The combination of the EGFR-targeting tyrosine kinase inhibitor osimertinib with platinum-based chemotherapy significantly improved overall survival as a first-line treatment for patients with EGFR-mutated, advanced, non–small cell lung cancer (NSCLC) compared with osimertinib monotherapy, according to the final overall survival data presented by David Planchard, MD, PhD, thoracic oncologist and Head of the Thoracic Pathology Committee at Gustave Roussy, Villejuif, France, at the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer.¹

In the phase III FLAURA2 trial, patients receiving osimertinib plus chemotherapy achieved a median overall survival of 47.5 months, marking a nearly 10-month improvement over the 37.6 months observed with osimertinib monotherapy (hazard ratio [HR] = 0.77; P = .02). This represents the longest reported median overall survival in a global phase III study for patients with EGFR-mutated, advanced NSCLC. Authors of the study emphasized that the overall survival benefit was consistent across all predefined subgroups, including those with brain metastases, and no new safety signals were observed with extended follow-up.

This compelling overall survival result confirms osimertinib plus chemotherapy as the new first-line standard of care in EGFR-mutated, advanced, non–small cell lung cancer.

— DAVID PLANCHARD, MD, PhD

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“This compelling overall survival result confirms osimertinib plus chemotherapy as the new first-line standard of care in EGFR-mutated, advanced, non–small cell lung cancer,” said lead study author Dr. Planchard.

As Dr. Planchard explained, EGFR is a pivotal protein in cell growth and division, and activating mutations in the EGFR gene are a well-established driver in a subset of patients with NSCLC. Osimertinib is a recommended first-line treatment of these patients because of its potent activity against common EGFR mutations and its ability to cross the blood-brain barrier.

Despite its efficacy, said Dr. Planchard, a significant proportion of patients eventually experience disease progression. The FLAURA2 study was designed to investigate whether integrating chemotherapy with osimertinib could further improve patient outcomes, particularly after previous reports indicated a statistically significant and clinically meaningful improvement in progression-free survival with the combination.

Study Methods

The FLAURA2 trial was a global, open-label, randomized phase III study that enrolled 557 previously untreated patients with locally advanced or metastatic NSCLC harboring common EGFR mutations (exon 19 deletion or L858R mutation). Patients with stable central nervous system (CNS) metastases were permitted to enroll. Patients were randomly assigned 1:1 to receive either osimertinib (80 mg once daily) plus pemetrexed with investigator’s choice of carboplatin or cisplatin every 3 weeks for up to four cycles, followed by maintenance with osimertinib and pemetrexed, or osimertinib monotherapy (80 mg once daily). Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. The final overall survival analysis was conducted at 57% maturity.

Baseline characteristics were well balanced between the two arms. Approximately 60% of patients in both arms had EGFR exon 19 deletions, and about 40% presented with brain metastases at baseline.

As previously reported in 2023, the primary endpoint of investigator-assessed progression-free-survival was significantly improved with the combination, achieving a median progression-free survival of 25.5 months compared with 16.7 months with osimertinib monotherapy (HR = 0.62). This progression-free survival benefit was consistent across all predefined subgroups, including patients with brain metastases and those with the EGFR L858R mutation.

Final Overall Survival Results

As Dr. Planchard reported, the final overall survival analysis confirmed the benefit of the combination. In addition to the clinically meaningful 9.9-month improvement in overall survival, the 3-year overall survival rate was 63% in the combination arm compared with 51% in the monotherapy arm.

“This overall survival benefit was consistent across all predefined subgroups, including patients with brain metastases and those with the EGFR L858R mutation, reinforcing the broad applicability of the combination,” said Dr. Planchard.

The median duration of osimertinib exposure was notably prolonged in the combination arm, reaching 30.5 months compared with 21.2 months in the monotherapy arm, with pemetrexed maintenance given for a median duration of 8.3 months. According to Dr. Planchard, this suggests that patients on the combination received osimertinib for a substantial period, even after the initial chemotherapy phase.

In terms of subsequent treatments, 69% of patients in the combination arm received a second line of therapy after disease progression, with platinum-based chemotherapy being the most common (44%). In the osimertinib monotherapy arm, 77% received a subsequent line, and 72% received platinum-based chemotherapy. The overall survival benefit with the combination was observed despite the high rate of platinum-based chemotherapy rechallenge in the monotherapy arm.

