ERBB4 (HER4) somatic activating mutations are identified in ~2–3% of NSCLC (mixed histolo...
Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.
| ID | BMA-ERBB4-NSCLC |
|---|---|
| Type | Actionability |
| Status | reviewed 2026-05-04 | pending_clinical_signoff | actionability review required |
| Diseases | DIS-NSCLC |
| Sources | SRC-ESMO-NSCLC-METASTATIC-2024 SRC-NCCN-NSCLC-2025 |
Actionability Facts
| Biomarker | BIO-ERBB4 |
|---|---|
| Variant | ERBB4 (HER4) somatic activating mutation in NSCLC (~2–3%); pan-HER inhibitors investigational; distinct from NRG1 fusion (actionable via ERBB4 signaling) |
| Disease | DIS-NSCLC |
| ESCAT tier | IIIB |
| Recommended combinations | Pembrolizumab ± platinum chemotherapy — standard 1L NSCLC regardless of ERBB4 status; histology and PD-L1 determine regimen, Afatinib 40 mg PO QD — investigational for ERBB4-mutant NSCLC; not FDA-approved for ERBB4 indication (approved for EGFR and HER2 exon 20 NSCLC) |
| Evidence summary | ERBB4 (HER4) somatic activating mutations are identified in ~2–3% of NSCLC (mixed histologies). ERBB4 is a member of the ERBB/HER RTK family; it signals via homo- or heterodimerization (primarily with EGFR or HER2) activating PI3K/AKT and MAPK pathways. Therapeutic considerations: (1) Afatinib (pan-HER1/2/4 irreversible inhibitor, FDA-approved for EGFR-mutant NSCLC and ERBB2 exon 20 insertion NSCLC): has in vitro activity against ERBB4-mutant cell lines, but no FDA-approved indication for ERBB4-selected NSCLC. (2) Neratinib (pan-HER1/2/4; FDA-approved for HER2-mutant NSCLC per NTRK basket, BreastFTD): investigational in ERBB4-mutant NSCLC. (3) SUMMIT basket trial (neratinib): included ERBB4-mutant patients across tumor types; NSCLC cohort showed 1/10 responses in ERBB4-mutant patients; insufficient for approval. (4) NRG1 fusions: NRG1 (neuregulin-1, the primary ERBB4 ligand) fusions in ~0.2% NSCLC activate ERBB3/ERBB4 signaling — zenocutuzumab (bispecific anti-HER2/HER3) ORR ~33% (eNRGy trial, FDA Breakthrough 2023). NRG1 fusion is the actionable alteration; ERBB4 mutation is a dist... |
Notes
ESCAT IIIB: ERBB4 mutation in NSCLC is an investigational target. Critical distinction: (1) ERBB4 somatic mutation (kinase/extracellular domain): rare, no approved therapy. (2) NRG1 gene fusion (NRG1 is the ERBB4 ligand): actionable — zenocutuzumab FDA Breakthrough Designation, ORR ~33% in NRG1-fusion NSCLC/pancreatic (eNRGy trial). NRG1 fusions require RNA-seq for detection (not captured on DNA-only panels). These are clinically distinct. (3) Afatinib is pan-HER (HER1/2/4) but its approvals are HER1-mutant NSCLC and HER2 exon 20 insertion NSCLC; using afatinib for ERBB4 mutation is off-label with limited evidence. (4) No companion diagnostic exists for ERBB4 mutation; standard NSCLC biomarker panel is sufficient.
Used By
No reverse references found in the YAML corpus.