High-level MET amplification (MET/CEP7 ratio ≥4.0 OR mean GCN ≥10) in metastatic NSCLC —...

Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.

ID	`RF-NSCLC-MET-AMP-ACTIONABLE`
Type	Red flag
Status	reviewed 2026-04-29 \| pending_clinical_signoff
Diseases	`DIS-NSCLC`
Sources	`SRC-ESMO-NSCLC-METASTATIC-2024` `SRC-GEOMETRY-WOLF-2020` `SRC-NCCN-NSCLC-2025`

Red Flag Origin

Definition	High-level MET amplification (MET/CEP7 ratio ≥4.0 OR mean GCN ≥10) in metastatic NSCLC — distinct from MET ex14 skipping. Two contexts: (1) De-novo MET-amp NSCLC (~1-5%) — capmatinib (GEOMETRY mono-1 high-amp cohort: ORR 40%, mPFS 5.5 mo; off-label expansion beyond ex14 label). (2) Acquired MET-amp post-osimertinib resistance in EGFR-mut NSCLC — osimertinib + savolitinib (SAVANNAH; not yet FDA- approved). Low-level amp (GCN 5-9) NOT actionable.
Clinical direction	intensify
Category	high-risk-biology
Shifts algorithm	ALGO-NSCLC-METASTATIC-2L

Trigger Logic

{
  "any_of": [
    {
      "finding": "met_amplification",
      "value": true
    },
    {
      "finding": "met_amplification",
      "value": "positive"
    },
    {
      "finding": "met_amp",
      "value": "positive"
    },
    {
      "finding": "met_cep7_ratio_ge_4",
      "value": true
    },
    {
      "finding": "met_gcn_ge_10",
      "value": true
    },
    {
      "finding": "met_status",
      "value": "amplified"
    }
  ],
  "type": "biomarker"
}

Notes

GEOMETRY mono-1 enrolled MET-amp cohort by GCN strata: GCN ≥10 cohort (high-amp) showed clinically meaningful response to capmatinib; GCN 6-9 cohort showed minimal benefit. Detection: FISH (Cappuzzo / Schildhaus criteria — MET/CEP7 ≥4 = high-level) preferred; NGS copy-number calls require assay-specific high-amp threshold. IHC alone is screening only — confirmation by FISH or NGS required. EGFR-mut NSCLC progressing on osimertinib: MET-amp is dominant non-T790M resistance mechanism; SAVANNAH (osi + savolitinib) showed ORR ~49% but not FDA-approved (covered indirectly by amivantamab + lazertinib via MET arm in MARIPOSA-2). Routes via ALGO-NSCLC-METASTATIC-2L step-10 area (parallel to MET ex14 — capmatinib regimen reused).

Used By

Algorithms

ALGO-NSCLC-METASTATIC-2L - ALGO-NSCLC-METASTATIC-2L