An exploratory overall survival analysis of the phase III FLAURA2 trial confirmed the overall survival benefit of adding osimertinib to chemotherapy in patients with non–small cell lung cancer (NSCLC) and mutations in the epidermal growth factor receptor (EGFR) not previously treated for advanced disease. The benefit was seen in patients with baseline factors heralding a poor prognosis, investigators reported at the European Society for Medical Oncology (ESMO) Congress 2025.¹ The findings were concurrently published in The New England Journal of Medicine.²

Pasi A. Jänne, MD, PhD

“In FLAURA2, the median overall survival with osimertinib plus platinum and pemetrexed was 47.5 months³—which is the longest seen in a global phase III study showing an overall survival benefit in patients with EGFR-mutated advanced NSCLC,” said Pasi A. Jänne, MD, PhD, Senior Vice President for Translational Medicine and Thoracic Medical Oncologist at the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, Boston, Massachusetts. “A survival benefit favoring osimertinib plus platinum-pemetrexed vs osimertinib monotherapy was consistently observed, regardless of baseline prognostic factors, reinforcing osimertinib plus platinum-pemetrexed as a first-line standard of care in this setting.”

About FLAURA2

The international, open-label phase III FLAURA2 trial included 557 patients with advanced NSCLC and EGFR mutations (exon 19 deletions or L858R mutations) not previously treated for advanced disease. Patients were randomly assigned to either osimertinib plus pemetrexed and cisplatin or carboplatin or osimertinib alone. Overall survival was a key secondary endpoint of the study.

In addition to the previously reported overall survival benefit (hazard ratio [HR] = 0.77; P = .02),³ investigators previously reported that osimertinib plus chemotherapy significantly reduced the risk for disease progression or death compared with osimertinib monotherapy (HR = 0.62; P < .001).⁴ At 24 months, 57% of the patients in the osimertinib-chemotherapy group and 41% in the osimertinib monotherapy group were alive and progression free.

Exploratory Analyses

As Dr. Jänne noted, prior studies have identified several baseline factors associated with worse prognoses in this setting, and outcomes were determined in patients with these baseline factors in the current exploratory analyses: central nervous system factors (yes vs no); EGFR L858R mutation (vs exon 19 del); bone metastases (yes vs no); tissue TP53 alteration (vs wild-type); liver metastases (yes vs no); and plasma EGFR-mutated circulating tumor (ct) DNA (detected vs undetected).

New Findings

Consistent survival benefits were observed from the Osimertinib combination regimen across all prognostic subgroups, with HRs consistent with that of the overall population, Dr. Jänne reported. Of note, in patients with baseline CNS metastases, the median overall survival was 40.9 months with the combination but was only 29.7 months with the single agent (HR = 0.72); the median overall survival in patients without CNS metastases was not reached with the osimertinib and chemotherapy combination and was 43.9 months with osimertinib monotherapy (HR = 0.77).

For the combination vs single agent in the other poor-prognosis groups, median overall survival was, respectively:

• 1 vs 32.4 months in patients with L858R mutations (HR = 0.76)
• 1 vs 43.1 months in patients with TP53 alterations (HR = 0.71)
• 4 vs 32.5 months in patients with EGFR-mutated ctDNA detected in plasma (HR = 0.79)
• 6 vs 28.0 months in patients with liver metastases (HR = 0.66)
• 2 vs 32.3 months in patients with bone metastases (HR = 0.76)

“An overall survival benefit with osimertinib plus platinum-pemetrexed vs osimertinib monotherapy was consistently observed, regardless of baseline prognostic factors,” Dr. Jänne said, noting that 3-year overall survival rates were always higher for the investigational vs control arms of these subsets.

DISCLOSURE: Dr. Jänne reported personal financial disclosures for AstraZeneca; Mirati Therapeutics, Inc.; Boehringer Ingelheim; Pfizer; Roche/Genentech; Chugai Pharmaceutical Co., Ltd.; Eli Lilly and Company; Ignyta; Takeda Pharmaceuticals; Novartis; Voronoi; SFJ Pharmaceuticals; Biocartis; LOXO Oncology; PUMA; Sanofi; TRANSCENTA HOLDING; Daiichi Sankyo; Bayer; Silicon Therapeutics; AbbVie Inc.; Monte Rosa Therapeutics; Merus; Allorion Therapeutics; Accutar Biotech; Scorpion Therapeutics; Frontier Medicines; Hongyun Biotechnology; Duality Biologics; Blueprint Medicines; Dizal Pharma; GSK; TOLREMO therapeutics; Myris Therapeutics; and Bristol Myers Squibb. He is also a co-inventor on a Dana-Farber Cancer Institute–owned patent on EGFR mutations licensed to Labcorp, and has received related royalties. He also reported grants or contracts with AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Takeda Pharmaceuticals, PUMA, Astellas, and Daiichi Sankyo. For full disclosures of the other study authors, visit esmo.my.site.com/doi/s/.

