A 52-year-old lifelong non-smoker woman is found to have a peripheral lung adenocarcinoma. Molecular testing reveals an EGFR exon 19 deletion. After initial response to osimertinib (3rd-generation EGFR-TKI), the patient progresses. Repeat biopsy shows EGFR T790M mutation is now absent. Which of the following resistance mechanisms is most likely responsible for osimertinib resistance without T790M?

• A Development of KRAS G12C mutation causing KRAS-driven proliferation bypassing EGFR completely
• B Loss of PTEN leading to constitutive PI3K-AKT activation accounts for >60% of osimertinib resistance cases
• C Promoter methylation of EGFR causes reduced drug-target interaction and acquired resistance without genetic mutation
• D MET amplification or EGFR C797S mutation are the most common mechanisms of acquired resistance to 3rd-generation EGFR TKIs; MET amplification activates PI3K-AKT and RAS-MAPK pathways downstream independently of EGFR, bypassing osimertinib blockade ✓

Explanation

Osimertinib (targeting EGFR including T790M) has well-characterized acquired resistance mechanisms. In the absence of T790M (either never present or selected-out), the most common mechanisms include: EGFR C797S mutation (which prevents covalent binding of osimertinib to Cys797 in the EGFR kinase domain); MET amplification (bypasses EGFR by activating PI3K-AKT/RAS-MAPK independently); and ERBB2 amplification. Less common mechanisms include transformation to SCLC histology, BRAF mutations, and RAS mutations. Knowing these resistance mechanisms guides next therapy choices (e.g., combination with MET inhibitors for MET-amplified cases).

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.