Osimertinib associated with longer overall survival versus comparator EGFR-TKIs

1. After a 3-year follow-up to a phase 3 trial, the epidermal growth factor receptor-tyrosine kinase inhibitor osimertinib resulted in a longer median overall survival versus comparator EGFR-TKIs with similar safety profiles.

2. Benefits appeared to extend across most predefined subgroups including sex, age, and smoking history, although there was substantial overlap between confidence intervals.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in managing sensitized non-small cell lung cancer. The third-generation irreversible EGFR-TKI osimertinib inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations and potentially penetrates the blood-brain barrier to directly interact with the central nervous system (CNS). The phase 3 FLAURA trial showed significantly longer progression-free survival in the osimertinib group than in the EGFR-TKI comparator group, but overall survival data were immature at the time of the primary analysis. In this final analysis, median overall survival was also found to be substantially higher in the osimertinib group. No new safety signals were detected, with grade 3 or higher adverse events and treatment discontinuation occurring at similar rates in both groups. Strengths of this study included a double-blind design, a representative trial population, and confirmation of mutation status. One limitation was that the newer EGFR-TKI afatinib was not included in the comparator group, somewhat limiting the clinical significance of the study’s results.

Click here to read the study in NEJM

Relevant Reading: Osimertinib in the treatment of non-small-cell lung cancer: design, development and place in therapy

In-Depth [randomized controlled trial]: In the double-blind, multicenter, phase 3 FLAURA trial, 556 patients with previously untreated, EGFR mutation-positive advanced NSCLC were stratified by mutation status (Ex19del or L858R) and race (Asian or Non-Asian) before being assigned in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg daily) or an earlier-generation EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). In the comparator group, 66% received gefitinib and 34% received erlotinib. The median progression-free survival was 18.9 months (95% confidence interval [CI], 15.2 to 21.4) in the osimertinib group and 10.2 months (95% CI, 9.6 to 11.1) in the standard EGFR-TKI group (hazard ratio for disease progression or death, 0.46; 95% CI, 0.37 to 0.57; P<0.001). At 18 months, progression-free survival among those with CNS metastases was 58% (95% CI, 40 to 72) in the osimertinib group and 40% (95% CI, 25 to 55) in the comparator group (HR for disease progression or death, 0.48; 95% CI, 0.26 to 0.86). The final analysis, conducted after 321 deaths had occurred (58% maturity), found that the median overall survival in the osimertinib group was 38.6 months (95% confidence interval [CI], 34.5 to 41.8) versus 31.8 months (95% CI, 26.6 to 36.0) in the comparator group (HR for death, 0.80; 95.05% CI, 0.64 to 1.00; P=0.046).

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