Zenocutuzumab Shows 37% Response Rate in Rare NRG1-Positive Cholangiocarcinoma
Key Insights
Zenocutuzumab demonstrated a 37% objective response rate in 19 patients with NRG1 (search)-positive cholangiocarcinoma (search) in the phase II eNRGy trial, with a median duration of response of 7.4 months.
The bispecific antibody targeting HER2 (search) and HER3 (search) achieved a median progression-free survival of 9.2 months in this rare cancer subtype that affects fewer than 1% of cholangiocarcinoma (search) patients.
All 16 evaluable patients showed declines in CA 19-9 cancer biomarker levels, with 69% experiencing more than 50% reduction, supporting the drug's anticancer activity.
Zenocutuzumab-zbco demonstrated significant clinical activity in patients with NRG1 (search)-positive cholangiocarcinoma (search), achieving objective responses in more than one-third of patients in the phase II eNRGy trial. The findings, presented at the 2025 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, suggest the bispecific antibody's therapeutic potential extends beyond its FDA-approved indications for lung and pancreatic cancers.
Clinical Efficacy Results
Among 19 evaluable patients with advanced NRG1 (search)-positive cholangiocarcinoma (search), zenocutuzumab achieved an objective response rate of 37%, with a median duration of response of 7.4 months (95% confidence interval = 4.6 months to not evaluable). The median time to response was 1.9 months, and the median progression-free survival reached 9.2 months (95% CI = 3.9–11.4 months). The clinical benefit rate was 58%.
"These data suggest that the benefit of zenocutuzumab extends beyond the FDA-approved indications of lung and pancreatic cancer to cholangiocarcinoma (search)," stated presenting study author Alison Schram, MD, Gynecologic Medical Oncologist and Early Drug Development Specialist at Memorial Sloan Kettering Cancer Center. "Zenocutuzumab is a potential new treatment for patients with NRG1 (search)-positive cholangiocarcinoma, which is a patient population that has significant unmet need."
Biomarker Response and Safety Profile
Cancer biomarker analysis revealed promising results across evaluable patients. Among 16 patients assessed for CA 19-9 levels, all experienced declines in this cholangiocarcinoma (search) biomarker, with 69% showing more than 50% reduction. Similarly, gamma-glutamyl transferase levels dropped in 84% of patients, with 74% experiencing more than 50% reduction.
The safety profile was generally manageable, with most adverse events being grade 1 or 2. Grade 3 or higher adverse events observed in at least two patients included anemia in 14%, hypomagnesemia in 9%, and gamma-glutamyl transferase increase in 9%.
Addressing Unmet Medical Need
Cholangiocarcinoma (search) represents a rare cancer type diagnosed in approximately 2,000 to 3,000 people annually in the United States. The disease originates in bile ducts, which transport bile to the gallbladder and small intestine. NRG1 (search)-positive cholangiocarcinomas comprise fewer than 1% of all cholangiocarcinomas but present particular treatment challenges.
"NRG1 (search)-positive cholangiocarcinomas are typically aggressive. The most common first-line treatment for advanced cholangiocarcinoma (search) is chemotherapy with immunotherapy, but the disease inevitably progresses," Dr. Schram explained. "NRG1-positive tumors usually lack other tumor drivers that might qualify them for approved targeted therapies, and there are very few effective treatments available to these patients after first-line chemoimmunotherapy stops working."
Mechanism of Action and Trial Design
Zenocutuzumab functions as a bispecific antibody targeting both HER2 (search) and HER3 (search) proteins on cell surfaces that regulate growth. NRG1 (search) fusion proteins bind to HER3, inducing structural changes that facilitate HER2-HER3 complex formation and activate downstream growth signaling. By targeting both receptors, zenocutuzumab blocks the formation of the growth-promoting HER2-HER3 complex and prevents HER3-mediated NRG1 signaling.
The eNRGy trial enrolled 22 patients with advanced NRG1 (search)-positive cholangiocarcinoma (search), with three excluded from efficacy analysis due to another driver mutation or prior anti-HER3 (search) antibody exposure. The median age of patients was 57 years, and 91% had received prior systemic therapy.
Regulatory Recognition
Based on these findings, the FDA granted zenocutuzumab Breakthrough Therapy designation for treating adults with advanced, unresectable, or metastatic cholangiocarcinoma (search) harboring an NRG1 (search) gene fusion. This designation builds upon the drug's December 4, 2024 accelerated approval for NRG1-positive non-small cell lung cancer (search) and pancreatic adenocarcinoma (search).
"It is challenging to conduct clinical trials for rare cancer types and for tumors driven by rare genomic alterations, like NRG1 (search) fusions, but it is not sufficient to extrapolate from tumors with different molecular characteristics," Dr. Schram noted. "It is increasingly evident that tumors driven by rare genomic alterations have distinct biology and respond differently to standard therapies."