Frontline Osimertinib Combo Prolongs Survival in Advanced EGFR+ NSCLC

Combining osimertinib (Tagrisso) with chemotherapy significantly prolonged overall survival (OS) vs osimertinib monotherapy among patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC) in the phase 3 FLAURA2 trial (NCT04035486), although the combination conferred a higher risk of reversible grade 3 or higher adverse effects (AEs), according to planned final OS analysis findings published in the New England Journal of Medicine.¹

With a median follow-up of 42.6 months (range, 0.1-60.4) in the osimertinib/chemotherapy arm and 35.7 months (range, 0.1-60.1) in the osimertinib monotherapy arm, data showed a median OS of 47.5 months (95% CI, 41.0-not calculable) vs 37.6 months (95% CI, 33.2-43.2) in each respective arm (HR, 0.77; 95% CI, 0.61-0.96; P = .02). Additionally, the 36-month OS rates were 63% (95% CI, 57%-69%) vs 51% (95% CI, 45%-57%).

Among patients with central nervous system (CNS) metastases at baseline, the 36-month OS rate was 57% (95% CI, 48%-66%) with osimertinib/chemotherapy and 40% (95% CI, 31%-49%) with osimertinib alone. The 36-month OS rates among patients without CNS metastases were 67% (95% CI, 59%-74%) vs 58% (95% CI, 50%-65%) in each respective arm. Additionally, the 36-month rates were 54% (95% CI, 44%-63%) vs 42% (95% CI, 32%-51%) among patients with EGFR L858R mutations and 69% (95% CI, 61%-75%) vs 57% (95% CI, 49%-64%) among those with EGFR exon 19 deletions.

When considering patients who discontinued frontline osimertinib following disease progression, 69% (n = 88/127) of patients in the combination therapy arm and 77% (n = 143/185) in the monotherapy arm received subsequent therapy. The most common types of first subsequent therapy in the combination arm included platinum-based chemotherapy (44%) and non–platinum-based chemotherapy (30%). Among patients who received osimertinib monotherapy, the most common kind of subsequent treatment was platinum-containing chemotherapy (72%).

“The combination therapy used in this trial was associated with a higher incidence of grade 3 or higher adverse events and of [AEs] leading to the discontinuation of treatment than osimertinib monotherapy. Most high-grade toxic effects associated with the combination therapy were related to myelosuppressive effects, which are generally dose-related and reversible, with supportive interventions available to ameliorate such effects,” lead study author Pasi A. Jänne, MD, PhD, senior vice president of Translational Medicine and professor in the Department of Medical Oncology at Lowe Center for Thoracic Oncology of Dana–Farber Cancer Institute, wrote with coauthors in the publication.¹ “Results from this trial provide evidence that first-line treatment with osimertinib plus platinum/pemetrexed led to significantly longer [OS] than osimertinib monotherapy among patients with EGFR-mutated advanced NSCLC.”

In the international, open-label, phase 3 FLAURA2 trial, patients were randomly assigned 1:1 to receive osimertinib at 80 mg once daily plus pemetrexed at 500 mg/m² and cisplatin at 75 mg/m² or pharmacologically guided carboplatin (n = 276) or osimertinib alone (n = 275).

The trial’s primary end point was investigator-assessed progression-free survival (PFS) per RECIST v1.1 criteria. OS was a key secondary end point. Other secondary end points included receipt of a first subsequent treatment or death, second PFS, and receipt of a second subsequent treatment or death.

Patients 18 years and older with pathologically confirmed nonsquamous NSCLC; newly diagnosed locally advanced, metastatic, or recurrent disease not amenable to curative surgery or radiotherapy; and EGFR mutations were eligible for enrollment on the trial.² Other requirements for study entry included having a WHO performance status of 0 or 1 and a life expectancy of more than 12 weeks.

The baseline characteristics were comparable between the trial arms. Treatment with osimertinib continued beyond progressive disease in 45% of patients in the combination therapy arm and 62% of the monotherapy arm.

At the time of the final OS analysis, 100% of patients in the osimertinib combination arm and 98% of those in the monotherapy arm had AEs of any grade, with 70% vs 34% experiencing grade 3 or higher toxicities. Additionally, 54% and 7% of patients from each respective arm had AEs leading to discontinuation of any study therapy. The most common toxicities in the combination and monotherapy arms, respectively, included anemia (48% vs 11%), diarrhea (47% vs 42%), nausea (43% vs 12%), decreased appetite (33% vs 11%), and constipation (32% vs 11%).

References

1. Jänne PA, Planchard D, Kobayashi K, et al. Survival with osimertinib plus chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2026;394(1):27-38. doi:10.1056/NEJMoa2510308.
2. A study of osimertinib with or without chemotherapy as 1st line treatment in patients with mutated epidermal growth factor receptor non-small cell lung cancer (FLAURA2) (FLAURA2). ClinicalTrials.gov. Updated October 10, 2025. Accessed January 13, 2026. https://tinyurl.com/4kjpfu8a