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NSCLC — SCE Medical Oncology MCQ

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HardLung CancerNSCLCSCE Medical Oncology

A tumour progressing after sequential gefitinib and osimertinib retains an activating EGFR deletion and contains both T790M and C797S. Phased sequencing shows T790M and C797S on different EGFR alleles. Which preclinical sensitivity pattern follows from this allelic configuration?

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Correct answer: E — Combined first- and third-generation EGFR inhibition may retain activity in the trans allelic configuration

When T790M and C797S are in trans, separate alleles can be inhibited by complementary first- and third-generation EGFR TKIs in preclinical models. C797S prevents covalent binding of third-generation inhibitors, while T790M confers resistance to first-generation monotherapy. In cis, the two mutations on one allele are resistant to the currently established EGFR-TKI combinations. C797S neither restores osimertinib binding nor implies an ALK fusion.

Reference: Niederst et al: allelic context of acquired EGFR C797S (Clinical Cancer Research 2015): https://pubmed.ncbi.nlm.nih.gov/25964297/