Oncology Drug Approval News Flash: FDA Approves Zenocutuzumab-zbco (Bizengri, Merus N.V.) for Advanced, Unresectable or Metastatic Cholangiocarcinoma

On May 13, 2025, the U.S. Food and Drug Administration (FDA) approved zenocutuzumab-zbco (brand name: Bizengri; sponsor: Merus N.V.) for adult patients with NRG1 fusion-positive advanced, unresectable, or metastatic cholangiocarcinoma. Bizengri is a bispecific antibody that simultaneously targets ErbB2 (HER2) and ErbB3 (HER3), blocking the oncogenic signaling driven by NRG1 (Neuregulin-1) fusion proteins—a mechanism of action entirely distinct from conventional HER2-directed therapies. NRG1 fusions represent a rare molecular subtype for which no approved targeted therapy had previously existed, making this approval a landmark advance in the precision oncology landscape for biliary tract cancers.

Eligible Patient Population

• Adult patients with NRG1 fusion-positive (confirmed by an FDA-approved companion diagnostic or appropriate validated assay) advanced, unresectable, or metastatic cholangiocarcinoma
• Primary intended population: patients with disease progression following prior systemic therapy (e.g., gemcitabine + cisplatin ± durvalumab); specific required prior lines to be confirmed in FDA labeling
• Detection of NRG1 fusions: RNA-based NGS panels are recommended given superior sensitivity over DNA-only assays; companion diagnostic details to be confirmed in official labeling
• ECOG performance status eligibility criteria: not confirmed in publicly available FDA materials as of the time of writing

Pivotal Trial Overview

The approval was based on the eNRGy trial (NCT02912949), an open-label, single-arm, basket Phase II study enrolling patients with NRG1 fusion-positive solid tumors across multiple histologies. The trial employed a tumor-agnostic basket design with histology-specific cohorts evaluated in parallel, of which the cholangiocarcinoma cohort served as the pivotal dataset supporting this approval.

The cholangiocarcinoma cohort enrolled approximately 20 or more evaluable patients based on publicly available information, though the precise enrollment figure should be confirmed against FDA-published materials. The treatment regimen consisted of zenocutuzumab-zbco 750 mg administered intravenously every two weeks (dose and schedule to be confirmed in the package insert). The primary endpoint was objective response rate (ORR) per RECIST v1.1 by independent central review, with secondary endpoints including duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

NRG1 fusions were detected using RNA-based and/or DNA-based NGS platforms across participating sites. The estimated prevalence of NRG1 fusions in all-comers cholangiocarcinoma is approximately 1–3% (literature-based estimate; not confirmed in FDA public documents), and the study utilized a biomarker-enrichment design to identify and enroll this rare molecular subtype. International multi-site participation is reported; Japanese site inclusion is not confirmed in available public sources.

Key Efficacy Results

The following efficacy data from the eNRGy cholangiocarcinoma cohort are organized based on publicly available information. Readers are strongly encouraged to verify all figures against the FDA-published label and review documents.

Across the broader eNRGy trial, consistent clinical activity was observed in NRG1 fusion-positive solid tumors beyond cholangiocarcinoma, including lung adenocarcinoma and pancreatic adenocarcinoma. The mechanistic rationale is well-grounded: NRG1 fusion proteins bind to the ligand-binding domain (domain III) of HER3, promoting HER2-HER3 heterodimerization and downstream activation of the PI3K/AKT and RAS/MAPK pathways. By physically blocking NRG1 fusion binding to HER3, zenocutuzumab-zbco disrupts this oncogenic cascade in a manner that is mechanistically distinct from HER2-amplification–directed agents such as trastuzumab or pertuzumab.

Safety Profile

The following adverse events were observed in the eNRGy trial. The presence of a Boxed Warning or REMS program requirement is not confirmed in publicly available FDA materials; the package insert must be consulted before clinical use.

Given the pharmacological class of bispecific HER2×HER3 targeting, clinicians should anticipate class-effect risks including cardiac dysfunction (LVEF reduction) characteristic of HER2-directed agents and dermatologic toxicities associated with ErbB pathway inhibition. ILD/pneumonitis, a recognized class effect of HER2/HER3-directed antibodies, warrants prompt evaluation upon onset of new respiratory symptoms. Embryo-fetal toxicity is anticipated based on class pharmacology and should be confirmed in the prescribing information.