REFERENCES

1. Jänne PA, Planchard D, Kobayashi K, et al: FLAURA2: exploratory overall survival analyses in patients with poorer prognostic factors treated with Osimertinib +/- platinum-pemetrexed as first-line treatment for EGFR-mutated advanced NSCLC. 2025 ESMO Congress. Abstract LBA77. Presented October 17, 2025.
2. Jänne PA, Planchard D, Kobayashi K, et al: Survival with osimertinib plus chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. October 17, 2025 (early release online).
3. Planchard D, Jänne PA, Kobayashi K, et al: First-line osimertinib + chemotherapy versus osimertinib monotherapy in EGFRm advanced NSCLC: FLAURA2 final overall survival. 2025 IASLC WCLC. Abstract PL02.06. Presented September 7, 2025.
4. Planchard D, Jänne PA, Cheng Y, et al: Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med 389:1935-1948, 2023.

EXPERT POINT OF VIEW

Christine M. Lovly, MD, PhD, FASCO, Associate Professor of Medicine (Hematology/Oncology) at Vanderbilt University Medical Center, Nashville, Tennessee, was the invited discussant of the phase III FLAURA2 trial analysis presentation.¹

Dr. Lovly highlighted the value brought by osimertinib to the EGFR-mutant NSCLC field, where improvements in both progression-free and overall survival have been achieved with this third-generation EGFR-targeted tyrosine kinase inhibitor. In the exploratory overall survival analysis of FLAURA2 presented at the European Society for Medical Oncology (ESMO) Congress 2025, the investigators assessed outcomes in historically poor-prognostic patient subgroups, which might help to determine whether clinical, radiographic, or molecular features could be used to identify which patients may benefit the most from treatment intensification (ie, osimertinib plus chemotherapy), she said.

Christine M. Lovly, MD, PhD, FASCO

“Basically, we saw that regardless of the subgroup, the variant, or the site of metastasis, there was a benefit to osimertinib plus chemotherapy. But I think we should also ask ourselves not just who needs intensification, but who maybe needs only the single agent, osimertinib,” Dr. Lovly suggested.

“As we think about the evolving field of EGFR-mutant lung cancer, two groups stood out to me as doing particularly better than the rest: Patients with non-detected plasma EGFR did not reach a median overall survival in the analysis, and patients with wild-type TP53 also did not reach median overall survival. Maybe these are the good actors, and we need to think about de-intensifying therapy for some of these patients,” she noted.

Dr. Lovly concluded, “I would say very strongly, it is time to move beyond single factors and develop a model that integrates clinical, pathological, molecular, and radiographic factors for prognostication, risk stratification, and treatment selection, so that we are able to tell a patient prospectively, ‘Here’s how we think you're going to do on these drugs.’”

DISCLOSURE: Dr. Lovly reported participating in advisory boards for and receiving honoraria from AbbVie; Amgen; AnHeart Therapeutics; AstraZeneca; Black Diamond Therapeutic; Bristol Myers Squibb; Boehringer Ingelheim; Daiichi Sankyo; Exact Sciences; Foresight Diagnostics; Foundation Medicine; Genentech; Gilead Sciences; Guardant Health; ImmunityBio; Jazz Pharmaceuticals; Johnson & Johnson; Merck; Nuvalent; Nuvation Bio; Onviv; Pfizer; Regeneron; Summit Therapeutics Inc.; Takeda Pharmaceuticals; Taiho Pharmaceutical Co., Ltd.; and Tempus. Additionally, she has received travel funds from Boehringer Ingelheim and Daiichi Sankyo.

REFERENCES

1. Jänne PA, Planchard D, Kobayashi K, et al. FLAURA2: exploratory overall survival analyses in patients with poorer prognostic factors treated with Osimertinib +/- platinum-pemetrexed as first-line treatment for EGFR-mutated advanced NSCLC. 2025 ESMO Congress. Abstract LBA77. Presented October 17, 2025.
2. Peters S, Camidge R, Dziadziuszko R, et al. Alectinib versus crizotinib in previously untreated ALK-positive advanced non-small cell lung cancer: final overall survival analysis of the phase III ALEX study. Ann Oncol. October 17, 2025 (early release online).