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  • Given its high frequency it is not


    Given its high frequency, it is not surprising that different strategies have been developed to restore the sensitivity of EGFR T790M-mutant ARCA EGFP mRNA to EGFR inhibition. To date, several different strategies have been evaluated in both preclinical and clinical models, but only few have been proved effective in vivo. Indeed, some promising in vitro strategies, such as the use of irreversible EGFR inhibitors (“second generation” EGFR TKIs) against T790M-mutants (Kobayashi et al., 2005b, Kwak et al., 2005, Engelman et al., 2007), failed in vivo due to a narrow therapeutic window (Sequist et al., 2010, Landi et al., 2014, Reckamp et al., 2014, Miller et al., 2012). Moreover, the use of a vertical blockage with an EGFR TKI and a monoclonal anti-EGFR antibody (i.e. Afatinib and Cetuximab), albeit proved effective against T790M-harboring tumors, is limited by the unfavorable toxicity profile (Janjigian et al., 2014). The use of mutant-selective, EGFR wild type sparing, “third generation” inhibitors is an emerging therapeutic strategy in patients with AR to 1st and 2nd generation inhibitors. These newer agents differ from quinazoline-based reversible (Gefitinib and Erlotinib) and irreversible EGFR TKIs (Afatinib, Dacomitinib, Neratinib), because of their aminopyrimidine scaffold and have been specifically developed to target EGFR mutations, including T790M, with only minimal activity against wild type EGFR. The first-in-class third generation EGFR TKI reported was WZ4002, which did not progress to clinical trials (Zhou et al., 2009), but now a few different 3rd generation EGFR TKIs are in active clinical development in NSCLC. In the following sections we will provide an overview of the latest preclinical and clinical data on three of the most promising agents of this novel class of EGFR TKIs.
    Osimertinib (AZD9291) Osimertinib (AZD9291; AstraZeneca) is a novel irreversible, small molecule inhibitor, developed to target both sensitizing and resistant mutant forms of the EGFR while sparing the wild type form of the receptor (Osimertinib, 2016). This mono-anilino–pyrimidine compound is structurally and pharmacologically distinct from all other TKIs. Osimertinib binds irreversibly to the EGFR kinase by targeting the cysteine-797 residue in the ATP binding site via covalent bond formation (Ward et al., 2013, Finlay et al., 2014). The drug exhibits nearly 200 times greater potency against L858R/T790M than wild type EGFR. Studies conducted in vivo, revealed that Osimertinib is metabolized to produce at least two circulating metabolite species, AZ5104 and AZ7550. AZ7550 had a comparable potency and selectivity profile, while AZ5104 is more potent against mutant and wild type EGFR forms (Cross et al., 2014, Yosaatmadja et al., 2015). In vitro studies indicate that Osimertinib has activity against mutant EGFR, including T790M+, but selectivity margin against wild type EGFR. The drug has minimal off-target activity, with a limited number of non-HER kinases inhibited, but conserves activity against HER2/4. In contrast, Osimertinib is not effective against lines harboring non-T790M resistance, such NRAS mutations, MET amplification, and epithelial-to-mesenchymal transition (EMT) (Cross et al., 2014). Studies conducted in vivo xenograft models demonstrated good bioavailability of Osimertinib and moderate clearance with half-life of 3h after oral dosing in the mouse. The circulating metabolites have a similar half-life and the total exposure level (AUC) were approximately 68% and 33% compared with parent compound for AZ7550 and AZ5104 respectively. Quantitative whole body autoradiography (QWBA) studies in rat brain indicate that Osimertinib has a brain-to-blood ratio of up to 2 over the first 24h, suggesting the potential of AZD9291 to penetrate the brain (Cross et al., 2014). Studies in mouse models indicate that Osimertinib is distributed in ARCA EGFP mRNA the CNS at greater extent than Gefitinib, Rociletinib and Afatinib (Ballard et al., 2016) and has potential activity also against leptomeningeal metastases (LMs) in both EGFR TKI-naïve and TKI-resistant tumors (Nanjo et al., 2016).