Background
Phase III, open-label, randomized controlled trial (FLAURA2). N=557 patients with EGFR-mutated (exon 19 deletion or L858R) advanced NSCLC, no prior systemic therapy for advanced disease. 1:1 randomization. Stratified by EGFR mutation type, CNS metastases, and race.
Interventions and follow up
Arm A: Osimertinib 80 mg PO daily + pemetrexed 500 mg/m² IV + cisplatin 75 mg/m² IV (or carboplatin AUC5) q3wk × 4 cycles, then osimertinib + pemetrexed maintenance (N=279)
Arm B: Osimertinib 80 mg PO daily monotherapy (N=278)
Primary endpoint: PFS by blinded independent central review
mFollow up: NR (key secondary OS)
Arm B: Osimertinib 80 mg PO daily monotherapy (N=278)
Primary endpoint: PFS by blinded independent central review
mFollow up: NR (key secondary OS)
Results
PFS (Planchard NEJM 2023): 25.5 vs 16.7 mo, HR 0.62, 95% CI 0.49–0.79, P<.001
OS (Jänne NEJM 2025): 47.5 vs 37.6 mo, HR 0.77, 95% CI 0.61–0.96, P=.02
OS (Jänne NEJM 2025): 47.5 vs 37.6 mo, HR 0.77, 95% CI 0.61–0.96, P=.02
Adverse events
Overall Grade ≥3: 70% (osi+chemo) vs 34% (osi mono)
Hematologic: neutropenia 19%, anemia 14%, thrombocytopenia 5%
Pulmonary: ILD 3.6% vs 3.6%
Cardiac: QTc prolongation 1.4%
Discontinuation (osimertinib): 12% vs 7%
Hematologic: neutropenia 19%, anemia 14%, thrombocytopenia 5%
Pulmonary: ILD 3.6% vs 3.6%
Cardiac: QTc prolongation 1.4%
Discontinuation (osimertinib): 12% vs 7%
Conclusions
Osimertinib + platinum-pemetrexed improved both PFS (HR 0.62) and OS (HR 0.77, P=.02) vs osimertinib monotherapy in 1L EGFR+ mNSCLC. The OS benefit of 9.9 months absolute (47.5 vs 37.6 months) is clinically meaningful but at the cost of substantially increased grade ≥3 toxicity (70% vs 34%).
Key Limitations
Grade ≥3 AEs doubled with combination (70% vs 34%) — a substantially higher toxicity burden. Osimertinib discontinuation higher (12% vs 7%), potentially affecting duration and real-world outcomes. Open-label design. Combination requires IV infusion access, reducing convenience vs oral osimertinib. No benefit data for exon 20 insertions or uncommon EGFR mutations. QoL data not fully reported. Future comparisons should include amivantamab + lazertinib (MARIPOSA).
Clinical Context
FLAURA2 offers an OS benefit over osimertinib monotherapy at the cost of substantially higher toxicity. FDA and EMA approved osimertinib + platinum-pemetrexed for first-line EGFR exon 19 del/L858R advanced NSCLC. Per ASCO and ESMO it is a first-line option, appropriate for fit patients with high disease burden, while osimertinib monotherapy remains preferred for less fit patients or those prioritizing quality of life. Amivantamab + lazertinib (MARIPOSA) is an emerging alternative. ESMO-MCBS score: 4.