FLAURA2 in the Frontline Management of EGFRm NSCLC: Key Considerations for Patient Selection

Summary of EGFR-Mutated NSCLC Frontline Management Discussion

The management landscape for advanced EGFR-mutated non–small cell lung cancer (NSCLC) has evolved significantly, with 3 primary frontline treatment options now available for patients with classical EGFR mutations. The traditional standard of care, osimertinib monotherapy based on the FLAURA study, remains a viable option due to its oral administration, excellent tolerability, superior central nervous system (CNS) activity, and improved outcomes compared to first-generation EGFR inhibitors. However, 2 combination regimens have demonstrated superiority in progression-free survival: FLAURA2 (osimertinib plus carboplatin-pemetrexed chemotherapy) and the MARIPOSA regimen.

The FLAURA2 regimen has shown clear benefits in progression-free survival with encouraging trends toward overall survival improvement, though final data remain pending. While this combination offers enhanced efficacy, it introduces the challenges of intravenous chemotherapy administration, including increased toxicities and more frequent clinic visits. The treatment selection approach has shifted from considering escalation for specific patients to a more comprehensive evaluation of when de-escalation might be appropriate. FLAURA2 is particularly favored for patients with higher disease burden, baseline CNS metastases, and other high-risk features such as p53 mutations or positive baseline circulating tumor DNA, while de-escalation to monotherapy may be considered for older, frail patients or those with limited renal function.

Treatment sequencing has become increasingly complex, requiring careful consideration of how frontline choices impact subsequent therapy options. For patients receiving osimertinib monotherapy up front, the MARIPOSA2 regimen (chemotherapy plus amivantamab) represents an attractive second-line option, having demonstrated improved progression-free survival compared to chemotherapy alone. However, the optimal sequencing strategy for patients who receive frontline chemotherapy combinations remains unclear, with potential options including chemotherapy rechallenge after a treatment-free interval or enrollment in clinical trials investigating novel therapies like antibody-drug conjugates.