High ratio of T790M to EGFR activating mutations correlate with the osimertinib response in non-small-cell lung cancer

Objectives: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that can overcome resistance due to the Thr790Met (T790M) mutation. However, osimertinib occasionally shows limited efficacy in a small population of patients. We investigated the correlation between the ratio of T790M to EGFR activating mutation and the response to osimertinib. Materials and methods: Between April 2016 and April 2017, 44 patients started osimertinib therapy at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. We performed EGFR mutation analysis of cytological samples from 33 patients using droplet digital PCR. We calculated the ratio of T790M to EGFR activating mutations and correlated it with the systemic response to osimertinib. Results: In tumors from the 33 patients, the average ratio of T790M to EGFR activating mutations was 0.420. Twenty-one of the 33 patients had tumors with a T790M ratio of >= 0.4. The osimertinib response rate was significantly higher (92.3%) in patients with a T790M ratio of >= 0.4 than in those with a T790M ratio of < 0.4 (52.6%; p = 0.0237). We examined the correlation between the T790M ratio and the tumor reduction rate and obtained a coefficient of r = 0.417 (p = 0.0175). In patients with a T790M ratio of >= 0.4, the median progression-free survival was 355 days, which was longer, but not significant, than that in patients with a T790M ratio of < 0.4 (median: 264 days). In patients with a T790M ratio of >= 0.4, the median treatment duration from first-line therapy onward was 931 days, which was significantly longer than that in patients with a T790M ratio of < 0.4 (median, 567.5 days) (p = 0.044). Conclusion: The T790M ratio to EGFR activating mutation in tumor may correlate with the response to osimertinib, and patients with a higher T790M ratio have a longer treatment history.