#WCLC25: Four-Year Median OS with Osimertinib/Chemotherapy Combination in Advanced EGFR-Mutation Positive NSCLC

The final overall survival (OS) analysis from the FLAURA2 trial was presented during the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer (WCLC) Presidential Symposium, firmly establishing osimertinib plus chemotherapy as a new first-line standard for patients with advanced epidermal growth factor receptor (EGFR)-mutated non–small cell lung cancer (NSCLC). The final OS analysis showed the longest survival yet reported in this population from a global phase 3 trial.

FLAURA2 enrolled 557 patients with untreated, locally advanced or metastatic EGFR exon 19 deletion or L858R NSCLC. Patients with stable brain metastases were allowed on study. Participants were randomized to receive osimertinib with carboplatin or cisplatin plus pemetrexed for four cycles followed by maintenance osimertinib–pemetrexed, or osimertinib monotherapy at 80 mg daily. Treatment beyond progression was permitted if investigators judged clinical benefit. Subsequent therapy was at investigator discretion. Progression-free survival (PFS) was the primary endpoint, and OS was a key secondary endpoint.

At the primary PFS analysis (data cut April 2023), the addition of chemotherapy reduced the risk of progression by 38% (HR 0.62; 95% CI 0.49–0.79; p<0.001), with median PFS of 25.5 months versus 16.7 months for osimertinib alone. These benefits were consistent across prespecified subgroups, including patients with brain metastases and those harboring L858R mutations.

With extended follow-up to June 2025 (57% maturity), median OS reached 47.5 months in the osimertinib–chemotherapy arm compared with 37.6 months with osimertinib monotherapy (HR 0.77; 95% CI 0.61–0.96; p=0.02). Three-year OS was 63% versus 51%, respectively. The OS advantage was maintained across all predefined subgroups.

Baseline characteristics from the phase 3 FLAURA2 trial in patients with untreated, advanced EGFR-mutated NSCLC.

Median osimertinib exposure was 30.5 months with the combination, versus 21.2 months with monotherapy. The median pemetrexed exposure in the experimental arm was 8.3 months, suggesting many patients experienced a prolonged chemotherapy-free interval.

Patterns of subsequent therapy highlighted clinical practice implications. After progression, platinum-based chemotherapy was the most common second-line treatment in both arms, given to 44% of patients in the combination arm and 72% after osimertinib alone. Importantly, the OS benefit for the upfront combination was preserved despite widespread use of platinum rechallenge after monotherapy.

Efficacy outcomes from the phase 3 FLAURA2 trial in patients with untreated, advanced EGFR-mutated NSCLC.

Grade ≥3 adverse events (AEs) were more common with the combination (70% vs 34%). Anemia, diarrhea, nausea, and decreased appetite were the most common any-grade AEs.  Adverse events led to discontinuation of osimertinib in 12% of patients in the combination arm and 7% with monotherapy. No new safety signals or treatment-related deaths emerged during longer follow-up.

Safety and treatment patterns from the phase 3 FLAURA2 trial in patients with untreated, advanced EGFR-mutated NSCLC.

These findings build on the FLAURA2 PFS advantage and confirm clinically meaningful OS improvement. Median OS of nearly four years represents the longest survival reported for EGFR-mutated NSCLC in a phase 3 global study. With compelling evidence across subgroups and no excess late toxicity, osimertinib plus chemotherapy is now firmly positioned as the frontline standard of care for EGFR-mutated advanced NSCLC.

References

Planchard D, Jänne PA, Kobayashi K, et al. First-line osimertinib plus chemotherapy versus osimertinib monotherapy in EGFR-mutated advanced NSCLC: FLAURA2 final overall survival. Presented at: IASLC World Conference on Lung Cancer (WCLC) 2025; September 7, 2025; Barcelona, Spain. Abstract PL01.06.