Optimizing Sequential Treatment With EGFR Tyrosine Kinase Inhibitor With a Simulation of the T790M Mutation Rate in EGFR–Mutated Lung Cancer

INTRODUCTION: The mutation rate of T790M might change the effective therapeutic sequence of EGFR tyrosine kinase inhibitors (TKIs). This simulation estimates the T790M positivity rate required for first-line first- or second-generation EGFR TKI to exceed overall progression-free survival (PFS) of first-line osimertinib. METHODS: The PFS of each treatment with EGFR TKIs as first-line treatment, with osimertinib as second-line treatment among T790M-positive cases, and chemotherapy as second-line treatment among T790M-negative cases was set based on phase 3 trials. Overall PFS A of “upfront osimertinib” and overall PFS B of “first- or second-generation EGFR TKIs followed by osimertinib or chemotherapy” were simulated at different T790M mutation rates, to estimate the T790M mutation rate at which PFS B exceeds PFS A. RESULTS: Upfront osimertinib: In the setting of PFS of 19 months with first-line osimertinib, the median overall PFS A was 24.8 months (95% confidence interval [CI]: 21.6–28.0 mo). Upfront first- or second-generation EGFR TKI: When the T790M positivity rate was set to 50% and the PFS of second-line osimertinib was 10 months, the total median PFS (PFS B) was 20.2 months (95% CI: 17.5–22.9 mo). Even at a T790M mutation rate of 100%, PFS B (24.7 mo; 95% CI: 21.9–27.9 mo) was shorter than PFS A. CONCLUSIONS: Even with a T790M mutation rate of 100%, upfront osimertinib treatment is associated with better median PFS than the upfront treatment with first- or second-generation EGFR TKIs. Consistent with the results of the FLAURA trial, with regard to EGFR TKI monotherapy in the first-line treatment, upfront osimertinib would contribute to good prognosis.