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.
Highlights
RESULTSSeveral phase III trials have established epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as a standard first-line treatment for patients with non–small cell lung cancer (NSCLC) harboring somatic driver mutations in the EGFR gene [1,2,3]
The AURA3 phase III trial revealed that the median progressionfree survival (PFS) for osimertinib was significantly longer than that for platinum chemotherapy plus pemetrexed (10.1 vs. 4.4 months; hazard ratio of 0.30 with a 95% confidence interval of 0.23–0.41; P < 0.001) in patients with EGFR mutation– positive NSCLC who acquired T790M and whose disease had progressed during previous EGFR-TKI therapy, indicating that osimertinib should be a new standard treatment for this population [8]
Rebiopsy to detect T790M at the time of progression is essential to determine the best subsequent treatment option for EGFR mutation–positive patients treated with EGFR-TKIs
Summary
Several phase III trials have established epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as a standard first-line treatment for patients with non–small cell lung cancer (NSCLC) harboring somatic driver mutations in the EGFR gene [1,2,3]. Eleven patients with an exon 19 deletion (11/21, 52.4%) and five patients with L858R (5/13, 38.5%) acquired T790M, whereas T790M was not detected in any of the three patients with an uncommon EGFR mutation (Figure 3B) Patient characteristics such as smoking history, sex, age, and performance status (PS) were not significantly associated with the emergence of T790M (Supplementary Figure 1).
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