Sensitivities to various epidermal growth factor receptor‐tyrosine kinase inhibitors of uncommon epidermal growth factor receptor mutations L861Q and S768I: What is the optimal epidermal growth factor receptor‐tyrosine kinase inhibitor?

Abstract

Most patients with non‐small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) mutations, such as deletions in exon 19 or the L858R mutation in exon 21, respond dramatically to EGFR tyrosine kinase inhibitors (EGFR‐TKI), and their sensitivities to various EGFR‐TKI have been well characterized. Our previous article showed the in vitro sensitivities of EGFR exon 18 mutations to EGFR‐TKI, but little information regarding the sensitivities of other uncommon EGFR mutations is available. First, stable transfectant Ba/F3 cell lines harboring EGFR L858R (Ba/F3‐L858R), L861Q (Ba/F3‐L861Q) or S768I (Ba/F3‐S768I) mutations were created and their drug sensitivities to various EGFR‐TKI were examined. Both the Ba/F3‐L861Q and Ba/F3‐S768I cell lines were less sensitive to erlotinib, compared with the Ba/F3‐L858R cell line, but their sensitivities to afatinib were similar to that of the Ba/F3‐L858R cell line. The Ba/F3‐L861Q cell line was similarly sensitive and the Ba/F3‐S768I cell line was less sensitive to osimertinib, compared with the Ba/F3‐L858R cell line. The results of western blot analyses were consistent with these sensitivities. Next, similar experiments were also performed using the KYSE270 (L861Q) and KYSE 450 (S768I) cell lines, and their results were compatible with those of the transfectant Ba/F3 cell lines. Our findings suggest that NSCLC harboring the EGFR L861Q mutation might be sensitive to afatinib or osimertinib and that NSCLC harboring the EGFR S768I mutation might be sensitive to afatinib. Overall, afatinib might be the optimal EGFR‐TKI against these uncommon EGFR mutations.

Sensitivity of epidermal growth factor receptor with single or double uncommon mutations to afatinib confirmed by a visual assay

“…Previous clinical reports have found that patients with NSCLC harboring uncommon mutations of EGFR tend to be less sensitive to reversible (first‐generation) EGFR‐TKI compared with those positive for common EGFR mutations . However, subset analysis of the LUX‐Lung 3 and LUX‐Lung 6 trials showed that the objective response rate for the second‐generation EGFR‐TKI afatinib was 77.8% and 56.3% in patients with G719X or L861Q mutations of EGFR , respectively .…”

“…However, subset analysis of the LUX‐Lung 3 and LUX‐Lung 6 trials showed that the objective response rate for the second‐generation EGFR‐TKI afatinib was 77.8% and 56.3% in patients with G719X or L861Q mutations of EGFR , respectively . In vitro studies found that EGFR with a single G719X mutation was more sensitive to second‐generation than to first‐generation or third‐generation EGFR‐TKI, and that EGFR with a single L861Q mutation was sensitive to both second‐generation and third‐generation EGFR‐TKI . These data thus suggest that afatinib is the most appropriate EGFR‐TKI for NSCLC harboring uncommon mutations of EGFR .…”

“…Previous clinical reports have found that patients with NSCLC harboring uncommon mutations of EGFR tend to be less sensitive to reversible (first-generation) EGFR-TKI compared with those positive for common EGFR mutations. 7 However, subset analysis of the LUX-Lung 3 and LUX-Lung 6 trials showed that the objective response rate for the second-generation EGFR-TKI afatinib was 77.8% and 56.3% in patients with G719X or L861Q mutations of EGFR, respectively. 2 In vitro studies found that EGFR with a single G719X mutation was more sensitive to second-generation than to firstgeneration or third-generation EGFR-TKI, and that EGFR with a single L861Q mutation was sensitive to both second-generation and third-generation EGFR-TKI.…”

Prevalence of EGFR Mutations in Lung Cancer in Uruguayan Population

“…The resistance mutation T790M in exon 20 was found in two cases, one de novo mutation and the other one being probably selected under treatment pressure, since this patient was previously treated with TKIs. Other uncommon described mutations found in our series (p.L861Q and p.768I) have been suggested as less sensitive for first-generation TKIs [46], but in vitro experimental research suggests sensitivity for second- and third-generation TKIs [47]. Lastly, some very rare mutations in exon 21 were observed: p.P848L ( n = 2), reported as a resistant to TKIs germ-line mutation by Prim et al [48], and p.A840T ( n = 1), also showing no benefit from TKIs [49].…”

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

“…In this in vitro study, afatinib showed very low half maximal inhibitory concentration (IC 50 ) value to S768I mutation, but both gefitinib and erlotinib had high values of IC 50. Osimertinib was less sensitive to S768I mutation than afatinib [6, 11]. A Korean phase II trial showed that osimertinib achieved partial response in 3 patients of 8 with EGFR-TKI naïve S768I mutation (ORR, 37.5%) [12].…”