Regulatory Significance and Clinical Positioning

① Regulatory significance: Expanding the rare biomarker-driven approval model
The approval of zenocutuzumab-zbco—whether under Accelerated Approval or Regular Approval (pathway to be confirmed in FDA documents)—exemplifies the FDA’s sustained commitment to enabling targeted therapies for ultra-rare molecular subtypes. Targeting NRG1 fusions, estimated to occur in only ~1–3% of cholangiocarcinoma cases, this approval follows the footsteps of larotrectinib (NTRK fusions) and selpercatinib (RET fusions) in validating the “rare fusion oncogene” approval paradigm. Critically, expanded access to RNA-based NGS diagnostics will be necessary to ensure equitable identification of eligible patients.

② Clinical positioning: A targeted option in the 2L+ biliary tract cancer setting
The current standard first-line therapy for advanced cholangiocarcinoma is gemcitabine + cisplatin + durvalumab (based on TOPAZ-1 data; ESMO/ASCO guidelines). In the 2L+ setting, molecularly guided therapies have rapidly expanded: pemigatinib, infigratinib, and futibatinib for FGFR2 fusion/rearrangement; ivosidenib for IDH1-mutant; pembrolizumab for MSI-H/dMMR. Zenocutuzumab-zbco fills the remaining gap for NRG1 fusion-positive patients who previously had no approved targeted option regardless of the line of therapy.

③ Competitive landscape: First-in-class advantage with diagnostic barriers ahead
As of May 2025, zenocutuzumab-zbco stands as the only FDA-approved therapy specifically targeting NRG1 fusions in solid tumors (based on publicly available information). Competing NRG1-directed agents remain in early-to-mid clinical development (not confirmed in FDA public documents). The principal market penetration barrier is diagnostic: DNA-only NGS panels frequently miss fusion events best detected by RNA-sequencing, creating a real-world gap between eligible patients and those who receive the drug.

My Thoughts and Future Outlook

For those newer to this field: cholangiocarcinoma has historically been one of oncology’s most challenging diseases, with a 5-year survival rate below 10% for unresectable or metastatic cases. The last decade has witnessed a remarkable molecular stratification of what was once treated as a uniform disease—FGFR2, IDH1, BRAF, HER2, MSI-H, and now NRG1 fusions each defining a distinct patient subgroup with a tailored treatment option. Zenocutuzumab-zbco’s approval is not merely a drug addition; it represents the continued validation of comprehensive molecular profiling as an indispensable standard of care in biliary oncology.

From an expert perspective, the future promise is considerable. The tumor-agnostic design of eNRGy positions zenocutuzumab-zbco for label expansions into lung adenocarcinoma, pancreatic cancer, and other NRG1 fusion-positive solid tumors—some of which represent the most therapeutically deprived patient populations in oncology. Pancreatic adenocarcinoma with NRG1 fusion is particularly compelling given the near-complete absence of actionable targets in that disease. Additionally, the mechanistic independence of NRG1 fusion-driven signaling from classical HER2 amplification opens intriguing questions about combination strategies with HER2-directed agents and the optimal sequencing in tumors co-harboring HER2/HER3 alterations.

The unmet needs are equally clear. First, the approval rests on single-arm, ORR-based evidence from a small basket cohort—robust randomized data confirming OS and PFS benefit are absent and essential for cementing the drug’s long-term clinical value. Second, the diagnostic infrastructure for RNA-based NRG1 fusion detection remains inconsistent globally, threatening equitable patient access. Third, mechanisms of acquired resistance to zenocutuzumab-zbco are essentially uncharacterized, and no established post-progression therapeutic strategy exists. Addressing these three gaps—randomized efficacy confirmation, diagnostic democratization, and resistance biology—will define the next chapter for NRG1-targeted oncology.

This article is an independent summary prepared by Morningglorysciences based on FDA public documents, sponsor press releases, and relevant peer-reviewed literature. All clinical decisions should be made by qualified healthcare professionals in reference to the original publications, current prescribing information, and applicable clinical guidelines.