EGFR-mutant lung cancer patients treated with first or second-generation EGFR inhibitors eventually develop drug resistance. About 50% to 65% of biopsies from resistant tumors are found to harbor the EGFR T790M mutation. Third-generation EGFR inhibitors can be used to treat those patients, however resistance may develop. To explore drug resistance mechanisms, scientists analyzed post-progression tumor biopsies and ctDNA of T790M-positive patients who were treated with the third-generation EGFR inhibitor rociletinib. Among 12 patients, 6 tumors were found to have reverted to wild-type EGFR, 2 of which underwent small cell lung cancer transformation. Three of 6 T790M-positive cancers had acquired EGFR amplification. Longitudinal ctDNA analysis of 6 patients revealed a decline of T790M ctDNA within days of initiating rociletinib, however eventually resistance was observed. Among 3 patients with EGFR del19 or L858R mutation and T790M mutation, both mutations re-emerging as radiographic progression was observed in one patient; for the other two patients, del19 or L858R ctDNA rose steadily while T790M ctDNA remained low. These results indicate that preexisting tumor heterogeneity regarding the T790 mutation status may be involved in mediating drug resistance.
Piotrowska Z, Niederst MJ, Karlovich CA, et al., Cancer Discov. 2015 Jul;5(7):713-22.