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.

Exploration of resistance mechanisms for epidermal growth factor receptor‐tyrosine kinase inhibitors based on plasma analysis by digital polymerase chain reaction and next‐generation sequencing

“…Our comprehensive assessment based on the T/A ratio indicated that T790M was positive in 13 (52.0%) of 25 patients at the time of systemic PD development (Table , Figure ). Median PFS for treatment with afatinib was longer in patients with than in those without T790M at systemic PD (15.1 vs 10.9 months, P = 0.25; Figure B), consistent with previous findings . Although median time to systemic PD was longer than median PFS in patients with T790M at systemic PD (17.9 vs 15.1 months), such a difference was not apparent in patients without T790M at this time (10.9 vs 10.9 months; Figure C).…”

“…Among the 14 plasma samples in which EGFR activating mutations were detected at the time of systemic PD development by NGS, the detection rate for T790M by NGS was 71.4% (10 of 14; ). These detection rates for T790M are much higher than those previously reported for tumor samples collected from patients who experienced resistance to first‐ or second‐generation EGFR‐TKI . Although such a high frequency of T790M might be the result of selection bias due to the small number of samples, we considered the possibility that highly sensitive methods such as dPCR and NGS might detect a small population of T790M alleles in cfDNA that is not responsible for resistance to EGFR‐TKI and give rise to the low specificity of plasma analysis for the detection of T790M compared with tumor analysis.…”

“…These detection rates for T790M are much higher than those previously reported for tumor samples collected from patients who experienced resistance to first-or second-generation EGFR-TKI. [23][24][25][26] Although such a high frequency of T790M might be the result of selection bias due to the small number of samples, we considered the possibility that highly sensitive methods such as dPCR and NGS might detect a small population of T790M alleles in cfDNA that is not responsible for resistance to EGFR-TKI and give rise to the low specificity of plasma analysis for the detection of T790M compared with tumor analysis. Such highly sensitive methods have been found to detect a small proportion of T790M alleles even in specimens obtained from NSCLC patients before treatment with EGFR-TKI.…”

Long non‐coding RNA LINC00968 acts as oncogene in NSCLC by activating the Wnt signaling pathway

“…Unfortunately, the five‐year survival rate of NSCLC still remains unsatisfactory because of early tumor metastasis and relapse in spite of great development of treatment method (Miller et al, ). In addition, it is of great significance to investigate mutant abundance in NSCLC due to the clinical response and prolongation of survival (Obradović et al, ; Tanaka, Nosaki, Otsubo, Azuma, & Sakata, ). Therefore, it is urgent to find novel therapeutic strategies to limit NSCLC progression.…”

Osimertinib Did Not Respond to a Pulmonary Adenocarcinoma with Triple Mutations of Epidermal Growth Factor Receptor, G719S, T790M and S768I

“…Emergence of T790M gatekeeper mutation is the most frequent mechanism of acquired drug resistance to first- and second-generation EGFR-tyrosine kinase inhibitors (TKIs) [4, 5]. Osimertinib, a third-generation EGFR-TKI, is a specific drug to overcome T790M resistance mutation.…”