The U.S. Food and Drug Administration (FDA) approved the HER2- and HER3-directed bispecific antibody zenocutuzumab-zbco (Bizengri) for adults with advanced, unresectable or metastatic cholangiocarcinoma harboring an NRG1 gene fusion with disease progression on or after prior systemic therapy. The approval was granted May 8, 2026.
Zenocutuzumab-zbco is a bispecific antibody that blocks HER2/HER3 dimerization and NRG1 fusion interactions with HER3, resulting in the suppression of these pathways. Comprehensive molecular testing—notably, the combination of tissue-based DNA and RNA next-generation sequencing—is essential to identify rare and actionable gene fusions like NRG1.
Phase II eNRGy Study
The FDA approved zenocutuzumab-zbco based on safety and efficacy data from the eNRGy trial, a multicenter, open-label, multi-cohort phase II clinical trial in adults with advanced solid tumors harboring NRG1 gene fusions. A total of 22 patients with unresectable or metastatic NRG1 fusion–positive cholangiocarcinoma were enrolled, with 19 evaluable for efficacy.
The major efficacy outcome measures were confirmed overall response rate and duration of response. The overall response rate was 36.8%, with a duration of response range of 2.8 to 12.9 months.
An analysis of the eNRGy study was presented at the 2026 ASCO Gastrointestinal Cancers Symposium.
NRG1 Fusion–Positive Cholangiocarcinoma
In a news statement, James Cleary, MD, PhD, a co-investigator of the eNRGy study, and Director of Clinical Research, Division of Gastrointestinal Oncology at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School, said, “NRG1 fusion–positive cholangiocarcinoma represents a rare but clinically important subset of disease with limited therapeutic options and poor outcomes. In the eNRGy study, zenocutuzumab demonstrated a clinically meaningful overall response rate, and the drug was well tolerated with a favorable safety profile. Less than 1% of patients discontinued treatment due to a drug-related adverse event, supporting its role as a targeted treatment option in this setting. These data further highlight the essential role of comprehensive molecular testing, particularly tissue-based RNA-based sequencing, to reliably detect gene fusions such as NRG1 and ensure patients are appropriately identified for targeted therapy.”
Zenocutuzumab was first approved under accelerated approval in 2024 in advanced, unresectable, or metastatic non–small cell lung cancer (NSCLC) and pancreatic adenocarcinoma for patients harboring an NRG1 gene fusion on or after systemic therapy.
Additionally, zenocutuzumab is included in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC, pancreatic adenocarcinoma, and cholangiocarcinoma.
NRG1 fusions are unique cancer drivers that create oncogenic chimeric ligands rather than the more widely described chimeric receptors (NTRK, RET, ROS1, ALK, and FGFR fusions). The chimeric ligands bind to HER3, triggering HER2/HER3 heterodimerization and activate downstream signaling pathways that cause cancer cells to grow and proliferate.
Safety and Administration
The prescribing information for zenocutuzumab includes warnings and precautions for infusion-related reactions/hypersensitivity/anaphylactic reactions, interstitial lung disease/pneumonitis, left ventricular dysfunction, and embryo-fetal toxicity. The most common adverse reactions seen with the agent include diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions, dyspnea, rash, constipation, vomiting, abdominal pain, and edema. The most common adverse reactions (≥ 20%), excluding laboratory findings, were fatigue, diarrhea, musculoskeletal pain, abdominal pain, nausea, cough, dyspnea, and decreased appetite.
The recommended zenocutuzumab-zbco dose is 750 mg as an intravenous infusion every 2 weeks until disease progression or unacceptable toxicity.
Priority Review
This application is part of the FDA Commissioner’s National Priority Review Voucher (CNPV) pilot program, which is designed to accelerate the review of products with the potential to address key national priorities.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the assessment. The FDA approved this application over 5 months ahead of the FDA goal date.
This application was granted priority review. Zenocutuzumab-zbco received Breakthrough Therapy and Orphan Drug designation.
