FDA Approves Zenocutuzumab for NRG1 Fusion+ Cholangiocarcinoma

The FDA has approved zenocutuzumab-zbco (Bizengri) for the treatment of adult patients with NRG1 fusion–positive advanced, unresectable, or metastatic cholangiocarcinoma (CCA) who have experienced disease progression on or after prior systemic therapy.^1,2

This regulatory decision was supported by findings from the single-arm phase 1/2 eNRGy trial (NCT02912949), in which evaluable patients with NRG1 fusion–positive CCA (n = 19) achieved an overall response rate (ORR) of 36.8% (95% CI, 16.3%-61.6%) per blinded independent central review (BICR). Additionally, the duration of response (DOR) ranged from 2.8 months to 12.9 months per BICR.

“Patients with this ultra-rare type of cancer desperately need new treatment options,” FDA Commissioner Marty Makary, MD, MPH, stated in a news release. “Through the national priority voucher pilot program, the FDA is accelerating therapies for rare diseases with unmet medical needs, reviewing applications in significantly shortened timelines.”

What is the mechanism of action of zenocutuzumab?

This agent is a full-length IgG1 bispecific antibody that targets both HER2 and HER3.³

What was the design of the eNRGy trial?

This multicenter, open-label, multicohort trial enrolled adult patients with advanced solid tumors, including 22 patients with unresectable or metastatic NRG1 fusion–positive CCA. Patients were required to have at least 1 measurable lesion per RECIST 1.1 criteria, an ECOG performance status of 0 to 2, and an estimated life expectancy of at least 12 weeks. Additionally, patients needed to have recovered from major surgery or other complications to grade 2 or less at baseline, have a maximum absolute neutrophil count of 1.5 x 10⁹/L without colony stimulating factor support for at least 7 days before screening, have a minimum platelet counts of 75 x 10⁹/L without transfusion support for at least 7 days before screening, and have hemoglobin levels of at least 8 g/dL or 5 mmol/L.

Patients were excluded if they were pregnant or lactating, had an uncontrolled infection or unexplained fever, had known hypersensitivity to any of the components of zenocutuzumab, had known HIV, had active hepatitis B and had not received antiviral treatment, had hepatitis C, had known symptomatic or unstable brain metastases, had a left ventricular ejection fraction below 50%, had a history or presence of any significant cardiovascular disease, had a previous or concurrent malignancy, or had any other medical or psychosocial condition that was deemed likely to interfere with ability to consent to or participate in the study.

Patients in the part 2 solid tumor basket portion of the study, including those with CCA, received intravenous zenocutuzumab at the recommended phase 2 dose of 750 mg every 2 weeks.

Investigator-assessed ORR and DOR according to RECIST 1.1 criteria served as the trials’s primary end points. Secondary end points included ORR, DOR, and clinical benefit rate (CBR) per BICR; locally assessed CBR; time to response assessed locally and by BICR; progression-free survival; overall survival; pharmacokinetics; and safety and tolerability.

What is the safety profile of zenocutuzumab?

Serious adverse effects (AEs) associated with zenocutuzumab include infusion-related reactions (IRRs), interstitial lung disease/pneumonitis, and left ventricular dysfunction. The most common AEs associated with this agent include diarrhea, musculoskeletal pain, fatigue, nausea, IRRs, dyspnea, rash, constipation, vomiting, abdominal pain, and edema.

Is zenocutuzumab guideline-recommended for CCA?

On April 15, 2026, the National Comprehensive Cancer Network announced that zenocutuzumab was added to its Clinical Practice Guidelines in Oncology for biliary tract cancers as a category 2A–recommended subsequent‑line therapy and as a category 2B–recommended first-line therapy for patients with NRG1 fusion–positive CCA.⁴ The agent’s inclusion in these guidelines was backed by data from eNRGy.

References

1. FDA grants seventh approval under the National Priority Voucher Pilot Program. FDA. May 8, 2026. Accessed May 8, 2026. https://www.fda.gov/news-events/press-announcements/fda-grants-seventh-approval-under-national-priority-voucher-pilot-program?utm_medium=email&utm_source=govdelivery
2. FDA approves zenocutuzumab-zbco for advanced, unresectable or metastatic cholangiocarcinoma. FDA. May 8, 2026. Accessed May 8, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zenocutuzumab-zbco-advanced-unresectable-or-metastatic-cholangiocarcinoma
3. A study of zenocutuzumab (MCLA-128) in patients with solid tumors harboring an NRG1 fusion (eNRGy). ClinicalTrials.gov. Updated April 29, 2025. Accessed May 8, 2026. https://clinicaltrials.gov/study/NCT02912949
4. NCCN. Clinical Practice Guidelines in Oncology. Biliary tract cancers, version 1.2026. March 10, 2026. Accessed May 8, 2026. https://www.nccn.org/professionals/physician_gls/pdf/btc.pdf