Osimertinib Plus Platinum–Pemetrexed Improves Overall Survival in EGFR-Mutated Advanced NSCLC (FLAURA2)

Final results from the phase III FLAURA2 trial demonstrate that adding platinum–pemetrexed chemotherapy to first-line osimertinib significantly improves overall survival (OS) in patients with EGFR-mutated advanced non–small-cell lung cancer (NSCLC). In the final overall survival analysis, median survival was 47.5 months with combination therapy compared with 37.6 months with osimertinib monotherapy, representing a 23% reduction in the risk of death. Although higher rates of grade 3 or greater adverse events were observed with the combination regimen, toxicities were largely chemotherapy-related and reversible. These findings establish osimertinib plus platinum–pemetrexed as a more effective first-line option for appropriate, fit patients and support treatment intensification beyond EGFR-targeted monotherapy.

Clinical Takeaway

First-line treatment with osimertinib + platinum-pemetrexed chemotherapy significantly improves OS compared with osimertinib monotherapy in patients with EGFR-mutated advanced NSCLC, with increased but manageable toxicity.

Drug Profile & Mechanism

• Agent: osimertinib + platinum-pemetrexed
• Class:
  • osimertinib: third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor
  • pemetrexed: antifolate antimetabolite chemotherapy
  • carboplatin or cisplatin: platinum-based DNA-damaging cytotoxic chemotherapy
• Mechanism of action:
  • osimertinib: Irreversibly inhibits mutant EGFR (exon 19 deletions or exon 21 L858R mutation positive), blocking downstream signaling pathways that drive tumor growth and survival
  • pemetrexed: inhibits multiple folate-dependent enzymes, disrupting RNA and DNA synthesis
  • Platinum agents: induce DNA crosslinking and apoptosis through direct DNA damage
• Route of administration:
  • osimertinib: oral
  • platinum-pemetrexed: intravenous
• Dosing Schedule:
  • osimertinib
    • 80 mg orally daily (continuous)
  • pemetrexed
    • 500 mg/m2 on day 1 of 21 day cycle x 4 cycles (~3 months)
  • carboplatin (AUC5)
    • AUC5 on day 1 of 21 day cycle x 4 cycles (~3 months)
  • cisplatin
    • 75 mg/m2 on day 1 of 21 day cycle x 4 cycles (~3 months)
• Target population: Patients with previously untreated, locally advanced or metastatic (stage IIIB–IV) non–small-cell lung cancer harboring EGFR exon 19 deletion or L858R mutation.

FLAURA2 Phase III trial Study Design (NCT04035486)

• Study Type: Phase III, international, randomized, open-label trial
• Population: 557 adults with previously untreated EGFR-mutated advanced NSCLC
• Comparator: osimertinib monotherapy
• Treatment Regimen: Osimertinib + platinum–pemetrexed vs osimertinib alone
• Follow Up Duration:
  • Patients followed until disease progression, death, or study completion
• Primary and Key Secondary Assessments:
  • Primary: PFS
  • Secondary: OS

NOTE: Event-free survival(EFS) and pathologic complete response (pCR) are not applicable in this metastatic, non-surgical study.

• Estimated study completion: 2025 (final OS analysis reported)
• Key Endpoints:
  • Primary:
    • PFS
  • Secondary:
    • OS
    • Objective response rate
    • Duration of Response
    • Safety and tolerability

Efficacy Outcomes

• Primary Endpoint Results:
  • Prior analyses demonstrated significantly prolonged PFS with osimertinib + platinum-pemetrexed versus osimertinib monotherapy
• Secondary Endpoint Results:
• OS (Final Analysis):
  • Median OS:
    • 47.5 months with combination therapy
    • 37.6 months with osimertinib alone
  • Hazard ratio for death: 0.77 (95% CI, 0.61-0.96; P = 0.02)
• pCR Rate: N/A

Regulatory Milestones

• Approval Status: osimertinib monotherapy approved for first-line EGFR-mutated metastatic NSCLC
• Regulatory Pathway: FLAURA2 provides confirmatory evidence supporting combination therapy as an intensified first-line option, rather than initial drug approval
• Regulatory Review: Data support guideline updates and inform regulatory and labeling considerations for combination first-line therapy.

Safety

• Overall AE Burden: Higher with combination therapy, consistent with chemotherapy exposure
• Grade ≥3 Events:
  • 70% with combination therapy
  • 34% with monotherapy
• Delayed Surgery: N/A
• Delayed Adjuvant Treatment: N/A
• Treatment-related deaths: Rare and balanced between treatment arms
• Notable toxicity patterns:
  • Increased hematologic toxicities
  • Higher rates of fatigue and gastrointestinal adverse events
  • Toxicities largely chemotherapy-related and reversible

Key Clinical Implications

✔ Establishes osimertinib plus platinum-pemetrexed as a more effective first-line strategy for eligible patients

✔ Demonstrates a clinically meaningful overall survival benefit

✔ Confirms manageable safety profile despite increased grade ≥ 3 events

✔ Supports individualized treatment intensification based on patient fitness

✔ Reinforces EGFR mutation-directed therapy as the foundation of care

Bottom Line

Adding platinum–pemetrexed chemotherapy to first-line osimertinib significantly improves survival in EGFR-mutated advanced NSCLC and represents a new benchmark for treatment intensification in appropriate patients.

Sources:

• U.S. Food and Drug Administration. (2024, February 16). FDA approves osimertinib with chemotherapy for EGFR-mutated non-small cell lung cancer. U.S. Department of Health and Human Services. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-chemotherapy-egfr-mutated-non-small-cell-lung-cancer
• Jänne, P. A., Planchard, D., Kobayashi, K., Yang, J. C.-H., Liu, Y., Valdiviezo, N., Kim, T. M., Jiang, L., Kagamu, H., Yanagitani, N., Wang, J., Biswas, B., Poltoratskiy, A., Neron, Y., Rojas, C., Koubkova, L., Escriu, C., Ezeife, D. A., Mann, H., … Lee, C. K. (2025). Survival with osimertinib plus chemotherapy in EGFR-mutated advanced non-small-cell lung cancer. New England Journal of Medicine, 394(1), 27–38. https://doi.org/10.1056/NEJMoa2510308
• U.S. National Library of Medicine. (2025). A Phase III, open-label, randomized study of osimertinib with or without platinum plus pemetrexed chemotherapy as first-line treatment in patients with epidermal growth factor receptor (EGFR)-mutated locally advanced or metastatic non-small cell lung cancer (FLAURA2) (ClinicalTrials.gov Identifier: NCT04035486). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT04035486