FDA Approves Zenocutuzumab-zbco (Bizengri) for NRG1 Fusion-Positive Cholangiocarcinoma

The U.S. Food and Drug Administration (FDA) approved the HER2- and HER3-directed bispecific antibody zenocutuzumab-zbco (Bizengri) on May 8, 2026, for adults with advanced, unresectable or metastatic cholangiocarcinoma harboring an NRG1 gene fusion with disease progression on or after prior systemic therapy. The approval marks the first targeted therapy approved specifically for NRG1+ cholangiocarcinoma and is the seventh approval under the FDA Commissioner's National Priority Voucher (CNPV) pilot program.

The FDA based the approval on safety and efficacy data from the eNRGy trial, a multicenter, open-label, multi-cohort phase 2 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 (ORR) and duration of response (DOR). The ORR was 36.8% (95% CI, 16.3–61.6), with a complete response rate of 5.3% and a partial response rate of 31.6%. The DOR ranged from 2.8 to 12.9 months, and a response duration of at least 6 months was observed in 28.6% of responders.

Results from the ongoing eNRGy trial reported manageable side effects and clinically meaningful efficacy, including a near doubling of progression-free survival compared to expectations with standard of care. The median progression-free survival was 9.2 months, and 57.9% of patients experienced clinical benefit. By comparison, standard second-line chemotherapy produces an objective radiological response in only five percent of patients, with a median progression-free survival of about four months. Zenocutuzumab was well tolerated; patients experienced low-grade side effects including diarrhea or infusion reactions, and less than 1% of patients discontinued treatment due to a drug-related adverse event.

The most common adverse reactions (≥20%), excluding laboratory findings, were fatigue, diarrhea, musculoskeletal pain, abdominal pain, nausea, cough, dyspnea, and decreased appetite. The prescribing information includes warnings and precautions for infusion-related reactions/hypersensitivity/anaphylactic reactions, interstitial lung disease/pneumonitis, left ventricular dysfunction, and embryo-fetal toxicity. The recommended zenocutuzumab-zbco dose is 750 mg administered as an intravenous infusion every 2 weeks until disease progression or unacceptable toxicity.

Zenocutuzumab is a bispecific antibody that blocks HER2/HER3 dimerization and NRG1 fusion interactions with HER3. NRG1 fusions occur in fewer than 1% of cholangiocarcinoma cases, a rare and aggressive malignancy of the bile ducts with an all-stage 5-year overall survival of less than 15%. NRG1 fusions typically occur in patients who are otherwise driver negative, and 25% of patients with NRG1-positive cholangiocarcinoma are under the age of 40. The drug was first approved under accelerated approval in 2024 for advanced, unresectable or metastatic NRG1 fusion-positive non-small cell lung cancer and pancreatic adenocarcinoma. Zenocutuzumab is also included in the NCCN Clinical Practice Guidelines in Oncology for non-small cell lung cancer, pancreatic adenocarcinoma, and cholangiocarcinoma. The FDA granted this application priority review, and zenocutuzumab-zbco received Breakthrough Therapy and Orphan Drug designation. The approval was granted over five months ahead of the FDA goal date, and the FDA will host a public meeting on June 4, 2026, to solicit feedback about the CNPV pilot program.