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  • br Discussion Nowadays data of uncommon


    Discussion Nowadays, data of uncommon EGFR mutations are limited, considering that patients carrying these rare alterations are usually excluded from clinical trials. Available survival data of activity of EGFR TKIs on this class of mutations, coming from a small number of usually retrospective studies, suggests that patients with these nonclassical mutations who received EGFR TKIs might present shorter PFS and OS compared with patients harboring common EGFR mutations (deletion in MTT of 19 and exon 21 L858R). However, these premises are not completely correct, considering that uncommon mutations are part of a heterogeneous group, in which we can potentially speculate the existence of 2 different cohorts: sensitive (exon 18 and CMs) and resistant (exon 20 insertions) uncommon EGFR mutations. In the previous articles that reported clinical outcomes of CMs, excluding co-occurring T790M mutations, treated with EGFR TKIs, median PFS was variable from 3.5 to 11.9 months.21, 22, 23, 24, 25, 26, 27, 28, 29, 30 In 2015, Chiu et al reported a PFS of 11.9 months on the basis of 19 patients who presented only G719X, L861Q, and S768I EGFR mutations, and were split into 2 groups (G719X/L861Q and G719X/S768I). In this analysis, MTT of response rates differed according to the co-occurring pattern of mutations: 89% for G719X/L861Q and 50% for G719X/S768I. In 2011, Wu and colleagues reported the results of a retrospective analysis of 1261 Asian patients diagnosed and treated at the National Taiwan University Hospital. In this analysis, 32 patients showed CMs excluding co-occurring T790M mutations, but more than 50% (20 of 32) of EGFR mutation data from evaluated patients lacked specification, and were reported as “other EGFR mutations,” comprising sensitive and resistant alterations. In this analysis, ORR was 56% and survival was lower than for common mutations, with a median PFS of 3.5 and median OS of 8.5 months, because of the heterogeneity of EGFR-uncommon characteristics, comprising sensitive and resistant mutations to EGFR TKIs; in 7 patients harboring 1 classical mutation in the complex presentation, the PFS grew to 10 months. Moreover, published data about exon 18 mutations showed a range of ORRs from 8.0% to 77.8%, and a median PFS from 2 to 13.8 months. These differences in efficacy were also detected in our analysis, for which we report an ORR of 31% and mPFS and OS, respectively, of 8.3 and 17.0 months. These data confirm that the exon 18 group might perform a bit worse than the common mutations during treatment with EGFR TKIs, in terms of response and survival. Analyzing the activity of the exon 18 group, it is very important to remember that this group is very heterogeneous, including many variants and mutations, such as G719A, G719C, G719S, G719X, E709K, E790S, or E790K, performing not all in the same way. Currently, overall data from 178 patients are reported in the literature on the basis of 9 retrospective studies; among these, Chiu et al reported the largest group of exon 18 mutations, in which 76 Asian patients presented a G719X mutation, achieving a median PFS of 6.3 months.21, 23, 25, 27, 28, 31, 32, 33, 34 To date, the only available data of uncommon EGFR patients in pivotal trials have been achieved with afatinib in the LL2, LL3, and LL6 studies. Instead, most of the retrospective studies published on this topic evaluated the role of erlotinib and gefitinib in this setting. As in the other retrospective analyses, in our research, most of the patients received treatment with first-generation EGFR TKIs: erlotinib (n = 21) and gefitinib (n = 52), because of the subsequent approval of afatinib (n = 15) in the same setting.
    Introduction The therapeutic landscape of Non Small Lung Cancer (NSCLC) has been profoundly changed over the last decade with the clinical introduction of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) and the discovery of EGFR activating mutations as the major predictive factor to these agents (Russo et al., 2015). Despite impressive clinical activity against EGFR-mutated NSCLCs and proved superiority over chemotherapy in the 1st line setting in molecularly-selected patients, the benefit seen with 1st and 2nd generation EGFR TKIs is usually transient and virtually all patients become resistant after approximately 9–13 months (Mok et al., 2009, Zhou et al., 2011, Wu et al., 2015, Wu et al., 2014, Sequist et al., 2013). Several different mechanisms of acquired resistance have been reported to date, but the vast majority of patients (41–62%) develop a secondary exon 20 mutation in the ATP-binding site of EGFR, namely T790M (Hata et al., 2013, Kuiper et al., 2014, Sequist et al., 2011, Yu et al., 2013). Various strategies have been studied to overcome T790M mutation, but only few have reported clinical meaningful benefit. The discovery of mutant-selective EGFR TKIs that selectively inhibit EGFR-mutants, including T790M-harboring NSCLCs, while sparing EGFR wild type, provide the opportunity for overcoming the major mechanism of acquired resistance to 1st and 2nd generation EGFR TKIs, with a relatively favorable toxicity profile. To date, three different 3rd generation EGFR TKIs are in advanced development stage, with the recent FDA and EMA approval of Osimertinib and the FDA breakthrough designation of Rociletinib and Olmutinib. The development of this novel class of EGFR inhibitors poses novel challenges in the rapidly evolving therapeutic paradigm of EGFR-mutated NSCLCs and the next few years will witness the beginning of a new era for EGFR inhibition in lung cancer. The aim of this paper is to provide a comprehensive overview of the increasing body of data emerging from the ongoing clinical trials with this promising novel therapeutic class of EGFR inhibitors.