Osimertinib Combo Exhibits OS Improvement in EGFR-Mutated Advanced NSCLC

The median OS was 47.5 months with osimertinib plus chemotherapy and 37.6 months with osimertinib, respectively, resulting in a 23% reduction in the risk of death.

Osimertinib (Tagrisso) plus chemotherapy exhibited a statistically significant and clinically meaningful overall survival (OS) improvement vs osimertinib alone when used as a first-line treatment in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC), according to results from the phase 3 FLAURA2 trial (NCT04035486) presented during the 2025 World Conference on Lung Cancer.^1,2

At a median follow-up of 51.2 months (range, 0.2-60.4) for osimertinib plus chemotherapy and 51.3 months (range, 0.1-60.1) for osimertinib alone, the median OS was 47.5 months (95% CI, 41.0-not calculable) and 37.6 months (95% CI, 33.2-43.2), respectively; this translates to a 23% reduction in the risk of death (HR, 0.77; 95% CI, 0.61-0.96; P = .02).¹ The 24-, 36-, and 48-month OS rates in the combination arm were 80%, 63%, and 49%, respectively; in the monotherapy arm, these respective rates were 72%, 51%, and 41%. Notably, OS benefit was observed across predefined subgroups.

“These compelling OS results from FLAURA2 confirm osimertinib-plus-chemotherapy as a first-line standard-of-care [SOC] treatment in EGFR-mutated advanced NSCLC,” David Planchard, MD, PhD, of the Department of Medical Oncology at the Institut Gustave Roussy, in Villejuif, France, and Faculty of Medicine at Université Paris-Saclay, in Paris, France, said in a presentation of the data.

What Did the FLAURA2 Study Examine?

The phase 3 study enrolled patients with treatment-naive, locally advanced or metastatic EGFR-mutated NSCLC who are at least 18 years of age, have pathologically confirmed nonsquamous disease, an EGFR exon 19 deletion or L858R mutation, and a World Health Organization (WHO) performance status of 0 or 1. Those with stable central nervous system (CNS) metastases were permitted, and brain scans were done at baseline.

Study participants (n = 557) were randomly assigned 1:1 to receive osimertinib at 80 mg once daily plus pemetrexed at 500 mg/m² and carboplatin at area under the curve 5 or cisplatin at 75 mg/m² every 3 weeks for 4 cycles for platinum-based treatments followed by maintenance osimertinib at 80 mg once daily plus pemetrexed at 500 mg/m² every 3 weeks or osimertinib alone at 80 mg once daily. Treatment beyond disease progression was permitted per investigator discretion.

Patients were stratified by race (Asian Chinese vs Asian non-Chinese vs non-Asian), EGFR mutation test (local vs central), and WHO performance status (0 vs 1).

The primary end point of the study was investigator-assessed progression-free survival (PFS) by RECIST 1.1 criteria, and OS served as a key secondary end points; final analysis was performed at 57% maturity. Other secondary end points included time to first subsequent treatment or death, duration of response, disease control rate, time from randomization to second progression on a subsequent treatment, time to second subsequent treatment or death, and health-related quality of life.

Across the combination and monotherapy arms, the median patient age was 61.5 years (range, 26-85) and more than half were female (62%; 61%). With regard to race, in the osimertinib/chemotherapy arm, 25% were Asian Chinese, 39% were Asian non-Chinese, 35% were non-Asian, and less than 1% had missing information; these respective rates in the osimertinib-alone arm were 25%, 38%, 36%, and 1%. More than half of patients had a WHO performance status of 1 (62%; 63%), were never smokers (67%; 65%), and had an EGFR exon 19 deletion mutation at baseline (61%; 60%). Almost all patients had adenocarcinoma histology (99%; 99%). Approximately 41% of patients had CNS metastases at baseline (42%; 40%).

Data from the primary analysis of the study, which had a data cutoff date of April 3, 2023, showed that osimertinib combined with chemotherapy significantly improved PFS vs single-agent osimertinib, at a median of 25.5 months (95% CI, 24.7-NC) vs 16.7 months (95% CI, 14.1-21.3), translating to a 38% reduction in the risk of disease progression or death (HR, 0.62; 95% CI, 0.49-0.79; P < .001).³ The data supported the FDA’s decision to approve osimertinib plus platinum-based chemotherapy for use in locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations in February 2024.⁴

What Are Additional Takeaways From the Final OS Data Analysis of FLAURA2?

