The final overall survival (OS) results of the FLAURA2 trial support osimertinib plus chemotherapy as the new first-line standard of care for EGFR-mutated non-small cell lung cancer (NSCLC), according to the study authors.

David Planchard, MD, PhD, of Institut Gustave Roussy in France, presented the results at the World Conference on Lung Cancer (WCLC) 2025. The study showed a significant 23% reduction in the risk of death (hazard ratio [HR], 0.77; 95% CI, 0.61-0.96; P = .02) with the combination regimen. 

The new trial findings suggest that first-line osimertinib plus chemotherapy significantly prolongs OS compared to osimertinib monotherapy in patients with advanced NSCLC of this type. The median OS reached 47.5 months in patients who received the combination therapy versus 37.6 months in patients who received osimertinib without chemotherapy.

"This is the longest global phase 3 study showing OS benefit in this population," noted Planchard during his talk.

Rationale and Study Design

Planchard explained that monotherapy with osimertinib, a third-generation CNS-active EGFR tyrosine kinase inhibitor (TKI), has been the preferred first-line treatment for patients with EGFR exon 19 deletion or L858R mutations since demonstrating superior efficacy over first-generation EGFR TKIs in the original FLAURA trial.

Daniel Tan, MBBS, PhD, of the National Cancer Centre Singapore, who served as the discussant, noted that, "since 2009, we've seen the subsequent developments of first-generation, second-generation, and third-generation EGFR TKIs, of which osimertinib remains the most widely prescribed one worldwide."

The FLAURA2 study investigated whether adding chemotherapy to osimertinib could further improve outcomes in previously untreated patients with EGFR-mutated NSCLC. This global, open-label, randomized phase 3 trial enrolled 557 patients with previously untreated locally advanced or metastatic EGFR-mutated NSCLC across 153 sites in 21 countries.

Patients were randomized 1:1 to receive osimertinib 80 mg daily plus four cycles of pemetrexed with carboplatin or cisplatin every 3 weeks, followed by maintenance osimertinib plus pemetrexed, or osimertinib monotherapy. The primary endpoint was investigator-assessed progression-free survival, and OS was a key secondary endpoint.

Final OS Results

During his presentation, Planchard explained that the final OS analysis was conducted at 57% maturity, with a median follow-up of approximately 51 months. Patients in the combination arm had a median OS of 47.5 months (95% CI, 41.0 months – not calculable), compared to 37.6 months (95% CI, 33.2-43.2 months) with osimertinib alone, a nearly 10-month improvement. Three-year OS rates were 63% with combination therapy versus 51% with osimertinib monotherapy. At 4 years, median OS rates were 49% and 41%, respectively.

"The OS benefit of osimertinib plus chemotherapy was consistent across all predefined subgroups, including patients with brain metastasis and EGFR-L858R mutations," Planchard emphasized during his presentation.

He also highlighted that the OS benefit was observed despite the high rates of subsequent platinum-based chemotherapy in the control arm. In the osimertinib monotherapy group, 77% of patients who progressed received subsequent treatment, with 72% receiving platinum-based chemotherapy as their first subsequent therapy.

Tan emphasized the significance of the OS benefit despite high crossover rates. "Despite the high crossover rate, we still managed to discern an OS benefit," adding that the 10-month improvement in median OS represents a clinically meaningful advance.

Safety Profile

With over 2 additional years of follow-up since the primary analysis of the FLAURA2 trial, the safety profile of osimertinib plus chemotherapy was expected, Planchard said.

"No new safety signals were observed, and no additional treatment-related deaths were observed in the osimertinib plus chemotherapy arm," he continued.

Treatment-emergent adverse events (TEAEs) leading to osimertinib discontinuation remained low at 12% in the combination arm versus 7% in the monotherapy arm. The most frequent grade 3 or higher TEAEs with combination therapy were anemia (48% any grade, 20% grade 3), neutropenia (25% any grade, 14% grade 3-4), and decreased neutrophil count (24% any grade, 12% grade 3-4). Planchard explained that these hematological toxicities mainly occurred during the induction period with platinum-based chemotherapy.

Gastrointestinal toxicities were also more frequent in the combination than monotherapy arm, including any grade nausea (43% vs 12%), diarrhea (46% vs 42%), and vomiting (29% vs 7%), although these adverse events were predominantly grade 1-2 in both treatment arms.

Clinical Implications and Future Directions

"These compelling OS results from FLAURA2 confirm that osimertinib plus chemotherapy should be a first-line standard of care treatment in EGFR-mutated advanced NSCLC," Planchard concluded.

Referring to the recent approval of amivantamab plus lazertinib as another combination option, Tan acknowledged the complexity of treatment decisions in the current treatment landscape for previously untreated EGFR-mutated NSCLC, which consists of one single-agent TKI and two combination options (amivantamab in combination with lazertinib and osimertinib in combination with chemotherapy).

"Given that the two combinations we have now probably have distinct mechanisms of action, the key priority is to discover biomarkers and identify defined populations who stand to benefit," Tan emphasized during his talk. "Shared decision-making based on individual preference is going to be key in determining the appropriate treatment."

Tan also highlighted the need for better risk stratification tools, calling for the development of biomarkers and the identification of defined populations with the largest magnitude of benefit to specific combinations.

The FLAURA2 study was funded by AstraZeneca. Planchard has reported financial relationships with AstraZeneca, Bristol Myers Squibb, Celgene, Merck, Novartis, Pfizer, Roche, Janssen, AbbVie, and Daiichi Sankyo. Tan has reported financial relationships with ACM Biolabs, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, C2i Genomics, DKSH, GlaxoSmithKline, Merck, Novartis, Oncoshot, Pfizer, Roche, and Takeda.

Christos Evangelou is a freelance medical writer.