What EGFR mutations in NSCLC are treated with Afatinib?

EGFR Mutations for Afatinib Treatment in NSCLC

Afatinib should be given for NSCLC with uncommon EGFR mutations including S768I, L861Q, and G719X, where it demonstrates particularly high response rates (100% for S768I, 77.8% for G719X, and 56.3% for L861Q). 1

Primary Indications

Uncommon EGFR Mutations (Preferred Indication)

The NCCN 2024 guidelines recommend afatinib as a preferred first-line therapy option for advanced or metastatic NSCLC with EGFR S768I, L861Q, and/or G719X mutations. 1

The evidence supporting this recommendation comes from:

• Post-hoc analysis of LUX-Lung trials (2,3, and 6) demonstrated median overall survival of 19.4 months in patients with these uncommon mutations 1
• Response rates by mutation type: 1
  • S768I: 100% response rate (8/8 patients)
  • G719X: 77.8% response rate (14/18 patients)
  • L861Q: 56.3% response rate (9/16 patients)

Common EGFR Mutations (Alternative Option)

Afatinib is FDA-approved for first-line treatment of metastatic NSCLC with common sensitizing EGFR mutations (exon 19 deletions and exon 21 L858R), though osimertinib is now preferred 1, 2

Clinical Decision Algorithm

When to Choose Afatinib Over Osimertinib

For uncommon mutations (S768I, L861Q, G719X):

• Afatinib and osimertinib are both preferred options with similar category 1 recommendations 1
• Consider afatinib specifically for S768I mutations where it showed 100% response rate versus only 38% with osimertinib 1
• Consider osimertinib for L861Q mutations where retrospective data suggest better response (78% vs 56.3% with afatinib) 1

For common mutations (exon 19 deletion, L858R):

• Osimertinib is preferred due to superior progression-free survival (18.9 vs 10.2 months) and better CNS penetration 1, 3
• Afatinib remains an acceptable alternative if osimertinib is unavailable or contraindicated 1

FDA-Approved Indications

The FDA has approved afatinib for: 2

• First-line treatment of metastatic NSCLC with non-resistant EGFR mutations detected by FDA-approved companion diagnostic (therascreen® EGFR RGQ PCR Kit)
• Previously treated metastatic squamous NSCLC that progressed after platinum-based chemotherapy (regardless of EGFR status)

Mutations Where Afatinib Should NOT Be Used

EGFR exon 20 insertion mutations are resistant to afatinib and should be treated with specialized agents like amivantamab 1

EGFR T790M resistance mutation (acquired after first/second-generation TKI failure) requires third-generation TKIs like osimertinib, not afatinib 1

Critical Dosing Considerations

• Standard starting dose: 40 mg orally once daily 2
• Dose adjustments required for severe renal impairment (reduce to 30 mg daily if eGFR 15-29 mL/min/1.73 m²) 2
• Take on empty stomach (at least 1 hour before or 3 hours after food) as high-fat meals decrease absorption by 50% 2

Common Pitfalls to Avoid

• Do not use afatinib for EGFR exon 20 insertions - these require different targeted therapies 1
• Do not assume all uncommon mutations respond equally - S768I has 100% response rate while L861Q has only 56.3% 1
• Monitor for dose-limiting toxicities (diarrhea, rash, paronychia) which occur more frequently than with osimertinib and often require dose reduction 2