For patients who have taken advantage of the

For patients who have taken advantage of the anti-TKIs and whose follow-up has been succeeded, some partial response has been noticed with 45% (9/20) for gefitinib, 39% (9/23) for erlotinib and 56.5% (13/23) for crizotinib. A disease progression has also been observed with 35% (7/20) for gefitinib, 34.7% (8/23) for erlotinib and 13% (3/23) for crizotinib. On the other hand, a stable disease was described with 15% (3/20) for gefitinib, 21.7% (5/23) for erlotinib and 20% (6/23) for crizotinib. By contrast, a complete response was shown in 3 cases: 1 case for gefitinib (Ulivi et al., 2016), 1 case for erlotininb (Office on Smoking and Health (US), 2006), and another case for crizotinib after a stable disease with erlotinib (Chen et al., 2013). It should be noted that all cases that developed a complete response have a Probenecid in exon 19 (Table 3, Fig. 4). To better study the effectiveness of the EGFR TKIs, The mutational status of EGFR and ALK was checked after the EGFR TKIs first-line treatments in 7 studies (Tiseo et al., 2011b; Santelmo et al., 2013; Chen et al., 2013; Baldi et al., 2014; Yang et al., 2014; Chiari et al., 2014; Zhao et al., 2015). We found out that the 51th patient showed a wild type EGFR after a partial response to Gefitinib and the 52th patient presented a wild type EGFR following a stable disease response to Erlotinib. No of all Studies reviewed has ever associated both treatments in the same patients simultaneously. Some promising results were noticed in 9 patients treated with Crizotinib only and were clinically followed: 8 cases (89%) showed a partial response while one (11%) presented a stable disease. The most striking results however, were recorded in 14 patients who benefited from crizotinib treatment after EGFR-TKIs: Six of them (43%) showed a partial response, five cases (36%) presented a stable disease, two (14%) displayed a progressive disease while the last case (7%) showed a complete response (Table 4). Finally, the only case treated with crizotinib before EGFR TKIs showed a progressive disease. Furthermore, We noticed that the cases 11, 12 (Wang et al., 2012) and 66 (Won et al., 2015) being all women, never smokers, Asians with adenocarcinoma in stage IV, harboring a concomitance between deletion in exon 19 and ALK-EML4 and having all been treated with gefitinib have not responded to the treatment in the same way. Therefore, a divergent response or resistance to the treatment in patients was reported in patients harboring simultaneous EGFR mutation and EML4-ALK rearrangement despite their similar clinicopathological features. This shows that there is no general rule concerning the efficient treatment to prescribe in these cases.
Conclusion The detection of the mutational status of EGFR and ALK genes opened a novel therapeutical pathway to lung cancer treatment. But these studies have also highlighted a real challenge with the discovery of the resistance to target therapy resulting from to the coexistence of EML4-ALK fusion and EGFR mutations. Although the cases reporting a concomitance between EGFR mutation and EML4-ALK translocation have significantly increased, the mechanism underlying the resistance to targeted therapy remains poorly understood.
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Introduction Lung cancer is the leading cause of cancer-related deaths worldwide [1], with 85–90% of diagnosed cases being non-small cell lung cancers (NSCLCs) [2]. Gene rearrangements of anaplastic lymphoma kinase (ALK) is identified in approximately 3–7% of NSCLCs, with the most common being the echinoderm microtubule-associated protein like-4 (EML4)-ALK fusion [3], [4], [5], [6], and their occurrences appear to be mutually exclusive with EGFR and KRAS mutations [7]. Structural characterization indicates that the amino terminal coiled-coil domain of EML4 causes ligand-independent oligomerization and consequently constitutive activation of the kinase domain of ALK [8]. ALK has also been found to partner with TFG, KIF5B, TPR, HIP1, DCTN1 and KLC1 genes in NSCLCs, although at a much lower frequency [9], [10], [11], [12], [13], [14].