ENRGY

NCT02912949 📎

Regimen

Experimental
Zenocutuzumab 750 mg IV q2w (bispecific antibody targeting HER2 and HER3; blocks NRG1-HER3 signaling by competitively inhibiting neuregulin-1 binding to HER3)
Control
single-arm / no comparator

Population

NRG1 fusion-positive advanced solid tumors after ≥1 prior therapy; pan-tumor basket spanning multiple histologies. Pancreatic cancer and lung cancer are most common NRG1 fusion-harboring types; BTC/CCA is represented with estimated n=3-5 of 64 in primary pub. NRG1 fusions occur in <1% BTC, comparable to RET and NTRK. Primary pub: Schram AM, NEJM 2025 (PMID 39908431). A CCA-specific analysis was reported as a conference abstract (Schram AM 2025, Mol Cancer Ther) — note abstract data, not peer-reviewed.

Key finding

Zenocutuzumab (Bizengri) received FDA accelerated approval in August 2024 for NRG1 fusion-positive NSCLC and pancreatic cancer (the two largest cohorts), with the broader tumor-agnostic data supporting use in rare NRG1 fusion-positive histologies including BTC. The CCA-specific analysis (Schram 2025 MCT abstract) showed responses in the BTC/CCA subgroup consistent with overall efficacy. NRG1 fusions differ mechanistically from most other oncogenic fusions — they create a ligand (NRG1) that activates HER2-HER3 signaling rather than encoding a constitutively active fusion kinase, which is why zenocutuzumab's anti-HER3 mechanism is specifically suited (blocking neuregulin-1 from binding HER3). PMID 39908431 (NEJM 2025) is PubMed-verified.

Source: PMID 39908431

Timeline

    Guideline citations

    • NCCN BTC (p.6)