Significance of micro-EGFR T790M mutations on EGFR-tyrosine kinase inhibitor efficacy in non-small cell lung cancer

Abstract

Small amounts of epidermal growth factor receptor (EGFR) T790M mutation (micro-T790M), which is detected using droplet digital PCR (ddPCR) but not conventional PCR, in formalin-fixed and paraffin-embedded (FFPE) samples have been investigated as a predictive factor for the efficacy of EGFR-tyrosine kinase inhibitors (TKIs). However, the predictive value of micro-T790M remains controversial, possibly owing to the failure to examine artificial T790M in FFPE specimens. Therefore, we examined the predictive value of micro-T790M in first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKI efficacy using a new method to exclude FFPE-derived artificial mutations in our retrospective cohort. The primary objective was time to treatment failure (TTF) of 1G, 2G, and 3G EGFR-TKIs according to micro-T790M status. In total, 315 patients with EGFR-positive non-small cell lung cancer treated with 1G, 2G, and 3G EGFR-TKIs were included in this study. The proportion of patients positive for micro-T790M in the 1G, 2G, and 3G EGFR-TKI groups was 48.2%, 47.1%, and 47.6%, respectively. In the micro-T790M-positive group, the TTF was significantly longer in the 2G and 3G EGFR-TKI groups than in the 1G TKI group. No differences in the micro-T790M-negative group were observed. Micro-T790M status detected using ddPCR, eliminating false positives, may be a valuable predictor of EGFR-TKI efficacy.

Figure 1

Flowchart of participants. EGFR-TKI, epidermal growth factor receptor-kinase inhibitors.

Figure 2

Kaplan–Meier analysis of the time-to-treatment failure between 1G, 2G, and 3G EGFR-TKIs. Patients in the micro-EGFR T790M-positive group (a) and micro-EGFR T790M-negative group (b). Patients with EGFR exon 19 deletion in the (c) micro-EGFR T790M-positive and (d) -negative groups, and patients with EGFR L858R mutation in the (e) micro-EGFR T790M-positive and (f) -negative groups. TTF time-to-treatment failure, CI confidence interval, 1G first-generation, 2G second-generation, 3G third generation, EGFR-TKIs epidermal growth factor receptor-kinase inhibitors.

Figure 3

Kaplan–Meier analysis of time-to-treatment failure in micro-EGFR T790M-positive and -negative patients. Patients treated with (a) 1G, (b) 2G, and (c) 3G EGFR-TKI. Patients with EGFR exon 19 deletion treated with (d) 1G, (e) 2G, and (f) 3G EGFR-TKI, and patients with EGFR L858R mutation treated with (g) 1G, (h) 2G, and (i) 3G EGFR-TKI. TTF time-to-treatment failure, CI confidence interval, 1G first-generation, 2G second-generation, 3G third generation, EGFR epidermal growth factor receptor.