Chemotherapy Plus Osimertinib Offers Overall Survival Benefit in EGFR-mutated NSCLC

Daniel Tuerff, MD University of Miami | Chinmay Jani, MD University of Miami Health System | Estelamari Rodriguez, MD, MPH University of Miami Health System

November 12, 2025

CT scan of a chest showing lung health, used in cancer diagnosis and treatment monitoring.
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EGFR tyrosine kinase inhibitors (TKIs) have transformed the first-line treatment paradigm for patients with EGFR-mutated non-small cell lung cancer (NSCLC). By selectively targeting oncogenic driver mutations, these agents have significantly improved survival outcomes compared with conventional chemotherapy. New generations of TKIs with activity against resistance mutations, such as T790M, have further enhanced clinical efficacy and overall survival (OS) in this patient population.

Osimertinib, a third-generation EGFR TKI, is effective against both EGFR exon 19 deletions and L858R mutations and has demonstrated robust central nervous system (CNS) penetration. The phase 3 FLAURA trial established osimertinib as the standard of care in the first-line setting, demonstrating superior progression-free survival (PFS) and OS compared with first-generation TKIs (erlotinib or gefitinib), with a median OS of 38.6 months versus 31.8 months, respectively.1,2 

The Phase 3 FLAURA2 Trial

Expanding upon FLAURA, the FLAURA2 trial evaluated whether combining osimertinib with platinum-based chemotherapy could further improve outcomes in patients with advanced EGFR-mutated NSCLC.3  This global, open-label, randomized phase 3 trial enrolled 557 patients with previously untreated, EGFR-mutated, locally advanced, or metastatic NSCLC. Participants were randomized 1:1 to receive either osimertinib plus chemotherapy or osimertinib monotherapy. Patients received 80 mg osimertinib once daily until disease progression or discontinuation criteria were met. In the combination arm, patients also received pemetrexed with cisplatin or carboplatin every 3 weeks for 4 cycles, followed by maintenance therapy with pemetrexed and osimertinib. The primary endpoint was PFS, and OS was a key secondary endpoint.

At the 2025 International Association for the Study of Lung Cancer’s World Conference on Lung Cancer, the much-anticipated OS results were presented. Osimertinib combined with chemotherapy demonstrated a statistically significant and clinically meaningful improvement in OS versus osimertinib monotherapy, with a median OS of 47.5 months compared with 37.6 months, and a hazard ratio of 0.77, at approximately 57% maturity (median follow-up 51.2 and 51.3 months, respectively).4 These data represent one of the longest survival durations ever reported in the metastatic EGFR-mutant NSCLC population.

The chemotherapy duration shown in FLAURA2, along with the fairly high crossover rates, were reassuring, supporting the durability and feasibility of the regimen. The osimertinib-chemotherapy combination maintained a manageable safety profile, consistent with the known toxicities of the individual agents, and no new safety signals were identified at longer follow-up. Adverse events leading to osimertinib discontinuation occurred in 12% of patients in the combination arm versus 7% in the monotherapy arm.

Trial Demographics in FLAURA2

The median duration of osimertinib treatment was longer with the combination regimen (30.5 months) versus osimertinib alone (21.2 months), indicating more durable disease control with added chemotherapy. The median age across both study arms was 61.5 years, and most participants were women (62% vs 61%). The racial distribution was comparable between groups, with Asian Chinese (25%), Asian non-Chinese (39% vs 38%), non-Asian (35% vs 36%), and <1% unreported. Consistent with the EGFR-mutant NSCLC population, the majority were never-smokers (67% vs 65%) and had EGFR exon 19 deletion mutations at baseline (61% vs 60%). Baseline CNS metastases were observed in approximately 41% of patients (42% vs 40%), reflecting the high incidence of brain involvement in this subset.

Subgroup analyses showed particularly notable benefits in patients younger than 65 years and in those with baseline CNS metastases. These findings highlight the regimen’s potential to overcome disease progression in traditionally higher-risk subsets. FLAURA2 confirmed that patients with EGFR-mutated NSCLC who can tolerate chemotherapy derive a meaningful OS advantage from combination therapy, supporting a new potential frontline standard for this patient population.

Future Directions

The management of EGFR-mutated advanced NSCLC continues to rapidly evolve with the emergence of novel targeted combinations. The MARIPOSA trial introduced another paradigm-shifting regimen, demonstrating a significant OS benefit with the combination of amivantamab, a bispecific antibody targeting EGFR and MET, plus lazertinib, compared with osimertinib monotherapy in the first-line setting.5,6  

While both FLAURA2 and MARIPOSA have established new benchmarks for survival in this molecular subset, these regimens have not yet been directly compared. Future comparative analyses and real-world data will be essential to guide optimal sequencing and selection between osimertinib–chemotherapy and amivantamab–lazertinib combinations, considering differences in toxicity profiles, resistance mechanisms, and CNS efficacy. 

As the therapeutic armamentarium expands, biomarker-driven treatment selection and adaptive strategies to overcome resistance will be crucial in maximizing long-term survival for patients with EGFR-mutant NSCLC.

References

  1. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer. New England Journal of Medicine. Published online January 11, 2018. doi:10.1056/NEJMoa1713137
  2. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. New England Journal of Medicine. Published online January 2, 2020. doi:10.1056/NEJMoa1913662
  3. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. New England Journal of Medicine. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434
  4. Jänne PA, Planchard D, Kobayashi K, et al. Survival with Osimertinib plus Chemotherapy in EGFR-Mutated Advanced NSCLC. New England Journal of Medicine. Published online October 17, 2025. doi:10.1056/NEJMoa2510308
  5. Cho BC, Lu S, Felip E, et al. Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC. New England Journal of Medicine. 2024;391(16):1486-1498. doi:10.1056/NEJMoa2403614
  6. Overall Survival with Amivantamab–Lazertinib in EGFR-Mutated Advanced NSCLC | New England Journal of Medicine. Accessed November 5, 2025. https://www.nejm.org/doi/full/10.1056/NEJMoa2503001