The current analysis had a data cutoff date of June 12, 2025.¹ A total of 557 patients underwent randomization and 551 of them were dosed; 276 were in the osimertinib/chemotherapy arm and 275 were in the osimertinib monotherapy arm. At cutoff, in the combination arm, 28% of patients were still on osimertinib and 4% of patients were still on pemetrexed; in the monotherapy arm, 18% of patients were still receiving osimertinib.

In the combination arm, 72% of patients had discontinued treatment. Of those who discontinued osimertinib (n = 200), the most common reason for doing so was progression (46%), followed by adverse effects (AEs; 12%). Of those who discontinued pemetrexed (n = 264), the most common reason was AEs (50%), followed by progression (18%). In the monotherapy arm (n = 226), 82% had discontinued treatment with osimertinib and most did so due to progression (67%) followed by AEs (7%).

The combination arm (n = 276) had a long chemotherapy-free period, according to Planchard. The median exposure to osimertinib vs pemetrexed was 30.5 months (range, 0.1-59.0) vs 8.3 months (range, 0.7-58.9). Median exposure to platinum was 2.8 months (range, 0.7-4.1). For the monotherapy arm (n = 275), the median exposure to osimertinib was 21.2 months (range, 0.1-59.2).

Additional data showed that in the combination arm, 69% of patients received first subsequent treatment (FST) after discontinuing osimertinib due to progression. The most common FST was platinum-based chemotherapy (44%), followed by non-platinum-based chemotherapy (30%), other (14%), EGFR targeted therapy (8%), and osimertinib plus targeted agent or investigational drug that was not chemotherapy (5%). In the monotherapy arm, 77% of patients received FST after osimertinib discontinuation due to disease progression. The most common FST was platinum-based chemotherapy (72%).

Planchard noted that an OS benefit with osimertinib plus chemotherapy was seen despite SOC chemotherapy being the most common FST following osimertinib monotherapy.

What Safety Data Were Reported From FLAURA2 on Osimertinib Plus Chemotherapy?

With 2 additional years of follow-up since the primary analysis, toxicity profiles remained as expected—manageable with no new signals observed. Any grade AEs occurred in all patients in the combination arm vs 98% of those in the monotherapy arm; they were grade 3 for 70% and 34% of patients, respectively, and serious for 46% and 27% of patients, respectively. AEs led to discontinuation of osimertinib, pemetrexed, or platinum for 12%, 50%, and 17% of patients in the combination arm, respectively. AEs led to discontinuation of osimertinib for 7% of those in the monotherapy arm.

“AEs leading to discontinuation of osimertinib remained low, and no new treatment-related deaths were observed with osimertinib plus chemotherapy vs 1 with osimertinib monotherapy,” Planchard noted.

The most common grade 3 AEs reported in the combination and monotherapy arms were anemia (20%; 1%), neutropenia (11%; 1%), decreased neutrophil count (9%; 1%), diarrhea (3%; <1%), decreased appetite (3%; 1%), fatigue (3%; <1%), increased alanine aminotransferase level (2%; 1%), nausea (1%; 0%), rash (1%; 0%), vomiting (1%; <1%), COVID-19 (1%; 0%), paronychia (1%; <1%), constipation (<1%; 0%), and stomatitis (<1%; <1%). The most common grade 4 AEs reported in the combination arm included neutropenia and decreased neutrophil counts (3% each).

References

1. Planchard D, Jänne PA, Kobayashi K, et al. First-line osimertinib + chemotherapy versus osimertinib monotherapy in EGFRm advanced NSCLC: FLAURA2 final overall survival. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract 1956.
2. FLAURA2 trial shows osimertinib plus chemotherapy improves overall survival in EGFR-mutated advanced NSCLC. Press release. International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer. September 7, 2025. Accessed September 7, 2025. https://wclc.iaslc.org/
3. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434
4. FDA approves osimertinib with chemotherapy with chemotherapy for EGFR-mutated non-small cell lung cancer. FDA. February 16, 2024. Accessed September 7, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-chemotherapy-egfr-mutated-non-small-cell-lung-cancer