These are typically tested on every new diagnosis, or required before systemic therapy decisions, under current U.S. clinical guidelines.
EGFR
Standard What it is: Epidermal Growth Factor Receptor mutations. Most common are exon 19 deletion and L858R point mutation. Less common: exon 20 insertion.
Why test: EGFR-mutated lung cancers respond to EGFR tyrosine kinase inhibitors with dramatic response rates. Higher prevalence in never-smokers and people of East Asian descent.
Therapies it unlocks: - Osimertinib (Tagrisso) — preferred first-line for common mutations
- Amivantamab + lazertinib for exon 20
- Mobocertinib for exon 20 (withdrawn 2023 — check current availability)
ALK
Standard What it is: Anaplastic Lymphoma Kinase rearrangement (a gene fusion). Detected via IHC, FISH, or NGS.
Why test: ALK-rearranged lung cancers respond to ALK inhibitors with long durations of response.
Therapies it unlocks: - Alectinib (Alecensa) — often first-line
- Brigatinib
- Lorlatinib
- Crizotinib
ROS1
Standard What it is: ROS1 gene rearrangement. Rare (~1-2% of NSCLC).
Why test: Opens targeted therapy eligibility.
Therapies it unlocks: - Entrectinib
- Repotrectinib
- Crizotinib
KRAS G12C
Standard What it is: A specific KRAS point mutation. Found in ~13% of NSCLC, more common in smokers.
Why test: Recently targetable after decades of being 'undruggable.' KRAS G12C inhibitors available.
Therapies it unlocks: - Sotorasib (Lumakras)
- Adagrasib (Krazati)
BRAF V600E
Standard What it is: A specific BRAF kinase mutation. Rare in lung cancer but highly actionable.
Why test: Opens eligibility for combination BRAF + MEK inhibitor therapy.
Therapies it unlocks: - Dabrafenib + trametinib
- Encorafenib + binimetinib (under investigation/off-label)
MET exon 14 skipping
Standard What it is: A splice mutation producing MET signaling dysregulation.
Why test: Targetable with MET inhibitors.
Therapies it unlocks: - Capmatinib (Tabrecta)
- Tepotinib (Tepmetko)
RET
Standard What it is: RET gene fusion. Rare in NSCLC but actionable.
Why test: Highly effective RET inhibitors available.
Therapies it unlocks: - Selpercatinib (Retevmo)
- Pralsetinib (Gavreto)
NTRK
Standard What it is: NTRK gene fusion. Very rare but tumor-agnostic targetable mutation.
Why test: Highly effective NTRK inhibitors across cancer types.
Therapies it unlocks: - Larotrectinib (Vitrakvi)
- Entrectinib (Rozlytrek)
PD-L1
Standard What it is: PD-L1 protein expression, reported as Tumor Proportion Score (TPS).
Why test: Guides first-line immunotherapy decisions. High PD-L1 favors pembrolizumab monotherapy; lower PD-L1 favors chemo + immunotherapy combinations.
Therapies it unlocks: - Pembrolizumab (Keytruda)
- Nivolumab + ipilimumab
- Atezolizumab
- Durvalumab
- Cemiplimab