Osimertinib for pretreated epidermal growth factor receptor Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), gefitinib, erlotinib, afatinib are effective in patients with advanced non-small cell lung cancer (NSCLC) harboring an EGFR-TKI sensitizing mutation (1). However, most patients have developed disease progression (2-4). EGFR Thr790Met mutation is the most common mechanism of acquired resistance (5). Osimertinib is an oral, selective and irreversible EGFR-TKI of both EGFR-sensitizing and Thr790Met resistance mutation (6). Two hundred and fifty three patients with locally advanced or metastatic NSCLC, who had radiologically documented disease progression following prior treatment with an EGFR-TKI, received osimertinib in the AURA trial. Thirty one patients were treated with osimertinib 20, 40, 80, 160 or 240 mg once daily in the dose-escalation cohorts. No dose-limiting toxic effects were observed at any dose levels. Two hundred and twenty two patients in five expansion cohorts received osimertinib (20, 40, 80, 160 or 240 mg once daily). The most common adverse events were diarrhea, rash, nausea, decreased appetite and dry skin. Six patients experienced potential pneumonitis-like events. Prolongation of QTc interval was observed in 11 patients. Grade 3–5 adverse events were reported in 32% of the patients. Adverse events led to dose reduction or drug discontinuation in 7% and 6% of patients, respectively. The overall objective tumor response rate (ORR) [confirmed partial response (PR) or complete response (CR)] was 51% [95% confidence interval (CI), 45–58] and the disease control rate (CR, PR or SD) was 84% (95% CI, 79–88). Among 127 patients with confirmed EGFR-Thr790Met, the ORR was 61% (95% CI, 52–70), and the disease control rate was 95% (95% CI, 90–98). Among 61 patients with no detectable EGFR-Thr790Met, the ORR was 21% (95% CI, 12–34), and the disease control rate was 61% (95% CI, 47–73). In EGFR-Thr790Met positive patients, the median progression-free survival (PFS) was 9.6 months (95% CI, 30% maturity). In EGFR-Thr790Met negative patients, the median PFS was 2.8 months (71% maturity). The ORRs across all osimertinib dose levels were similar in patients with detectable EGFR-Thr790Met. The incidence and the severity of the adverse events increased at the 160 and 240 mg dose levels. Therefore, 80 mg once daily was determined as the recommended dose of osimertinib (7).