Osimertinib for EGFR T790M positive non-small cell lung cancer—making it happen, turning good idea into great results

Epidermal growth factor receptor (EGFR) activating mutations account for approximately 50% of non-small cell lung cancer (NSCLC) in Asian population and about 20% in Caucasians (1-4). Several famous phase III clinical trials have demonstrated the superior efficacy and quality of life of the first or second generation EGFR tyrosine kinase inhibitors (TKIs) including gefitinib, erlotinib, icotinib and afatinib in patients with EGFR-mutant advanced NSCLC when compared to first-line standard platinum-based chemotherapy (5-8). To date, EGFR-TKIs have been extensively accepted for the first choice for patients with untreated advanced NSCLC and EGFR activating mutation. Despite the substantial benefit of EGFR-TKIs, the vast majority of patients would experience disease relapse so called acquired resistance within about 1–2 years (2,3,9). Previously, a large number of studies have revealed the mechanism of acquired resistance against first-generation EGFR-TKIs and they can be summarized into four parts: (I) second mutations in EGFR; (II) histological transformation; (III) bypass signaling pathway activation and (IV) other mechanisms. Among them, the most common mechanism was the gatekeeper mutation involving the substitution of threonine at position 790 with methionine of EGFR exon 20, known as EGFR T790M mutation (10).