The US FDA has approved Bizengri (zenocutuzumab-zbco) for adults with advanced, unresectable or metastatic cholangiocarcinoma harboring an NRG1 gene fusion, marking the first targeted therapy approved for this molecularly defined cancer subtype. The approval extends the label for Lexington, Massachusetts-based Partner Therapeutics, which had previously received accelerated approval for Bizengri in NRG1 fusion-positive non-small cell lung cancer and pancreatic adenocarcinoma in 2024.
The cholangiocarcinoma indication covers patients with disease progression on or after prior systemic therapy. Unlike the earlier NSCLC and pancreatic adenocarcinoma approvals, which were granted under accelerated approval, the cholangiocarcinoma approval is a standard approval. The review timeline was shortened following Partner Therapeutics’ receipt of a Commissioner’s National Priority Voucher, a pilot program designed to accelerate FDA review for selected therapies. Bizengri had previously received Breakthrough Therapy Designation and Orphan Drug Designation for this indication.
The approval is supported by data from the eNRGy trial, a multicenter, open-label, multi-cohort Phase II study in adults with advanced solid tumors harboring NRG1 gene fusions. Of 22 enrolled patients with NRG1 fusion-positive cholangiocarcinoma, 19 were evaluable for efficacy. The primary efficacy measures were confirmed overall response rate and duration of response. The ORR was 36.8%, with a duration of response ranging from 2.8 to 12.9 months. The most common adverse reactions, occurring in 20% or more of patients, included fatigue, diarrhea, musculoskeletal pain, abdominal pain, nausea, cough, dyspnea, and decreased appetite. Serious adverse reactions occurred in 23% of patients in this cohort.
Cholangiocarcinoma carries an all-stage five-year overall survival rate of under 15%, and NRG1 fusions occur in fewer than 1% of cases, leaving an extremely small patient population with no previously approved targeted option. Standard second-line cytotoxic regimens such as FOLFOX produce objective responses in approximately 5% of patients, a benchmark against which Bizengri’s 36.8% ORR in this cohort offers a material contrast, though the trial’s small evaluable population limits broader interpretation. NRG1 fusions function through a distinct mechanism from more commonly targeted fusions such as NTRK, RET, or ALK: the fusion creates a chimeric ligand that binds HER3, driving HER2/HER3 heterodimerization and downstream proliferative signaling. Zenocutuzumab-zbco is a bispecific antibody designed to block this interaction. No other targeted therapy is currently approved for NRG1 fusion-positive cholangiocarcinoma.
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