What is the most common actionable mutation in non‑small cell lung cancer?

Most Common Actionable Mutation in NSCLC

EGFR mutations are the most common actionable genetic alteration in non-small cell lung cancer, occurring in approximately 10% of Caucasian patients and up to 50-63% of Asian patients with adenocarcinoma. 1

Prevalence and Geographic Distribution

• EGFR mutations represent the predominant actionable driver in Asian populations, with prevalence ranging from 39-63% in Chinese cohorts, making it the single most frequent targetable alteration in this demographic 1, 2
• In Western (Caucasian) populations, EGFR mutations occur in 5-20% of lung adenocarcinomas, making them less common than in Asian patients but still representing the most therapeutically relevant actionable mutation 1, 2
• KRAS mutations are more prevalent in Western patients (20-31%) but are not considered "actionable" in the same therapeutic sense, as they confer resistance to EGFR-TKIs and lack approved targeted therapies until recently 2

Specific EGFR Mutation Subtypes

• Exon 19 deletions account for approximately 45% of all EGFR mutations and are highly sensitive to EGFR tyrosine kinase inhibitors 1
• The L858R point mutation in exon 21 represents approximately 40% of EGFR mutations and also predicts response to EGFR-TKIs, though potentially with slightly lower efficacy than exon 19 deletions 1, 3
• Complete sequencing of EGFR exons 18-21 by next-generation sequencing is strongly recommended to identify all clinically relevant sensitizing mutations, including less common variants like L861Q and G719X 1, 2

Clinical Characteristics Associated with EGFR Mutations

• EGFR mutations are enriched in patients with adenocarcinoma histology, never-smoking or light-smoking history, female sex, and East Asian ancestry 1
• Testing should not be restricted based on clinical characteristics alone, as EGFR mutations can occur in patients without these typical features 1

Therapeutic Implications

• EGFR-mutant NSCLC demonstrates objective response rates of 55-80% to EGFR tyrosine kinase inhibitors, with median progression-free survival of 9-13 months with first- and second-generation TKIs 1
• Osimertinib is the preferred first-line treatment for EGFR-mutated metastatic NSCLC due to superior CNS penetration and efficacy 4
• EGFR mutations are predictive biomarkers for treatment benefit with EGFR-TKIs, not merely prognostic markers of survival 1

Comparison with Other Actionable Mutations

• ALK rearrangements occur in only 2-7% of NSCLC patients, making them substantially less common than EGFR mutations 1
• ROS1 fusions are found in approximately 2.4% of Asian patients with lung adenocarcinoma, representing a much smaller subset than EGFR-mutant disease 1
• These driver mutations (EGFR, ALK, KRAS, ROS1) are typically mutually exclusive, supporting distinct pathogenic pathways 2

Critical Testing Recommendations

• DNA mutational analysis is the preferred method to assess EGFR status; FISH for gene copy number and immunohistochemistry for protein expression have no clinical utility and should not be performed 1, 2
• Comprehensive biomarker testing is essential before initiating any treatment to identify all therapeutically targetable oncogenic drivers 1, 4
• Testing for T790M resistance mutation should be performed at progression on first- or second-generation EGFR-TKIs, as this mutation occurs in 50-60% of acquired resistance cases and predicts response to osimertinib 1

Common Pitfall

Clinicians should avoid assuming EGFR is the most common driver mutation globally—this predominance is limited to Asian populations, whereas KRAS mutations are more frequent in Western cohorts, though KRAS has only recently become actionable with specific inhibitors 2