Zenocutuzumab: The First Targeted Therapy for NRG1 Fusion-Positive Cholangiocarcinoma

A New Corner of the Molecular Map of Biliary Tract Cancer

Why are NRG1 fusions different from "the others"?

The classic fusions that come to mind when we discuss targeted treatment in oncology today — NTRK, RET, ROS1, ALK, FGFR2 — all share the same basic structure: these fusions form a chimeric receptor ; the enzymatic domain (kinase) and membrane-binding domain come together to produce a receptor tyrosine kinase that remains automatically active. The target is then clear: a small molecule that directly inhibits the chimeric receptor (larotrectinib, selpercatinib, crizotinib, alectinib, pemigatinib).

NRG1 fusions tell a different story. NRG1 (neuregulin 1, formerly known as heregulin), which binds to the HER3 receptor on the cell surface, is a ligand —a molecule that initiates signaling and acts like a key. Fusion of the NRG1 gene with another partner gene (most commonly CD74, SLC3A2, ATP1B1, RBPMS) produces not a chimeric receptor, but a chimeric ligand . This chimeric ligand anchors to the cell membrane and continually binds to neighboring HER3. HER3 by itself is a weak signal transmitter; when it forms a heterodimer with HER2, it activates the PI3K/AKT and MAPK pathways. The result: a ligand-receptor interaction on the cell surface that does not switch off, and continuously active oncogenic signaling.

How common are NRG1 fusions in patients with cholangiocarcinoma?

Not very. Across all solid tumors, NRG1 fusions are detected at a frequency of approximately %0,2 . According to large-scale molecular profiling data from Caris Life Sciences, the distribution by tumor type is as follows: breast cancer leads at 0,30%, followed by cholangiocarcinoma at 0,26%, NSCLC at 0,23%, cancer of unknown primary at 0,21%, and pancreatic ductal adenocarcinoma at 0,19%. In other series, the prevalence of NRG1 fusions in cholangiocarcinoma can reach 0,5%—still far below the rates of FGFR2 fusions (10–15% in intrahepatic cholangiocarcinoma) or IDH1 mutations (also 15–20% in intrahepatic cholangiocarcinoma).

Although numerically small, this is critical in practice: cholangiocarcinoma is a cancer diagnosed in approximately 165.000 (one hundred and sixty-five thousand) people worldwide annually, with 5-year survival ranging from 5–20%. In the United States, 8.000–10.000 (eight to ten thousand) new cases are expected each year. Of these, NRG1 fusion-positive cases are limited to 25–50 patients per year. Yet until 8 May 2026 there was no approved targeted therapy for these patients; the standard approach consisted of cytotoxic regimens with limited efficacy, such as FOLFOX after gemcitabine-cisplatin.

The Data at a Glance

The eNRGy study (NCT02912949) is a multicenter, open-label, multicohort Phase 1/2 basket study. The first approvals in December 2024 were based on data from 64 patients with NRG1+ NSCLC and 30 patients with NRG1+ pancreatic adenocarcinoma. The cohort submitted for the 8 May 2026 approval comprised patients with NRG1 fusion-positive cholangiocarcinoma: 22 patients were enrolled and 19 were considered evaluable for efficacy. The data cutoff was April 2025; the results were presented at the AACR-NCI-EORTC International Conference in October 2025.

Side Effects to Know

The prescribing information contains four important warnings and precautions: infusion-related reactions / hypersensitivity / anaphylactic reactions; interstitial lung disease (ILD) / pneumonitis; left ventricular dysfunction (the classic cardiac signature of HER2-directed antibodies); and embryo-fetal toxicity. The most common adverse reactions are diarrhea, musculoskeletal pain, fatigue, nausea, infusion reactions, dyspnea, rash, constipation, vomiting, abdominal pain, and edema.

This approval was assessed under the FDA's newly launched Commissioner's National Priority Voucher (CNPV) pilot program. CNPV is a pathway beyond accelerated review, designed to expedite review of products addressing national priorities (for example, rare diseases, areas with therapeutic gaps, and health security). This voucher gives the applicant company a substantial time saving relative to the normally applicable PDUFA target date; the zenocutuzumab approval came 5 months early. CNPV is a new layer added to the FDA's traditional priority review and breakthrough designation tools.

NRG1+ cholangiocarcinoma cases are occasionally referred through international patient coordination at Memorial Göztepe Cancer Center, Acıbadem, Anadolu Sağlık, and other major Turkish centers; screening for NRG1 through comprehensive genomic profiling and a fusion panel should now become standard in these patients. This new indication is an important additional option for patients with advanced biliary tract cancer coming from the Turkic republics, the Balkans, and the Middle East.

NRG1 fusion-directed treatment of cholangiocarcinoma now fits into the following decision tree: after diagnosis of advanced disease, comprehensive genomic profiling is performed (including RNA); for an FGFR2 fusion, pemigatinib/futibatinib; for an IDH1 mutation, ivosidenib; for BRAF V600E, dabrafenib + trametinib; for HER2 amplification, trastuzumab + tucatinib (in some indications); for KRAS G12C, sotorasib/adagrasib (within a clinical trial); for an NTRK fusion, larotrectinib/entrectinib; and now, for an NRG1 fusion, zenocutuzumab—alongside the initial approach in which gemcitabine-cisplatin-durvalumab is preferred in first line. These decisions should be made with the full map of the genomic profile; a single mutation-test tool is insufficient.

• Small sample. With 19 evaluable patients, the 95% confidence interval remains very wide (16,3–61,6); the true ORR could be lower or higher. A confirmatory study is necessary.
• No comparator arm. A single-arm basket design; direct comparison with sotc is not possible until a randomized study is conducted.
• Overall survival (OS) data are still immature. PFS was reported in the company presentation (9,2 months), but mature OS data are not available.
• The biology of resistance is uncertain. Mechanisms of acquired resistance to zenocutuzumab (HER2 amplification, activation of bypass pathways, loss of NRG1 expression?) have not been studied systematically.
• NGS coverage is limited. Standard DNA-based panels may miss a substantial proportion of NRG1 fusions; RNA-based sequencing is necessary—but is not routine in most centers, including those in Türkiye.

This article is intended as medical news/information and does not provide individualized treatment guidance. Treatment of NRG1 fusion-positive cholangiocarcinoma requires a multidisciplinary biliary oncology tumor board decision, comprehensive genomic profiling (including an RNA-based fusion panel), and evaluation of response to previous treatment. In Türkiye, zenocutuzumab-zbco is not covered by SGK; early access may be possible through individual-use authorization (the Regulation on Procuring Medicines from Abroad). Editor's note: This article is based on the FDA Approval Notification dated 8 May 2026, data from the first FDA approval in December 2024, and the October 2025 AACR-NCI-EORTC presentation data from the eNRGy study.