Heterogeneity of EGFR activating and resistance mutations in lung adenocarcinoma: clinical relevance

In lung adenocarcinoma, activating mutation of EGFR (aEGFR) and EGFR-T790M can coexist. T790M confers resistance to 1st and 2nd generation TKIs. T790M may also be observed at diagnosis (preT790M+) in 0,5-3% cases using standard techniques and up to 30% with highly sensitive ones. FDA and EMA approved osimertinib, a 3rd generation TKI overcoming T790M resistance, for 2nd-line in patients T790M+; FDA approved it also for 1st-line of aEGFR+ metastatic disease. Current guidelines make no distinction in aEGFR patients with or without preT790M+. Aim of this study was to find differences in terms of survival and response rate between preT790M+ and wild-type for T790M (WT), detecting T790M at diagnosis with a highly sensitive technique (RainDrop Digital PCR). We selected 28 aEGFR+ lung adenocarcinoma that received 1st or 2nd generation TKI in 1st line. For statistical analysis we used Kaplan-Meyer method and log-rank test. At diagnosis, all were WT for T790M with standard techniques. With RainDrop Digital PCR, preT790M+ were 28,6% (n=8). In ≥2nd lines 50% of preT790M+ and 30% of WT received osimertinib. 1-yr and 2-yr survival were, respectively, 100% and 89% for preT790M+; 68% and 60% for WT. Median OS (mOS) of preT790M+ was not reached at the end of follow-up and 32.7 months for WT (p=0.098). There were no differences in mOS stratifying by osimertinib use the study population (p=0.792) and preT790M+ subgroup (p=1.000). RR was 87,5% for preT790M+, 60% for WT (p=0.241). The coexistence at diagnosis of aEGFR and T790M is not negligible. PreT790M+ seems to be an independent prognostic factor; preT790M+ tumors could represent a more indolent disease. Further studies are needed to define the optimal timing for osimertinib in these patients.