FDA Grants BTD to Zenocutuzumab in NRG1+ Cholangiocarcinoma

For patients with NRG1+ cholangiocarcinoma, zenocutuzumab may be a therapy option, according to results from the phase 2 eNRGY trial.

The FDA has approved breakthrough therapy designation to zenocutuzumab-zbco (Bizengri) for patients with advanced unresectable or metastatic cholangiocarcinoma with NRG1 gene fusion, according to a press release from Partner Therapeutics.1

The decision was made based on results from the phase 2 eNRGy trial (NCT02912949), which assessed the efficacy and safety of patients with NRG1-fusion-positive cancer.2 The full findings will be presented in an oral and poster session during the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. Additionally, a supplemental biologics license application will be submitted to the FDA in 2026.

In December 2024, zenocutuzumab was approved by the FDA for patients with non–small cell lung cancer and pancreatic cancer, based on results from the eNRGy trial.

“NRG1 fusions represent a rare but actionable driver in cholangiocarcinoma, and the data from the eNRGy trial continue to highlight the potential of zenocutuzumab to offer meaningful clinical benefit for these patients. I’m honored to present these findings at AACR-NCI-EORTC, where we can advance the dialogue around targeted therapies in hard-to-treat cancers,” lead study author Alison Schram, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, said in the press release.

The eNRGy trial assessed 161 patients in the primary analysis across 10 different tumor types, with cholangiocarcinoma making up 6% of the population. At the time of the primary analysis, the median patient age was 62 years old and 60% of patients were female.

At the data cutoff of January 31, 2024, the median duration of exposure was 5.5 months, and treatment remained ongoing in 52 patients.

There were 158 patients in the primary efficacy population with measurable disease, and 47 had an investigator-assessed confirmed objective response, with 1 complete response. This incurred an incidence of response of 30% (95% CI, 23%-37%).

For patients with a confirmed response, the median duration of response was 11 months (95% CI, 7.4-12.9). Of note, 19% of responses were ongoing at data cutoff, with a median follow-up of 7.1 months. At 6 and 12 months, the estimated duration of response was 77% and 42%, respectively. The median time to response was 1.8 months.

Regarding efficacy for the cholangiocarcinoma-specific population, an objective response was observed in 2 patients. In the primary efficacy population, the median progression-free survival was 6.8 months (95% CI, 5.5-9.1).

In the prespecified subgroup analysis across NRG1 fusion partners, a confirmed response was observed in 38% of patients with measurable disease who were assessed for response, across the number of lines of therapy, and across other demographic and disease characteristics.

Regarding safety, adverse effects (AEs) occurred in 10% of patients. For patients given zenocutuzumab at 750 mg every 2 weeks, 95% of patients had at least 1 AE. The most common grade 3/4 AEs included anemia (5%), increased γ-glutamyltransferase level (4%), and pneumonia (3%).

Infusion-related reactions occurred in 14% of patients and were all grade 1/2. Of note, 2 patients had 2 infusion-related reactions. AEs of grade 3/4 that were found by the investigators to be related to treatment were noted in 7% of patients.

Treatment discontinuation occurred in 1 patient due to a drug-related toxic effect. Treatment delays due to AEs occurred in 31% of patients, and AEs relating to infusion interruption occurred in 10%.

References

1. 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 October 24, 2025. https://tinyurl.com/3f8883ys
2. Schram AM, Goto K, Kim DW, et al. Efficacy of zenocutuzumab in NRG1 fusion-positive cancer. N Engl J Med. 2025;392(6):566-576. doi:10.1056/NEJMoa2405008