Hydrochlorothiazide ELUXA HM EMSI is an ongoing pivotal Phas
ELUXA 1 (HM-EMSI-202) is an ongoing pivotal Phase II global clinical trial, designed to further investigate the efficacy and safety of Olmutinib in patients T790M-positive NSCLC with acquired resistance after first-line EGFR TKIs. Primary endpoint is ORR according to RECIST 1.1, while secondary endpoints are DCR, DoR, PFS, OS, TTP, tumor shrinkage, patients reported outcomes (PROs), and safety (Park et al., 2016b). The ELUXA pivotal trial program (Table 3) will include also the initiation of two Phase III studies in 2016 comparing Olmutinib with chemotherapy in previously treated T790M+ NSCLCs (ELUXA 2) and in the first line setting versus Afatinib (ELUXA 3).
Other 3rd Generation EGFR TKIs EGF816 (Novartis Pharmaceuticals) is a covalent, irreversible, EGFR TKI with high in vitro activity against EGFR mutants, including T790M. Preliminary results of the multi-arm phase I/II study (NCT02108964) in advanced NSCLC patients harboring T790M mutation showed a manageable safety profile, with the most common grade 3/4 AEs were maculo-papular rash (14%), anemia (6%), and diarrhea (6%), and an intriguing clinical activity with a confirmed 44% ORR and a 91% DCR. Median PFS was 9.2 months (95% CI 9.0-NE) (Tan et al., 2016). ASP8273 (Astellas Pharma Inc) is another small molecule mutant-selective, irreversible EGFR inhibitor with higher in vitro affinity against EGFR-mutants than wild type that is being evaluated in phase II/III studies in EGFR-mutated NSCLCs. At the recommended phase II dose of 300mg/d, ASP8273 showed a robust antitumor activity in both subjects with pre-treated EGFR mutation-positive NSCLC and T790M+. For the 45 subjects treated with ASP8273 300mg with evaluable data, DCR was 62%, with 16 patients achieving a PR and 12 a SD. For the 40 T790M+ subjects with evaluable data, DCR was 65% with 15 PR and 11 SD. Preliminary median PFS was 6.7 months in both overall population and T790M+ patients (Yu HA et al., 2016). The ongoing phase III trial SOLAR will compare the activity of ASP8273 in the first line setting versus 1st generation EGFR TKIs. Brigatinib (ARIAD Pharmaceuticals), also known as AP26113, is dual ALK/EGFR with preclinical activity against the oncogenic ALK fusion protein and mutants resistant to Crizotinib, but also against activated and T790M-mutant EGFR (Rivera et al., 2012). Brigatinib received Breakthrough Therapy designation from the FDA in October 2014 for the treatment of patients with ALK-rearranged NSCLC with acquired resistance to Crizotinib and data from the phase I/II study (NCT01449461) in EGFR-mutated NSCLC are awaited.
Emerging mechanisms of acquired resistance to 3rd generation EGFR TKIs Prior studies, evaluating the structural analogue tool Hydrochlorothiazide WZ4002, reported activation of MAPK and IGF1R pathways as possible mechanisms of acquired resistance to irreversible mutant-selective EGFR TKIs (Cortot et al., 2013, Ercan et al., 2012), but no additional mutations, a largely anticipated mechanism of resistance, were reported until recently. This class of agents has been developed to inhibit EGFR T790M mutations, binding covalently to the cysteine residue 797 (Zhou et al., 2009). Therefore, it is not surprising that EGFR T790M+ cells acquiring resistance to mutant selective EGFR TKIs, due to the selective pressure of these agents, may develop a tertiary mutation that results in a cysteine to serine change at position 797 (C797S) in a region of the ATP-binding pocket of EGFR that is opposite to that of T790M. The EGFR C797S mutation resembles the acquired C481S mutation to the irreversible BTK (Bruton tyrosine kinase) inhibitor Ibrutinib in patients with chronic lymphocytic leukemia (Woyach et al., 2014), suggesting that this mutation type may represent a common mechanism of AR to covalent kinase inhibitors. Indeed, preclinical studies, using cultured patient-derived EGFR exon19del/T790M cell lines (MGH121) and through mutagenesis screen in EGFR mutant cells with or without T790M, reported the development of three tertiary mutations (C797S, L844V and L718Q) in the EGFR after acquiring resistance to the 3rd generation compound WZ4002 (Niederst et al., 2015b, Ercan et al., 2015). The presence of these mutations and their allelic/genomic context has been reported to influence their sensitivity to the different EGFR TKIs available. Indeed, C797S conferred resistance to all the 3rd generation EGFR TKIs evaluated (WZ4002, Osimertinib and Rociletinib), but was sensitive to 1st and 2nd generation inhibitors (with reduced sensitivity in the context of L858R/C797S cells), L844V was associated with resistance to WZ4002 and Rociletinib, but not to Osimertinib (independently of the presence of T790M mutation), Gefitinib and Afatinib, while L718Q exhibited resistance to WZ4002 and Rociletinib, but not to Osimertinib, only in the context of exon19 del/L718Q (Ercan et al., 2015). A possible explanation may be found in the inherited differences in the molecular structure of Rociletinib and Osimertinib, since the first is structurally more similar to WZ4002 than the latter. Moreover, Niederst et al. reported that the allelic context of this acquired resistance may be essential for the therapeutic strategy of patients with EGFR mutation, since the development in the same alleles of T790M and C797S mutations (i.e. in cis mutations) confers resistance to all the EGFR TKIs known, but the development of these mutations in different alleles (i.e. in trans) may pave the way to a combinatory approach of both 1st and 3rd generation TKIs. Moreover, the front-line use of mutant-selective inhibitors and the subsequent development of C797S mutation may raise the opportunity of the use of 1st generation agents, since del19/C797S mutations are still sensitive to Gefitinib (Niederst et al., 2015b).