FDA Grants Breakthrough Therapy Status to Zenocutuzumab for Patients with NRG1 Fusion

The FDA has granted breakthrough therapy designation to zenocutuzumab (Bizengri) for the treatment of patients with advanced unresectable or metastatic cholangiocarcinoma harboring a neuregulin 1 (NRG1) gene fusion. This designation was supported by results from the ongoing phase 2 eNRGy trial (NCT02912949).¹

Findings from the trial were presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston, Massachusetts, on October 23, 2025, and will serve as the basis for a supplemental biologics license application that will be submitted to the FDA in 2026.

Results from the eNRGy trial show that in 19 evaluable patients, there was an overall response rate (ORR) of 37%, a median duration of response (DOR) of 7.4 months, and a median time of response of 1.9 months. The progression-free survival (PFS) was 9.2 months with a clinical benefit rate of 58%. Most adverse events were grade 1 or 2 and remained consistent among the trial population.

The eNRGy trial is a 2-part study. Part 1, dose escalation, has been completed, and part 2 is a dose-expansion cohort. New patient populations in part 2 examine patients with non–small cell lung cancer (NSCLC) with documented NRG1 fusion and patients with pancreatic adenocarcinoma with documented NRG1 fusion. The primary end point of the trial is ORR, and the secondary end points are DOR, clinical benefit rate, PFS, and safety.

The median age of patients was 57.5 years, with an ECOG score of 0 to 2. Patients received 750 mg of zenocutuzumab intravenously every 2 weeks.

"In December 2024, zenocutuzumab received accelerated approval for the treatment of adults with advanced unresectable or metastatic [NSCLC] and pancreatic adenocarcinoma harboring a[n] RG1 gene fusion with disease progression on or after prior systemic therapy. The new data from the eNRGy trial highlight the potential of zenocutuzumab-zbco as a promising treatment option for patients with NRG1 fusion–positive cholangiocarcinoma," Pritesh J. Gandhi, PharmD, chief development officer of Partner Therapeutics, said in a press release.² "With the growing number of genomic alternations and gene fusions that are now actionable, it is imperative that oncologists order upfront tissue-based RNA next-generation sequencing [NGS] to ensure that gene fusions, of which NRG1 is just one, are not missed."

In July 2023, the drug received FDA breakthrough designation for the treatment of patients with advanced unresectable or metastatic NRG1 fusion–positive pancreatic cancer. In May 2024, the FDA granted priority review to the biologics license application of zenocutuzumab in patients with NRG1-positive NSCLC and pancreatic ductal adenocarcinoma (PDAC). In December 2024, the FDA approved zenocutuzumab, making it the first and only approved targeted therapy for patients with NRG1-positive NSCLC and PDAC.

"Patients with cholangiocarcinoma face an aggressive disease with limited standard therapy options," Juan W. Valle, MD, chief medical officer of the Cholangiocarcinoma Foundation, said in a press release.² "The eNRGy trial results are encouraging, and they underscore how critical comprehensive molecular testing, notably tissue-based RNA NGS, is to ensure that patients with rare drivers such as NRG1 fusions are identified and can potentially have access to targeted treatments."

REFERENCES:

1. A study of zenocutuzumab (MCLA-128) in patients with solid tumors harboring an NRG1 fusion (eNRGy). ClinicalTrials.gov. Updated April 29, 2025. Accessed October 24, 2025. https://clinicaltrials.gov/study/NCT02912949 

2. Zenocutuzumab-zbco granted FDA breakthrough therapy designation for NRG1+ cholangiocarcinoma; data highlighting potential of zenocutuzumab-zbco in NRG1+ cholangiocarcinoma to be presented at AACR-NCI-EORTC. News release. Partner Therapeutics. October 24, 2025. Accessed October 24, 2025. https://tinyurl.com/4uesa2dv