Zenocutuzumab sBLA Filed With FDA for NRG1-Positive Cholangiocarcinoma

Partner Therapeutics has submitted a supplemental biologics license application (sBLA) to the FDA for zenocutuzumab-zbco (Bizengri) for adults with advanced unresectable or metastatic cholangiocarcinoma harboring an NRG1 gene fusion. Concurrently, the NCCN has added 2 recommendations for use of the bispecific antibody to its clinical practice guidelines.¹ 

The sBLA is supported by efficacy and safety data from the cholangiocarcinoma cohort of the phase 2 eNRGy trial (NCT02912949), an open-label, registrational, multicenter study evaluating zenocutuzumab across multiple solid tumor types harboring NRG1 fusions.¹ In the cholangiocarcinoma cohort, zenocutuzumab demonstrated an overall response rate (ORR) of 36.8% (95% CI, 16.3%-61.6%) and a median duration of response (DOR) of 12.9 months as assessed by blinded independent central review. Of note, no patients in this cohort discontinued therapy due to adverse events.

"This submission marks an important step in advancing [zenocutuzumab] for patients with NRG1 fusion–positive cholangiocarcinoma, a population with limited treatment options and historically poor outcomes," Pritesh J. Gandhi, chief development officer at Partner Therapeutics, stated in a news release.¹ "Cholangiocarcinoma remains a challenging and aggressive disease, and we believe these data support the potential of [zenocutuzumab] to address a critical unmet need for patients whose tumors are driven by NRG1 gene fusions."

The sBLA builds on zenocutuzumab's existing FDA accelerated approval, granted in December 2024, for adults with advanced unresectable or metastatic non–small cell lung cancer (NSCLC) and pancreatic adenocarcinoma harboring NRG1 gene fusions following prior systemic therapy. That approval was based on registrational data from the broader eNRGy trial, in which zenocutuzumab produced an ORR of 29% (95% CI, 20%-39%) in 93 patients with NSCLC and 42% (95% CI, 25%-59%) in 36 patients with pancreatic adenocarcinoma, with a median DOR of 11.1 months across the evaluable population.²

Regarding the NCCN update, zenocutuzumab has been added to the biliary tract cancer guidelines as a Category 2A recommendation for subsequent-line therapy and as a Category 2B recommendation for frontline treatment of NRG1 fusion–positive cholangiocarcinoma—the first time the agent has appeared in guidelines for this indication.

"Cholangiocarcinoma remains a devastating disease, particularly in the advanced setting," James Cleary, MD, PhD, of Dana-Farber Cancer Institute, stated in the news release.¹ "The identification of NRG1 gene fusions has highlighted an actionable biomarker, and the eNRGy study data suggest that targeted inhibition with zenocutuzumab may represent a meaningful treatment approach for these patients."

Mechanism and Testing Considerations

NRG1 fusions function differently from more familiar oncogenic fusion drivers such as NTRK, RET, ROS1, ALK, and FGFR. Rather than generating chimeric receptors, NRG1 fusions produce chimeric ligands that bind to HER3, triggering HER2/HER3 heterodimerization and downstream proliferative signaling.¹ Zenocutuzumab is a bispecific antibody that blocks both HER2/HER3 dimerization and the interaction of NRG1 fusion proteins with HER3.¹

Standard DNA-based next-generation sequencing panels may miss these alterations; tissue-based RNA sequencing is required for reliable detection. "Tissue-based RNA testing is essential to identify rare oncogenic fusions such as NRG1 and ensure patients with these actionable alterations are not overlooked," Gandhi emphasized.¹ 

Safety Profile

The overall safety profile of zenocutuzumab across the eNRGy trial was characterized by predominantly grade 1 or 2 adverse events.² Infusion-related reactions (IRRs) occurred in 13% of patients across the trial, with 91% arising during the first infusion; all were grade 1 or 2. Grade 2 interstitial lung disease/pneumonitis occurred in 0.6% of patients, resulting in permanent discontinuation.^2,3 Clinicians should assess left ventricular ejection fraction (LVEF) at baseline and monitor periodically during treatment, as grade 2 LVEF decreases were observed in 2% of evaluable patients.^2,3 

The FDA review timeline for the sBLA in cholangiocarcinoma has not yet been disclosed. If approved, zenocutuzumab would represent the first targeted therapy specifically indicated for NRG1 fusion–positive cholangiocarcinoma.¹

REFERENCES

1. Partner Therapeutics, Inc. Partner Therapeutics announces submission of supplemental Biologics License Application (sBLA) to FDA for BIZENGRI® (zenocutuzumab-zbco) in NRG1 fusion positive cholangiocarcinoma. Press release. April 14, 2026. https://tinyurl.com/3yw2pk2a

2. Schram AM, Goto K, Kim DW, et al. Efficacy of zenocutuzumab in NRG1 fusion–positive cancer. N Engl J Med. 2025;392:566-576.

3. BIZENGRI (zenocutuzumab-zbco) [prescribing information]. Lexington, MA: Partner Therapeutics, Inc.; 2024.