Kathryn F. Mileham
The final OS analysis of FLAURA reaffirms the choice of osimertinib over other EGFR TKIs as first-line treatment for EGFR-mutated metastatic NSCLC.
After reaching the primary endpoint of PFS in the initial analysis of the FLAURA trial (18.9 months vs. 10.2 months), osimertinib was widely adopted as standard-of-care treatment for this indication. Despite the impressive PFS results, demonstrable central nervous system penetration and favorable side effect profile, many awaited the OS results to determine if osimertinib in the first line provides at least as long OS as sequential treatment with osimertinib in the second line for those with EGFR T790M acquisition as mechanism of resistance to first-line treatment. Based on these matured OS results, this is the first study demonstrating an OS benefit with an EGFR TKI in the first-line treatment of EGFR-mutated metastatic NSCLC.
The results also argue against sequencing with a first- or second-generation EGFR TKI as first-line treatment followed by osimertinib at progression. In previous studies that compared first- or second-generation EGFR TKIs with chemotherapy, OS was similar between arms, often felt to be confounded by crossover to EGFR TKI upon progression. Additionally, only 50% of patients acquire the T790M mutation at progression, limiting those eligible to receive osimertinib in next-line treatment, as proven to be effective in previous AURA studies.
FLAURA showed that even with 31% crossover allowing for osimertinib among those with T790M acquisition, the statistically significant OS benefit was maintained by those who received osimertinib first rather than in sequence. Notably, nearly 30% of patients from each arm of FLAURA received no subsequent treatment, owing to death among about 70% of these patients. This sobering statistic emphasizes the need to provide the most effective therapy first. In the setting of EGFR-mutated metastatic NSCLC, the most effective first-line treatment is proven to be osimertinib.
Prior to the FLAURA OS data maturing, multiple other clinical trials combined first- or second-generation EGFR TKIs with other agents in hopes of extending survival and overcoming resistance. These have yet to demonstrate a comparable OS benefit, tolerability and safety profile, and effective CNS penetration. New EGFR TKIs or treatment combinations must surpass what has been demonstrated with osimertinib in the first-line setting to become practically relevant. There are ongoing combination trials with osimertinib plus either ramucirumab (Cyramza, Eli Lilly; NCT02789345) or bevacizumab (Avastin, Genentech; NCT02803203, NCT02971501 and NCT 03133546).
Moving forward, based on the OS results of the FLAURA trial, osimertinib is not only the preferred standard in first-line treatment of EGFR-mutated metastatic NSCLC, but also should be the standard comparator or the combination backbone of future trials in first-line treatment of this disease.
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Sheenu Sheela, MD, FACP
Kathryn F. Mileham, MD, FACP
Levine Cancer Institute at Atrium Health
Disclosures: Mileham reports an advisory board role with AstraZeneca. Sheela reports no relevant financial disclosures.