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?

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.

Banno E ，Togashi Y ，Nakamura Y ，Chiba M ，Kobayashi Y ，Hayashi H ，Terashima M ，de Velasco MA ，Sakai K ，Fujita Y ，Mitsudomi T ，Nishio K ... -  《-》

Osimertinib, an Irreversible Next-Generation EGFR Tyrosine Kinase Inhibitor, Exerts Antitumor Activity in Various Preclinical NSCLC Models Harboring the Uncommon EGFR Mutations G719X or L861Q or S768I.

Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M-resistance mutations with lower activity against wild-type EGFR and has demonstrated efficacy in non-small cell lung cancer (NSCLC) CNS metastases. The sensitizing mutations, the in-frame deletions in exon 19 and the L858R point mutation in exon 21, represent between 80% and 90% of all EGFR mutations. The remaining 10% to 20% are referred to as uncommon activating mutations and are a diverse group of mutations in exons 18 to 21 within the kinase domain of the EGFR gene. Excluding those found as insertion mutations in exon 20, the uncommon mutations involving codons G719, S768, and L861 are the most prevalent.Although the efficacy of EGFR-TKIs for the common EGFR mutations is well established, much less is known about rare EGFR mutations, such as exon 20 insertions, G719X, L861Q, S768I, as most of the data consist of single case reports or small case series.Using available patient-derived xenografts (PDX) and cell lines derived from two of these PDXs that harbor the G719X mutation, we have evaluated in vitro and in vivo the preclinical activity of osimertinib. We report osimertinib inhibits signaling pathways and cellular growth in G719X-mutant cell lines in vitro and demonstrate sustained tumor growth inhibition of PDX harboring the G719X mutation alone or in combination with L861Q and S768I.Together, these data support clinical testing of osimertinib in patients with uncommon EGFR NSCLC.

Floc'h N ，Lim S ，Bickerton S ，Ahmed A ，Orme J ，Urosevic J ，Martin MJ ，Cross DAE ，Cho BC ，Smith PD ... -  《-》

Case report: Durable response to afatinib in a patient with lung cancer harboring two uncommon mutations of EGFR and a KRAS mutation.

Comprehensive genomic profiling for non-small cell lung cancer (NSCLC) is likely to identify more patients with rare genetic alterations including uncommon epidermal growth factor receptor gene (EGFR) mutations. It remains unclear how such patients should be treated, however. We here report a case of NSCLC positive for two uncommon mutations of EGFR and a KRAS mutation, including its treatment with the second-generation EGFR tyrosine kinase inhibitor (TKI) afatinib. Tumor specimen obtained by a NSCLC patient with no smoking history was analyzed by next-generation sequencing. Comprehensive genomic profiling revealed that the patient harbored the EGFR mutations G719C and S768I as well as the E49K mutation of KRAS. Treatment with afatinib was clinically effective as confirmed by PET-CT scans of bone metastases and by a marked decrease in the serum concentration of carcinoembryonic antigen. Afatinib was the most effective among seven EGFR-TKIs tested in inhibiting the growth of Ba/F3 cells expressing EGFR(S768I), showing an efficacy similar to that apparent with cells expressing the common EGFR mutant L858R, whereas first- and third-generation EGFR-TKIs were markedly less effective against EGFR(S768I) than against EGFR(L858R). These data suggest that EGFR-TKIs differ in their activity toward cells expressing EGFR(S768I) in vitro. Consistently, afatinib was clinically effective for the treatment of NSCLC harboring G719C and S768I mutations of EGFR. Further studies are warranted to determine the most appropriate EGFR-TKI for treatment of NSCLC harboring uncommon EGFR mutations.

Tanizaki J ，Banno E ，Togashi Y ，Hayashi H ，Sakai K ，Takeda M ，Kaneda H ，Nishio K ，Nakagawa K ... -  《-》

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Treatment Response in Advanced Lung Adenocarcinomas with G719X/L861Q/S768I Mutations.

Chiu CH ，Yang CT ，Shih JY ，Huang MS ，Su WC ，Lai RS ，Wang CC ，Hsiao SH ，Lin YC ，Ho CL ，Hsia TC ，Wu MF ，Lai CL ，Lee KY ，Lin CB ，Yu-Wung Yeh D ，Chuang CY ，Chang FK ，Tsai CM ，Perng RP ，Chih-Hsin Yang J ... -  《-》

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer harboring uncommon EGFR mutations: Focus on afatinib.

The development of first-, second-, and third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of patients with non-small cell lung cancer (NSCLC) harboring mutations in the EGFR. However, limited data are available regarding the activity of available EGFR TKIs against uncommon EGFR mutations. This is an important question because improvements in screening techniques are facilitating the identification of patients with uncommon mutations for whom optimal treatment has not yet been clarified. This uncertainty reflects the fact that most prospective clinical trials of EGFR TKIs have been restricted to patients with tumor harboring common (Del19 or L858R) mutations. In this article, we discuss the nature of EGFR mutation heterogeneity in NSCLC and review recent preclinical and clinical data that have assessed the sensitivity of different mutations to different EGFR TKIs. Recent preclinical data indicate that second-generation ErbB family blockers, such as afatinib, have a broad activity profile across uncommon EGFR mutations. Emerging evidence indicates that the preclinical data for afatinib are reflected in the clinic. Subanalysis of clinical trials, and real-world data, demonstrate that EGFRs with defined, but uncommon mutations such as G719X, S768I, and L861Q are sensitive to afatinib, which is now approved for tumors harboring these mutations. A recent clinical trial has demonstrated that EGFRs harboring some of these less common mutations also appear to be sensitive to the third-generation EGFR TKI, osimertinib. Treatment options for tumors with other uncommon mutations, notably exon 20 insertion, remain an area of unmet need, although osimertinib has shown preclinical activity in this setting, and early clinical activity has been seen with the dual EGFR/HER2 TKIs, poziotinib and TAK-788. Further data are required to help drive appropriate treatment decisions in patients whose tumors harbor these uncommon EGFR mutations. To see an abstract video summarising the content of the paper, please visit http://usscicomms.com/oncology/masood/seminars-in-oncology/.

Masood A ，Kancha RK ，Subramanian J 《-》