investigator assessment, and secondary end points included duration of response, clinical benefit rate, progression-free survival, and blinded independent central review efficacy in addition to safety.
As of the data cut of April 9, 2025, 22 patients with cholangiocarcinoma had been treated, including 19 that were evaluable for efficacy. Half were male, half were female. Median age was 57 years old, with a wide range from 23 to 82, and generally, patients had advanced disease. Ninety-five percent had stage IV disease and 1 patient had stage IIIB disease. The majority had intrahepatic cholangiocarcinoma—of the 22 patients, 18 with a known location had intrahepatic cholangiocarcinoma and 4 were unknown. Patients were heavily pretreated. The vast majority had had chemotherapy (84%), immunotherapy (16%), or anti-VEGF or transarterial chemoembolization. The median time since diagnosis was 9.3 months and the median number of prior systemic therapies was 1, with a range from 0 to 4, with most patients having received 1 or 2 prior lines of systemic therapy. The overall response rate per RECIST was 37%, and the clinical benefit rate—defined as a response or stable disease for 24 weeks—was 58% so more than half of patients had a clinical benefit, and many patients were on zenocutuzumab for longer than their prior chemotherapy. The median duration of exposure to zenocutuzumab was 9.2 months. The time to response was 1.9 months—so quick responses—and the median duration of response was 7.4 months, meaning there were durable responses. The median progression-free survival was 9.2 months, and the median overall survival had not been reached. At a median follow-up of 15.2 months, all patients who had CA 19-9 that was elevated at baseline had a decline in their CA 19-9 while on trial. Sixty-nine percent of patients had a decline of 50% or more, and the median time to first 50% reduction was 1 month. Of the 11 patients with an elevated CEA, 64% had a 50% reduction or greater—again, median time to first 50% reduction was 1 month.
Zenocutuzumab was extremely well tolerated. There were very few treatment-related adverse events. There was only 1 treatment-related grade 3 adverse event of anemia, and that did not result in treatment discontinuation. Treatment-emergent adverse events, regardless of causality, were most often anemia or diarrhea, and most adverse events were grade 1 or grade 2 and reversible.
In conclusion, zenocutuzumab demonstrated meaningful clinical activity in patients with NRG1 fusion–positive cholangiocarcinoma, with an overall response rate of 37% and clinical benefit rate of 58%. CA 19-9 declined in all of the patients with an elevated CA 19-9 at baseline, and zenocutuzumab was very well tolerated in this population. These results are consistent with the observed zenocutuzumab activity in other solid tumors, such as NRG1 fusion–positive lung cancer and pancreatic cancer, and zenocutuzumab therefore offers a potential new therapeutic option for patients with NRG1 fusion–positive cholangiocarcinoma.
Source:
Scrham AM, Cleary JM, Arnold D. Zenocutuzumab efficacy and safety in advanced NRG1+ cholangiocarcinoma: Analysis from the phase 2 eNRGy Trial. Presented at the 2025 AACR-NCI EORTC International Conference on Molecular Targets and Cancer Therapeutics Meeting. October 22 – 26, 2025; Boston, Massachusetts. A102.
