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  • In vitro studies in NSCLC cell


    In vitro studies in NSCLC cell lines expressing EGFR mutants (T790M mutation, exon 19 deletion E746-A750, L858R/T790M double mutation), demonstrated that Rociletinib potently inhibits proliferation in the mutant EGFR NSCLC Antagonist G mg with Growth inhibition (GI50) values ranging from 7 to 32 nmol/L. In comparison, the GI50 value for wild type EGFR cells was 547 nmol/L. CO-1686 also inhibits NRAS and KRAS mutations in WT EGFR cells at concentrations of 4275 and 1806 nmol/L, respectively. The efficacy of CO-1686 was also examined against other EGFR mutants including the exon 18 mutation G719S, an exon 19 insertion mutant (I744-K745insKIPVAI), an exon 20 insertion (H773-V774HVdup), and the exon 21 mutation L861Q. Rociletinib was active against these rare mutants also, with the exception of exon 20 insertions (Walter et al., 2013). The TIGER program was an accelerated clinical development program for Rociletinib in patients with mutant EGFR NSCLC in different therapeutic settings (Table 2). The phase I/II dose-finding TIGER-X evaluated Rociletinib in EGFR-mutated NSCLCs progressing after previous 1st/2nd generation EGFR TKIs. The study consisted of two parts, the phase I dose-escalation component followed by the phase 2 expansion part (requiring T790M status assessment before enrollment) to assess efficacy at 500mg twice daily, 625mg twice daily, and 750mg twice daily. Two different formulations of Rociletinib were initially developed, the free-base form (entered the clinic in March 2013) and the hydrogen bromide salt (HBr), designed to improve the pharmacokinetic profile, introduced during dose escalation from August 2013 that replaced the free-base form. Primary objectives of the phase I were safety, toxicity profile, and pharmacokinetic characteristics of Rociletinib. Secondary end points included ORR, DoR, PFS, and QoL. Primary end points of the phase II part were ORR and DoR, whereas secondary and exploratory end points were the same as in the phase I component. A MTD was not defined in the phase I portion. Preliminary results, based on 130 patients enrolled, reported an ORR among 46 patients with centrally confirmed T790M-positive tumors 59%, with a DCR of 93%. Response rates were similar between patients with exon deletion 19 or L858R EGFR mutation. The estimated median PFS was 13.1 months. The ORR among 17 T790M-negative patients was 29%, with a DCR of 59% and a median PFS of 5.6 months. Among 20 patients whose tumors were not assessable for T790M the ORR was 15%. The predominant grade 3 AE was hyperglycemia (22%), which was generally manageable and did not result in treatment discontinuation (Sequist et al., 2015). Preclinical studies suggest that hyperglycemia is caused by a Rociletinib metabolite that inhibits the type I insulin-like growth factor receptor (IGF-IR) and induces activation of the IGFIR pathway, a proposed resistance mechanism for EGFR inhibition (Cortot et al., 2013), although the contribution of the IGF-IR inhibitory effect of Rociletinib to its antitumor activity is currently unknown. These preliminary results prompted the establishment of a rapid developmental program (Table 2) and granted, in May 2014, the U.S. FDA Breakthrough Therapy designation for the treatment of mutant NSCLCs with the T790M mutation after progression on EGFR-directed therapy. Unfortunately, on May 2016 Clovis inc. announced the interruption of clinical development of Rociletinib and terminated enrollment in all ongoing sponsored clinical studies based on the unsatisfactory results of a pooled analysis of TIGER-X and TIGER-2 trials submitted to the US FDA, reporting a 32% ORR (95% CI 25, 40) with a median DoR of 8.8 months in T790M+ patients treated with Rociletinib at the doses of 625mg BID and 23% ORR (95% CI 14, 34) with a median DoR of 9.1 months in patients who received 500mg BID (Anon, 2016).
    Olmutinib (BI1482694/HM61713) The safety and pharmacokinetic profile of this agent was evaluated in the phase I/II HM-EMSI-101 study, a multicenter trial conducted in Korean patients previously treated with at least one EGFR TKI. At the recommended phase II dose (RP2D: 800mg qd), all eligible patients had to have confirmed T790M mutation in the tumor. The primary endpoint was ORR; secondary endpoints included DOR, DCR, PFS and safety. Data of patients treated at the RP2D of 800mg qd were recently presented: 54% confirmed ORR by independent review and 90% DCR in T790M-positive TKI-pretreated NSCLCs with a favorable safety profile (Park et al., 2016a).