Osimertinib improves progression-free survival in EGFR-mutated non-small-cell lung cancer: The FLAURA trial
1. Osimertinib demonstrated a significantly longer duration of progression-free survival compared to standard of care epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) in patients with untreated EGFR-mutated locally-advanced or metastatic non-small-cell lung cancer (NSCLC).
2. Osimertinib treated patients had fewer grade 3 or higher adverse events compared to patients treated with standard EGFR-TKI therapy.
Study Rundown: Osimertinib is an oral third-generation, irreversible EGFR-TKI that inhibits both EGFR-sensitizing and EGFR T790M resistance mutations presently approved for previously treated patients with T790M-positive NSCLC. Although recent phase 1 data suggests osimertinib may be effective as first-line therapy for locally-advanced or metastatic EGFR-mutated NSCLC, it is not yet approved for this purpose. This study evaluated osimertinib versus standard of care EGFR-TKI therapy (gefitinib or erlotinib) in treatment naïve patients with locally-advanced or metastatic EGFR-mutated NSCLC. The duration of progression-free survival (primary end point) was significantly longer in the osimertinib group compared to standard therapy. Among secondary end points, osimertinib was associated with improved disease-control rate, reduction in tumor size, and fewer adverse events. The significant increase in progression-free survival supports use of osimertinib as the new standard of care for EGFR-mutated NSCLC.
Major strengths of this trial are the confirmation of EGFR-mutation type in the majority of patients, inclusion of patients with and without CNS metastases, and the comparison to the two most widely used EGFR-TKIs. As data for overall survival is still pending, however, universal use of osimertinib as first-line therapy may not be universally implemented. Additionally, magnetic resonance imaging was not required to detect brain metastasis, and asymptomatic metastases are well-documented in NSCLC.
In-Depth [randomized controlled trial]: This was a double-blind, phase 3 trial of patients with locally-advanced or metastatic NSCLC with a confirmed EGFR exon 19 deletion and/or p.Leu858Arg mutation. Patients (n = 556) were randomized in a 1:1 ratio to either oral osimertinib (n = 279) or a standard oral EGFR-TKI (gefitinib or erlotinib; n = 277) and assessed via the Response Evaluation Criteria in Solid Tumors (RECIST) criteria until disease progression. The primary end point was the duration of progression-free survival according to RECIST. Secondary end points included overall survival, objective response rate, duration of response, disease-control rate, and safety.
The median progression-free survival was 18.9 months (95% confidence interval [CI], 15.2 to 21.4) in the osimertinib group versus 10.2 months (95% CI, 9.6 to 11.1) in the standard EGFR-TKI group (hazard ratio [HR], 0.46; 95% CI, 0.37 to 0.57; p < 0.001). This increased duration was consistent across all predefined subgroups (including Asian versus non-Asian, EGFR mutation type, and presence or absence of central nervous system [CNS] metastases at trial entry). A statistically significant benefit was found in the osimertinib group with respect to disease-control rate (97% vs. 92%; odds ratio, 2.78; 95% CI, 1.25 to 6.78; p = 0.01) and median best percentage change in target-lesion size (-54.7% vs. -48.5% in standard group; p = 0.003). Events of CNS progression occurred in 6% in the osimertinib group versus 15% in the standard therapy group. No significant difference in objective response rate (odds ratio [OR], 1.27; 95% CI, 0.85 to 1.90; p = 0.24) was found. Median overall survival could not be calculated due to data immaturity. Adverse events of grade 3 or higher were reported in fewer patients in the osimertinib group (34% vs. 45%) and osimertinib was associated with a lower rate of adverse events leading to treatment discontinuation. QT interval prolongation was reported in a higher percentage of patients in the osimertinib group (10% vs. 5%); however, the majority were grade 1 or grade 2 and no fatal cases of torsades des pointes were reported in either group.
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