Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor-naïve patients with non-small cell lung cancer harboring EGFR mutations

Abstract

The T790M secondary mutation of the epidermal growth factor receptor (EGFR) gene accounts for 50% to 60% of cases of resistance to the first-generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. The prevalence of T790M in EGFR mutation-positive patients who acquire resistance to the irreversible, second-generation EGFR-TKI afatinib has remained unclear, however. We here determined the frequency of T790M acquisition at diagnosis of progressive disease in patients with EGFR-mutated non-small cell lung cancer (NSCLC) treated with afatinib as first-line EGFR-TKI. Among 56 enrolled patients, 37 individuals underwent molecular analysis at rebiopsy. Of these 37 patients, 16 individuals (43.2%) had acquired T790M, including 11/21 patients (52.4%) with an exon 19 deletion of EGFR and 5/13 patients (38.5%) with L858R. None of three patients with an uncommon EGFR mutation harbored T790M. T790M was detected in 14/29 patients (48.3%) with a partial response to afatinib, 1/4 patients (25%) with stable disease, and 1/4 patients (25%) with progressive disease as the best response. Median progression-free survival after initiation of afatinib treatment was significantly (P = 0.043) longer in patients who acquired T790M (11.9 months; 95% confidence interval, 8.7-15.1) than in those who did not (4.5 months; 95% confidence interval, 2.0-7.0). Together, our results show that EGFR-mutated NSCLC patients treated with afatinib as first-line EGFR-TKI acquire T790M at the time of progression at a frequency similar to that for patients treated with gefitinib or erlotinib. They further underline the importance of rebiopsy for detection of T790M in afatinib-treated patients.

Keywords: T790M; acquired resistance; afatinib; non–small cell lung cancer (NSCLC); rebiopsy.

Figure 1. Flow chart for the study patients (pts)

Figure 2. Characteristics, response to afatinib, and T790M status for the 37 patients with sufficient rebiopsy material for molecular analysis

For dose reduction, Yes* indicates reduction to 30 mg/day and Yes** to 20 mg/day. Abbreviations: del, deletion; LN, lymph node.

Figure 3

Prevalence of T790M for all patients (A) or according to type of activating EGFR mutation (B) or response to afatinib (C).

Figure 4. Comparison of PFS after the onset of afatinib treatment between patients who acquired T790M and those who did not

Each circle or square indicates one patient. Thick horizontal bars indicate median values; error bars indicate median ± quartile deviation. The P value was calculated with Student’s t test.