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Resistance to EGFR Inhibitors: Fitness, Competition, and Diversity

*April 2023*

There is still a lot to be learned regarding resistance mechanisms in EGFR-mutant NSCLC, especially when osimertinib is used in the first-line setting and especially in the category of pathway indifference resistance cancers. In this issue of the Journal of Thoracic Oncology, Choudhury et al. set out to characterize mechanisms of acquired resistance to first-line osimertinib in advanced EGFR-mutant lung cancers. They reported a single-center retrospective analysis on patients with EGFR-mutant NSCLC who received osimertinib as first-line therapy, regarding clinical characteristics and genetic association with clinical outcome.

In the 95 patients with postprogression biopsies, known resistance mechanisms were identified in approximately half of the cases, confirming that acquired “on-target” EGFR reactivation by means of acquired EGFR mutations, such as C797S or G724S, and “off-target” bypass pathway activation, such as MET amplification, or RET or BRAF fusions, were still observed, similar to prior reports.  In this cohort, approximately 15% of the patients had histology transformation as the resistance mechanism and there were remaining patients (47.5%) with unknown resistance mechanisms. Interestingly and to a degree surprising, in the clinical outcome analysis, the histology transformation was not associated with inferior outcomes. In the comparison of the postresistance survival durations, the three categories of the known resistance mechanism group and the remaining patients without classified resistant mechanism had similar survival duration (p = 0.07). On further analysis, the authors found that tailored therapy at resistance was the key factor for a better outcome and small cell targeting therapy was classified as tailored therapy. This result is important for clinical practice and strongly argues that a repeat biopsy and molecular profiling is a crucial part of clinical decision-making for patients with osimertinib resistance NSCLC, which is consistent with current National Comprehensive Cancer Network guidelines. Read more.