Osimertinib is a third-generation EGFR-TKI effective against the T790M resistance mutation. When osimertinib resistance develops via a C797S mutation, which combination treatment rationale applies?

• A C797S mutation activates MET amplification as a bypass pathway; cetuximab can overcome this
• B C797S in trans with T790M allows first-generation erlotinib + third-generation osimertinib combination (each TKI binds a different subpopulation); C797S in cis with T790M renders all EGFR-TKI classes ineffective ✓
• C C797S prevents osimertinib binding but restores afatinib activity by switching to the reversible binding mode
• D All C797S mutations respond to amivantamab (anti-EGFR/MET bispecific antibody) regardless of allele configuration

Explanation

Osimertinib covalently binds Cys797 of EGFR. The C797S mutation replaces cysteine with serine, eliminating the covalent bond and conferring resistance. The clinical significance depends on whether C797S is on the same allele (cis) or different allele (trans) as the activating sensitizing mutation and T790M. If C797S and T790M are on DIFFERENT alleles (trans configuration), first-generation erlotinib can inhibit the allele bearing only T790M, while osimertinib acts on the other — combining both TKIs overcomes resistance. If C797S and T790M are on the SAME allele (cis), no EGFR-TKI can overcome both mutations simultaneously, requiring a different strategy (allosteric EGFR inhibitors, platinum-based chemotherapy).

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.