First- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are current standard first-line therapy for EGFR-mutated non-small cell lung cancer (NSCLC). Despite initial response to these agents, the majority of patients develop acquired resistance within approximately one year of treatment initiation. In more than 50% of patients, the mechanism of acquired resistance is the development of EGFR T790M mutation. The third-generation EGFR TKI osimertinib is a selective and potent inhibitor of both EGFR-sensitive mutations and T790M mutations and is currently approved for treatment of patients who have developed T790M-mediated resistance to TKI treatment. However, early clinical data indicate that osimertinib also has high activity in the front-line setting.
During the first Presidential Symposium of the 2017 European Society for Medical Oncology meeting, Suresh Ramalingam, MD (Emory University, Atlanta, Georgia, United States), presented interim results from the randomized, double-blind phase III FLAURA trial (N = 556) that compared osimertinib 80 mg daily to a standard first-line EGFR TKI (either gefitinib 250 mg daily or erlotinib 150 mg daily) in treatment-naïve patients with EGFR-mutated metastatic NSCLC (LBA2_PR).
Treatment with osimertinib was associated with a median progression-free survival (PFS) of 18.9 months versus 10.2 months with standard of care (HR 0.46, P<.0001). This benefit was maintained across all prespecified subgroups, including in patients with central nervous system (CNS) metastases at study entry. In these patients, osimertinib resulted in a median PFS of 15.2 months versus 9.6 months with standard of care (HR 0.47, P = .0009), while in patients without CNS metastases median PFS was 19.1 months versus 10.9 months, respectively (HR 0.46, P<.0001). The objective response rate was similar between the two treatment groups (80% with osimertinib vs 76% with standard of care), but responses to osimertinib lasted a median of 8.7 months longer. Although data were immature at the time of the interim analysis, there was a trend toward improved overall survival (OS) with osimertinib that had not yet reached statistical significance.
Overall, rates of adverse events (AEs) were similar between the two arms, though there were fewer AEs of grade 3 or higher in patients receiving osimertinib compared with standard of care (34% vs 45%). Standard of care was associated with higher rates of any grade dermatitis acneiform and liver enzyme increase compared with osimertinib.
In his conclusion, Dr Ramalingam indicated that the almost doubled PFS, the promising signal of an OS benefit, and the favorable toxicity profile of osimertinib support osimertinib as the new standard of care for first-line treatment of EGFR-mutated advanced NSCLC. Tony Mok, MD (Chinese University of Hong Kong, Hong Kong, China), a discussant of the FLAURA trial results, highlighted that osimertinib is undoubtedly a “winner” in terms of efficacy and safety, but he cautioned against use as a first-line therapy universally for all patients. He pointed out that optimal sequencing for OS remains unclear and that OS data from AURA3 and FLAURA are pending. In addition, he mentioned that the mechanism and treatment strategy for patients who failed first-line osimertinib is unclear. Despite his caution, Dr Mok agreed that osimertinib is the optimal first-line treatment option for patients with EGFR mutations who present with CNS metastases.