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Brief description/objective

First-generation EGFR tyrosine kinase inhibitors provide significant clinical benefit in patients with advanced EGFR-mutant (EGFRm) non–small cell lung carcinoma (NSCLC). However, all patients ultimately develop disease progres-sion, driven – as the most prevalent identified biological mechanism – by the acquisition of a second T790M EGFR TKI resistance mutation. Osimertinib (AZD9291) is a novel oral, potent, and selective third-generation irreversible in-hibitor of both EGFRm-sensitizing and T790M resistance mutants. This mono–anilino– pyrimidine compound is structurally distinct from other third-generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier first and second generation EGFR TKIs. Preclinical-ly, the drug potently inhibits signaling pathways and cellular growth in both EGFRm and EGFRm plus T790M cell line in vitro, with lower activity against wild-type EGFR lines. In the recently published osimertinib phase I trial, a total of 253 patients were treated. Among 31 patients enroled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated. An additional 222 patients were treated in five expansion cohorts. The most common all-cause adverse events were diarrhoea, rash, nausea, and decreased appetite, however were significantly reduced in occurrence and severity as compared to first/second EGFR TKIs. The overall objective tumour response rate of osimertinib was 51% (95% CI, 45 - 58). Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 - 70). In contrast, among 61 patients without centrally detectable EGFR T790M who could be evaluated for response, the response rate was 21% (95% CI, 12 - 34). The median progression-free survival was 9.6 months (95% CI, 8.3 to not yet reached) in patients with EGFR T790M and 2.8 months (95% CI, 2.1 - 4.3) in patients without EGFR T790M. Osimertinib is being evaluated in several prospective clinical trials, notably in frontline treatment, in the adjuvant setting, and in combination with later lines in EGFRm positive advanced disease.