Osimertinib for EGFR -mutant non-small cell lung cancer: place in therapy and future perspectives

In the last 20 years the clinical management of patients with advanced non-small cell lung cancer (NSCLC) has shifted form a histology-driven to a molecularly-based approach due to the identification of actionable genetic alterations and the subsequent development of highly efficacious targeted therapies. As result, genomic analysis has now become routine in clinical practice to identity the molecular predictors of targeted therapies efficacy, including somatic epidermal growth factor receptor (EGFR) mutations (1). Over the last decade, patients harboring a sensitizing EGFR mutation, typically exon 19 deletion and exon 21 L858R point mutation, have been preferentially treated with first- (gefitinib, erlotinib) or second-generation generation (afatinib) EGFR tyrosine kinase inhibitors (TKIs), which excelled chemotherapy in terms of objective response rate (ORR), progression-free survival (PFS) and quality of life (QoL) in large randomized clinical trials (2-9). Despite these drugs produce prolonged responses in the vast majority of patients harboring EGFR sensitizing mutations, relapse invariably occur after a median of 9–12 months due to the development of acquired resistance (10). Osimertinib mesylate is a novel pyrimidine-based irreversible, covalent third-generation EGFR-TKI and potent inhibitor of EGFR T790M mutation, the most common mechanism of acquired resistance to first-generation EGFR-TKIs. In the phase I, dose-expansion arms of AURA 1, osimertinib produced an ORR of 61% (95% CI, 52–70%), and a median PFS of 9.6 months in patients harboring the T790M mutation (11). These data have been further corroborated in the phase II AURA extension and the phase II AURA 2 trial where osimertinib produced ORRs of 62% (95% CI, 54–68%) and 70% (95% CI, 64–77%), respectively, and a median PFS of 12.3 and 9.9 months in heavily pretreated patients with T790M-positive NSCLC (12,13). More recently, in the randomized phase III AURA 3 trial osimertinib improved the ORR (71% versus 31%, P<0.001) and the median PFS (10.1 versus 4.4 months, HR: 0.30; 95% CI, 0.23–0.41; P<0.001) over cisplatin/pemetrexed chemotherapy as second-line treatment in patients who had progressed on or following first- or second-generation EGFR TKIs (14). The extended clinical benefit of the sequential treatment with a first-generation EGFR TKI followed by osimertinib observed in this study led to the approval of this compound for patients with NSCLC harboring the T790M mutation and disease progression after treatment with first- or second-generation EGFR TKIs. However, in the recent