Superior progression-free survival with osimertinib over erlotinib, or gefitinib in the upfront treatment of EGFR mutated NSCLC

Data from the phase III FLAURA study demonstrated that the third generation EGFR tyrosine kinase inhibitor (TKI) osimertinib is superior to the first generation EGFR TKIs erlotinib and gefitinib in the first line treatment of patients with EGFR mutated non-small-cell lung cancer (NSCLC). Osimertinib significantly improved the progression-free survival (PFS) by 54% compared to standard first line therapy and extended the median time to progression by about 9 months. Interestingly, the PFS benefit of osimertinib was almost identical for patients with and without brain metastases.

EGFR mutations are present in around 15% of NSCLC patients in Western populations, rising to 35% in Asian populations. It is well known that EGFR inhibitors are superior to chemotherapy in the first line treatment of these patients. However, despite high response rates and good progression-free survival, patients invariably develop resistance to drugs such as erlotinib and gefitinib. In the majority of patients this resistance is mediated by a T790M mutation.

Osimertinib is a third generation EGFR TKI that potently and selectively inhibits both mutant EGFR and EGFR harboring a T790M resistance mutation. A preliminary study in 60 treatment naïve patients with EGFR mutations found that the median PFS with osimertinib was 20.5 months, which was almost two-fold higher than results achieved with erlotinib or gefitinib. These findings formed the basis for the phase III FLAURA study.

FLAURA is a randomised phase III clinical trial in which 556 patients with EGFR mutated advanced NSCLC, who did not receive prior EGFR TKI or systemic anti-cancer therapy for advanced disease, were randomized 1:1 to osimertinib (80mg once daily, qd po), or standard of care EGFR TKI (gefitinib 250mg or erlotinib 150mg qd po). The primary endpoint of the trial was PFS.

The presented data revealed that the median PFS was 18.9 months with osimertinib, which was more than 8 months longer than the 10.2 months median PFS seen with the standard therapy. This translates into a 54% reduction in the risk of progression or death in favor of osimertinib (HR[95%CI]: 0.46[0.37–0.57]; p<0.0001). The benefit in PFS was consistent across all subgroups, including patients with brain metastases at the start of the study (N = 116; median PFS 15.2 versus 9.6 months; HR[95%CI]: 0.47[0.30-0.74]; p= 0.0009). The median duration of response was two-fold higher for patients treated with osimertinib (17.2 months) versus standard of care (8.5 months). The overall response rate (ORR) was 80% with osimertinib as compared to 76% with standard of care treatment. The data for overall survival (OS) were not yet mature, but appeared to favor osimertinib with a hazard ratio of 0.63 although this was not statistically significant at the interim OS analysis (25% maturity). The median OS was not reached for either of the treatment arms at the time of this analysis.

The median total treatment duration was 16.2 months with osimertinib as compared to 11.5 months with standard of care. Adverse events were seen in 98% of patients in both treatment arms. The rate of grade 3/4 adverse events was lower with osimertinib than with standard of care: 35% versus 45%. Adverse events led to treatment discontinuation in 13% of patients randomized to osimertinib and in 18% of the erlotinib/gefitinib treated patients. The most common adverse events with osimertinib included diarrhea (58% [Grade ≥3: 2%]) and dry skin (32% [Grade ≥3: <1%]). With standard of care diarrhea was seen in 57% of patients (grade ≥3: 3%), and dermatitis acneiform was reported by 48% of patients (Grade ≥3: 5%).

In summary, osimertinib is superior to standard first line treatment in patients with EGFR mutated NSCLC. The PFS benefit for patients with and without brain metastases was almost identical, suggesting that osimertinib is active in the brain as well as in systemic sites. This is of particular importance given the high incidence of brain metastases in this setting. The safety profile of osimertinib was more favorable despite longer treatment duration (16.2 months) compared to standard of care (11.5 months). Based on these results, osimertinib should be considered as new first line treatment option for patients with EGFR mutations.

Reference

Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Presented at ESMO 2017; abstract LBA2_PR.