FDA Grants Orphan Drug Designation to Zenocutuzumab in Cholangiocarcinoma

Zenocutuzumab-zbco (Bizengri) has received orphan drug designation from the FDA for the treatment of adults with advanced unresectable or metastatic cholangiocarcinoma (CCA), according to a press release from the developer, Partner Therapeutics, Inc.¹ The designation represents a regulatory milestone for the bispecific antibody, which is designed to block the HER2-HER3 receptor axis driven by these rare oncogenic alterations.

This designation follows the FDA granting breakthrough therapy designation to zenocutuzumab for the same patient population in October 2025, a decision supported by data from the phase 2 eNRGy trial (NCT02912949).² Furthermore, the agent previously received accelerated approval in December 2024 for the treatment of adults with advanced NRG1 fusion–positive non–small cell lung cancer and pancreatic ductal adenocarcinoma.

Clinical Efficacy

Efficacy results from the CCA cohort of the eNRGy trial demonstrate meaningful clinical activity for zenocutuzumab in this hard-to-treat population.³ Among 19 evaluable patients with advanced NRG1-positive CCA, the investigator-assessed overall response rate (ORR) was 37%. The clinical benefit rate was 58%.

The median duration of response (DOR) was 7.4 months (95% CI, 4.6-not evaluable [NE]), while the median time to response was 1.9 months. In terms of survival outcomes, the median progression-free survival (PFS) was 9.2 months (95% CI, 3.9-11.4). Tumor marker analysis also supported these findings, with all 16 patients with evaluable CA 19-9 data experiencing a decline in serum levels, including a 50% or greater reduction in 69% of cases.

“Patients with cholangiocarcinoma [have] a particularly aggressive cancer with poor prognosis and limited treatment options,” stated Juan W. Valle, MD, chief medical officer of the Cholangiocarcinoma Foundation, in the press release.¹ “Receiving orphan drug designation for zenocutuzumab in patients with CCA harboring the NRG1 gene fusion is a significant regulatory milestone for Partner Therapeutics and highlights the urgent need for new and effective treatment options for patients with this disease.”

Trial Breakdown

The global, open-label phase 1/2 eNRGy trial is evaluating the safety and antitumor activity of zenocutuzumab across several NRG1 fusion–positive solid tumor cohorts. The treatment regimen consists of zenocutuzumab administered at the recommended phase 2 dose of 750 mg via intravenous infusion every 2 weeks until disease progression or unacceptable toxicity.

Eligibility criteria required patients to have histologically or cytologically confirmed advanced unresectable or metastatic solid tumors harboring an NRG1 gene fusion as identified by comprehensive molecular profiling, specifically DNA- or RNA-based next-generation sequencing. Patients were required to have at least 1 measurable lesion per RECIST v1.1 guidelines, an ECOG performance status of 0 to 2, and at least 18 years of age. All patients had either already received prior treatment or were unable to receive standard therapy.

Safety Results

The safety profile of zenocutuzumab was generally manageable and consistent with the overall study population. Most treatment-emergent adverse effects (TEAEs) were grade 1 or 2. Grade 3 or 4 TEAEs included anemia (14%), hypomagnesemia (9%), and increased gamma-glutamyl transferase levels (9%).

The prescribing information for zenocutuzumab includes a boxed warning for embryo-fetal toxicity, and patients are further advised of the potential for lung inflammation and heart dysfunction.

“NRG1 fusions represent a rare but actionable driver in [CCA], and the data from the eNRGy trial continue to highlight the potential of zenocutuzumab to offer meaningful clinical benefit for these patients,” study investigator Alison M. Schram, MD, a gynecologic medical oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center, stated in a press release at the time of the breakthrough therapy designation.²

References

1. Zenocutuzumab‑zbco receives FDA orphan drug designation for treatment of cholangiocarcinoma. News release. Partner Therapeutics, Inc. February 5, 2026. Accessed February 9, 2026. https://tinyurl.com/ymstnwkw
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. October 24, 2024. Accessed February 9, 2026. https://tinyurl.com/3f8883ys
3. Schram AM, Cleary JM, Arnold D, et al. Zenocutuzumab efficacy and safety in advanced NRG1+ cholangiocarcinoma: analysis from the phase 2 eNRGy trial. Mol Cancer Ther. 2025;24(suppl 10):A102. doi:10.1158/1535-7163.TARG-25-A102