The safety profile of osimertinib plus chemotherapy remained consistent with previously reported data and was reported to be manageable with extended follow-up (over 2 additional years). No new safety signals were observed, and no new treatment-related deaths occurred with the combination. The adverse events leading to osimertinib discontinuation were slightly higher in the combination arm (12% vs 7%), although they remained low overall. Grade 3 or higher adverse events were more frequent in the combination arm, largely during the induction phase with platinum-based chemotherapy.

“This regimen provides a powerful new option for patients with EGFR-mutated advanced NSCLC, particularly for those with a higher disease burden or brain metastases, where initial intensive therapy may be critical,” Dr. Planchard concluded.

DISCLOSURE: Dr. Planchard has received honoraria from Medscape, Peer CME, and Prime Oncology; served as a consultant or advisor to AbbVie, Anheart Therapeutics, ArriVent Biopharma, AstraZeneca, BeOne Medicines (formerly BeiGene), Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Daiichi Sankyo/Astra Zeneca, Ellipses Pharma, Gilead Sciences, Janssen, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche, Samsung, and Seagen; and has received research funding from AbbVie, ArriVent Biopharma, AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Ellipses Pharma, Janssen, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi/Aventis, Seagen, and Taiho Pharmaceutical.

REFERENCE

1. Planchard D, et al: 2025 World Conference on Lung Cancer. Abstract PL02.04. Presented September 7, 2025.

EXPERT POINT OF VIEW

Invited discussant Daniel S.W. Tan, MBBS, PhD, underscored the significance of the FLAURA2 results, highlighting that the combination of osimertinib and chemotherapy extended median overall survival by nearly 10 months. Dr. Tan is Senior Consultant Medical Oncologist at the Division of Medical Oncology at National Cancer Centre Singapore, Professor at Duke-NUS Medical School, and a Senior Clinician-Scientist at Genome Institute of Singapore.

Daniel S.W. Tan, MBBS, PhD

Dr. Tan contextualized these findings within the broader evolution of EGFR tyrosine kinase inhibitors for non–small cell lung cancer. Despite the advancements through first-, second-, and third-generation agents, he noted, current strategies still exhibit deficiencies, including early disease progression in some patients and a lack of a durable “tail” on survival curves even beyond 5 years.

Dr. Tan attributed the observed overall survival benefit in FLAURA2 to several factors, including the previously reported improved progression-free survival and enhanced central nervous system (CNS) control. In addition, he pointed to a significant increase in complete response rates for patients with evaluable brain metastases in the combination arm. Dr. Tan also emphasized that the overall survival benefit was discernible despite a high rate of subsequent platinum-based chemotherapy use in the osimertinib monotherapy arm (72%), underscoring the combination’s early and sustained impact.

Clinical Decision-Making

According to Dr. Tan, with the advent of the FLAURA2 results, clinicians now face three distinct front-line options: single-agent osimertinib, osimertinib plus chemotherapy, and the combination of the bispecific monoclonal antibody amivantamab-vmjw (which targets EGFR and MET) plus the third-generation EGFR tyrosine kinase inhibitor lazertinib (from the MARIPOSA trial). Dr. Tan posed critical questions for clinical practice: “Is there still a role for a single-agent tyrosine kinase inhibitor? Who should receive combination therapy? When is the best time? Which combination is most appropriate?” Dr. Tan stressed that these decisions necessitate balancing trade-offs related to side-effect profiles, cost, treatment schedules, and financial toxicity.

Dr. Tan emphasized the need for improved risk stratification and biomarker discovery to identify which patient populations would derive the most benefit from each distinct combination strategy. He offered the analogy of building a “GPS-enabled map” for EGFR-mutated lung cancer to facilitate a more tailored, individualized approach to patient care. Ultimately, Dr. Tan advocated for shared decision-making based on individual patient preferences to optimize outcomes and strive toward extending the “tail of the curve” in hopes of achieving cure.

DISCLOSURE: Dr. Tan has received honoraria from Merck, Novartis, Pfizer, Roche, and Takeda; has served as a consultant or advisor to Amgen, AstraZeneca, Bayer, DKSH, Genmab, Merck, Pfizer, PRISM.AI, Regeneron, Roche, and Zymeworks; has received research funding from ACM Biolabs, AstraZeneca, GlaxoSmithKline, Novartis, and Pfizer; and has received travel expenses from Boehringer Ingelheim, Brilliant Pharmaceuticals, Pfizer, and Roche.