A 35-year-old non-smoker woman with lung adenocarcinoma is tested for molecular targets. The EGFR mutation most predictive of response to first-generation EGFR tyrosine kinase inhibitors (gefitinib, erlotinib) is:

• A Exon 20 T790M substitution
• B KRAS G12C substitution
• C ALK gene rearrangement (EML4-ALK fusion)
• D Exon 19 in-frame deletions or exon 21 L858R point mutation ✓

Explanation

Sensitizing EGFR mutations — exon 19 deletions (most common, ~45%) and exon 21 L858R point mutation (~40%) — predict high response rates to first-generation EGFR TKIs (gefitinib, erlotinib, afatinib) with objective response rates of 60–70%. The T790M gatekeeper mutation in exon 20 is the primary mechanism of acquired resistance to first-generation TKIs and is targeted by osimertinib (third-generation). KRAS mutations and ALK fusions are separate druggable targets not responsive to EGFR TKIs.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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