The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation (BTD) to zenocutuzumab-zbco for the treatment of adults with advanced unresectable or metastatic cholangiocarcinoma harboring a neuregulin-1 (NRG1) gene fusion. This marks another major milestone in precision oncology, supported by promising data from the Phase 2 eNRGy trial, which reported a 37% overall response rate (ORR) and a median duration of response of 7.4 months. The results will be featured at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics and will serve as the foundation for a supplemental Biologics License Application (sBLA) expected in 2026.
Scientific Significance
Zenocutuzumab-zbco represents an important advance in molecularly targeted therapy, addressing a rare but actionable genomic driver—NRG1 fusions—that activates the HER2/HER3 signaling pathway and drives oncogenesis across several tumor types. The bispecific antibody is designed to block HER2/HER3 dimerization and disrupt oncogenic signaling, thereby halting tumor growth. In the eNRGy trial, among 19 evaluable patients with advanced NRG1+ cholangiocarcinoma, the drug achieved a median progression-free survival of 9.2 months and a clinical benefit rate of 58%, with mostly mild (grade 1–2) adverse events.
Dr. Alison M. Schram of Memorial Sloan Kettering Cancer Center noted,
“NRG1 fusions are rare but actionable drivers in cholangiocarcinoma. The data from the eNRGy trial continue to highlight the potential of zenocutuzumab to offer meaningful clinical benefit for these patients.”’
Regulatory Significance
The Breakthrough Therapy Designation is one of the FDA’s most powerful tools to accelerate the development of treatments for serious conditions showing potential superiority over current standards. This designation grants priority review, rolling submission, and frequent FDA engagement, helping expedite patient access to promising drugs. The recognition follows zenocutuzumab-zbco’s accelerated approval in December 2024 for NRG1+ non-small cell lung cancer (NSCLC) and pancreatic adenocarcinoma, solidifying its role as the first and only FDA-approved therapy directly targeting NRG1 fusions.
Business Significance
For Partner Therapeutics (PTx), the BTD represents both clinical validation and a strategic commercial opportunity. Under its licensing agreement with Merus N.V., PTx holds exclusive U.S. rights to develop, manufacture, and market zenocutuzumab-zbco, while offering named-patient access outside the U.S. This designation strengthens PTx’s oncology portfolio, which also includes sargramostim and other immuno-modulating biologics.
Dr. Pritesh J. Gandhi, Chief Development Officer of PTx, emphasized the importance of genomic testing:
“With more actionable gene fusions being discovered, it’s essential that oncologists perform comprehensive RNA-based sequencing to identify patients who could benefit from targeted treatments such as zenocutuzumab-zbco.”
Patient Significance
Cholangiocarcinoma remains one of the most aggressive and lethal cancers, with few effective treatment options. For patients with NRG1-positive tumors, zenocutuzumab-zbco offers a rationally designed precision therapy that targets the tumor’s genetic driver.
Dr. Juan W. Valle, Chief Medical Officer of the Cholangiocarcinoma Foundation, stated,
“The eNRGy trial results are encouraging, and they underscore how critical comprehensive molecular testing is for identifying rare genetic drivers such as NRG1.”
For patients with limited options, this FDA designation brings renewed hope for longer survival and improved quality of life through earlier access to effective targeted therapies.
Policy and Broader Impact
The FDA’s decision highlights its commitment to advancing precision medicine and ensuring rapid access to therapies for biomarker-defined subgroups. It aligns with federal initiatives like the Cancer Moonshot, which promote genomic testing, personalized care, and regulatory flexibility for rare cancers. By prioritizing breakthrough therapies, the FDA continues to drive innovation in biomarker-driven oncology.
You Can Watch More on OncoDaily Youtube TV