Zenocutuzumab-zbco yielded clinical activity in more than one-third of patients with cholangiocarcinoma and an NRG1 fusion, according to findings from the phase II eNRGy trial presented at the 2025 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (Abstract A102).
“These data suggest that the benefit of zenocutuzumab extends beyond the FDA-approved indications of lung and pancreatic cancer to cholangiocarcinoma,” stated presenting study author Alison Schram, MD, Gynecologic Medical Oncologist and Early Drug Development Specialist at Memorial Sloan Kettering Cancer Center, New York. “Zenocutuzumab is a potential new treatment for patients with NRG1-positive cholangiocarcinoma, which is a patient population that has significant unmet need.”
Study Rationale and Methods
Zenocutuzumab is a bispecific antibody that targets both HER2 and HER3 to stop the HER2-HER3 growth-promoting complex from forming and to block HER3-mediated NRG1 signaling. The agent is being investigated in the ongoing, open-label, single-arm phase II eNRGy trial of patients with advanced solid tumors harboring an NRG1 fusion. Based on results from the study, zenocutuzumab was granted accelerated approval by the U.S. Food and Drug Administration (FDA) on December 4, 2024, for the treatment of adults with advanced, unresectable, or metastatic non–small cell lung cancer harboring an NRG1 gene fusion with disease progression on or after prior systemic therapy, as well as for the treatment of adults with advanced, unresectable, or metastatic pancreatic adenocarcinoma harboring an NRG1 gene fusion with disease progression on or after prior systemic therapy.
In the eNRGy trial, 22 patients with advanced NRG1-positive cholangiocarcinoma were enrolled. Three of these patients were excluded from the efficacy analysis due to another driver mutation or prior exposure to an anti-HER3 antibody.
“NRG1-positive cholangiocarcinomas are typically aggressive. The most common first-line treatment for advanced cholangiocarcinoma is chemotherapy with immunotherapy, but the disease inevitably progresses,” Dr. Schram said. “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.”
Key Study Findings
Among the 19 evaluable patients with NRG1-positive cholangiocarcinoma, the objective response rate was 37%, with a median duration of response of 7.4 months (95% confidence interval [CI] = 4.6 months to not evaluable), and the median time to response was 1.9 months. The median progression-free survival was 9.2 months (95% CI = 3.9–11.4 months), and the clinical benefit rate was 58%.
A total of 16 patients were evaluable for CA 19-9, and levels of CA 19-9 declined in all of these patients, with more than a 50% reduction noted in 69% of these patients. Gamma-glutamyl transferase levels also dropped in 84% of patients, with more than a 50% reduction noted in 74% of patients.
The majority of adverse events were 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%.
“It is challenging to conduct clinical trials for rare cancer types and for tumors driven by rare genomic alterations, like NRG1 fusions, but it is not sufficient to extrapolate from tumors with different molecular characteristics. It is increasingly evident that tumors driven by rare genomic alterations have distinct biology and respond differently to standard therapies,” Dr. Schram noted.
These findings led to the FDA granting zenocutuzumab a Breakthrough Therapy designation for the treatment of adults with advanced, unresectable, or metastatic cholangiocarcinoma harboring an NRG1 gene fusion.
Disclosure: The study was supported by Merus and Partner Therapeutics. Dr. Schram has served on the advisory boards of Relay Therapeutics, Mersana Therapeutics, Merus, Partner Therapeutics, PMV Pharma, Schrodinger, Repare Therapeutics, Revolution Medicines, Endeavor BioMedicines, Day One Biopharmaceuticals, TransCode Therapeutics, and Guardant Health; has consulted for Blueprint Bio, Flagship Pioneering, Redona Therapeutics, Pro Clinical Solutions, and Guidepoint; has served on steering committees for Merus, Pfizer, and Relay Therapeutics; has had speaking roles for Ovarian Cancer Research Alliance and STOP Cancer; and has received institutional research funding from AstraZeneca, ArQule/Merck, BeOne Medicines/SpringWorks, Black Diamond Therapeutics, Boehringer Ingelheim, Elevation Oncology/Concentra Biosciences, Kura Oncology, Lilly, Merus, Northern Biologics, Partner Therapeutics, Pfizer, Pheon Therapeutics, PMV Pharma, Relay Therapeutics, Repare Therapeutics, Revolution Medicines, and Surface Oncology/Coherus Oncology. For full disclosures of the study authors, visit aacrjournals.org.
