NRG1 fusions (~0.2% NSCLC; enriched in invasive mucinous adenocarcinoma, never-smokers) d...
Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.
| ID | BMA-NRG1-FUSION-NSCLC |
|---|---|
| Type | Actionability |
| Status | reviewed 2026-05-03 | pending_clinical_signoff | actionability review required |
| Diseases | DIS-NSCLC |
| Sources | SRC-ESMO-NSCLC-METASTATIC-2024 SRC-NCCN-NSCLC-2025 |
Actionability Facts
| Biomarker | BIO-NRG1-FUSION |
|---|---|
| Variant | NRG1 gene fusion — any fusion partner (CD74-NRG1 most common in lung mucinous adenocarcinoma; ATP1B1-NRG1, SLC3A2-NRG1; detected by RNA-seq or FISH) |
| Disease | DIS-NSCLC |
| ESCAT tier | IIA |
| Recommended combinations | zenocutuzumab 750 mg IV q2w monotherapy (post-platinum or post-ICI; CRESTONE regimen) |
| Evidence summary | NRG1 fusions (~0.2% NSCLC; enriched in invasive mucinous adenocarcinoma, never-smokers) drive tumor growth via HER3 activation and downstream PI3K/AKT signaling. Zenocutuzumab (MCLA-128), an anti-HER2/HER3 bispecific antibody that blocks NRG1 binding to HER3, received FDA accelerated approval (Nov 2024) for NRG1 fusion-positive locally advanced or metastatic NSCLC and pancreatic adenocarcinoma after prior systemic therapy. CRESTONE trial (Schram et al. JCO 2024): NRG1-fusion NSCLC cohort — ORR 33% (RECIST), mDOR 7.4 mo, mPFS 8.1 mo in previously treated patients; disease control rate 73%. NRG1 fusions are mutually exclusive with EGFR, ALK, ROS1, KRAS G12C in the vast majority of cases. Standard NTRK/RET/MET panel may miss NRG1 — RNA-based sequencing required. |
Notes
ESCAT IIA (accelerated approval, basket trial data; confirmatory phase III pending). RNA sequencing is required — NRG1 fusions are not reliably detected by DNA-based NGS panels due to large intronic breakpoints. Zenocutuzumab mechanism: blocks NRG1 ligand from binding HER3, preventing HER2-HER3 heterodimerization and downstream oncogenic signaling — distinct from kinase inhibitors and not susceptible to gatekeeper mutations. NRG1-fusion NSCLC tumors are typically ICI-resistant (low TMB, low PD-L1); do not delay zenocutuzumab for ICI rechallenge. KRAS, EGFR, ALK testing still required — NRG1 rarely co-occurs with these drivers.
Used By
No reverse references found in the YAML corpus.