AstraZeneca’s Press Release: FLAURA2 trials results- Osimertinib Plus Chemotherapy Improves NSCLC Survival

The FLAURA2 Phase III trial is a global, randomized, open-label study designed to evaluate whether the addition of platinum-based chemotherapy (platinum + pemetrexed) to osimertinib (Tagrisso) can improve clinical outcomes for patients with previously untreated, EGFR-mutated advanced non-small cell lung cancer (NSCLC). This trial builds upon the findings of the original FLAURA study, which established osimertinib as the standard first-line therapy for this patient population.

In its July 2025 press release, AstraZeneca announced the final overall survival (OS) results from the global Phase III FLAURA2 trial. The data show that adding platinum–pemetrexed chemotherapy to frontline osimertinib (Tagrisso) in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC) led to a statistically significant and clinically meaningful improvement in OS compared to osimertinib alone. This builds on earlier interim findings and confirms the combination as a potent first-line regimen.

What drug is Osimertinib?

Osimertinib is a third-generation, irreversible EGFR tyrosine kinase inhibitor specifically engineered to target both activating EGFR mutations (exon 19 deletions and L858R) and the EGFR T790M resistance mutation, which commonly emerges after treatment with first- and second-generation EGFR TKIs. Its mechanism of action centers on covalent binding to the cysteine 797 (C797) residue in the ATP-binding pocket of the EGFR kinase domain. This irreversible interaction leads to sustained inhibition of EGFR signaling, which suppresses downstream pathways such as PI3K/AKT/mTOR and RAS/RAF/MEK/ERK, ultimately resulting in reduced cell proliferation and increased apoptosis in tumor cells harboring mutant EGFR.

Crucially, osimertinib demonstrates ~200-fold selectivity for mutant EGFR over wild-type EGFR, which minimizes off-target effects seen with earlier TKIs. Additionally, its lipophilic structure and low affinity for P-glycoprotein (ABCB1) and BCRP (ABCG2) allow for effective blood–brain barrier penetration, making it highly active against brain metastases and leptomeningeal disease. This unique combination of irreversible mutant-selective binding, broad downstream pathway blockade, and CNS activity defines osimertinib’s therapeutic potency in EGFR-mutated NSCLC.

FLAURA2 Trial

FLAURA2 (NCT04035486) was designed as a global, open-label, multicenter Phase III trial conducted across 151 sites in 21 countries. The study enrolled treatment-naïve patients (aged ≥18 years, ≥20 in Japan) with stage IIIB–IV NSCLC harboring exon 19 deletion or L858R mutation. Both asymptomatic and controlled (stable or treated) CNS metastases were allowed. Eligible participants had ECOG performance status of 0–1. Patients were randomized 1:1 to receive:

• Osimertinib monotherapy: 80 mg orally once daily
• Osimertinib + Chemotherapy: 80 mg osimertinib daily plus four cycles of pemetrexed (500 mg/m²) and platinum (cisplatin or carboplatin AUC 5), followed by maintenance osimertinib and pemetrexed every three weeks.

Primary endpoint: investigator-assessed PFS. Secondary endpoints: OS, objective response rate (ORR), duration of response, safety, and CNS outcomes

Study Design and Methods

A total of 557 patients were randomized evenly between the two arms. Baseline characteristics were well-balanced: median age ~63 years, nearly equal gender distribution, with approximately two-thirds of participants being Asian. CNS involvement at baseline was present and included in stratification. The open-label design aimed to mimic real-world clinical practice. Data were analyzed for investigator-assessed PFS primarily, with blinded independent central review to confirm findings. OS and OS trends were examined in follow-up analyses

Results

The efficacy and safety outcomes of the FLAURA2 trial demonstrated meaningful differences between the two treatment arms. Below are the primary and secondary endpoint findings, including progression-free survival, response rates, and emerging overall survival data.

Initial Findings (2023–2024)

• Osimertinib + Chemo: Median PFS of 25.5 months.
• Osimertinib alone: Median PFS of 16.7 months.
• Hazard Ratio (HR): 0.62 (95% Confidence Interval [CI] 0.49–0.79; P < 0.001)
• At 24 months, 57% (95% CI 50–63) in the combination arm remained progression-free compared to 41% (95% CI 35–47) in the monotherapy arm.
• Blinded independent central review corroborated the PFS HR of 0.62 (95% CI 0.48–0.80).

Objective Response Rate (ORR) and Duration

• ORR: 83% with osimertinib + chemo vs. 76% with osimertinib alone.
• Median duration of response: 24.0 months (95% CI 20.9–27.8) with combination vs. 15.3 months (95% CI 12.7–19.4) without

Overall Survival (OS)

• OS data were immature for mature survival outcomes at the time of the primary NEJM report.

Interim data released later hinted at an OS trend favoring the combination arm (HR ~0.75 at ~41% maturity). Final OS results in July 2025 confirmed statistically significant survival improvement.

Key Findings ( 2023-2024)

• Substantial PFS advantage: Osimertinib + Chemo extended disease control by nearly 9 months (HR 0.62; P < 0.001).
• Superior durability of response: Improved ORR and prolonged duration of response compared to monotherapy.
• Promising OS trajectory: Interim data indicated HR ~0.75; later confirmed benefit suggests long-term survival advantage.
• CNS activity: Both arms effectively managed intracranial disease; subgroup analyses supported benefits of combination therapy in patients with baseline brain metastases.
• Acceptable safety: Despite more severe AEs, the profile was predictable and clinically manageable, supporting feasibility of the combination in routine practice

By March 2024, updated OS data showed a favorable trend:

• OS hazard ratio: 0.75 (95% CI: 0.57–0.97), suggesting a 25% reduction in risk of death, though this result had not yet met the threshold for statistical significance.

Final Overall Survival Results (July 2025)

AstraZeneca announced in July 2025 that the final analysis of FLAURA2 showed a statistically significant and clinically meaningful improvement in overall survival with the osimertinib + chemotherapy combination, confirming the earlier trend:
This establishes the combination as an effective first-line treatment strategy in EGFR-mutant NSCLC.

Safety and Tolerability

While the addition of chemotherapy increased expected side effects—such as hematologic toxicity and gastrointestinal events—the overall safety profile was manageable. No new safety signals were identified.

The final analysis of the FLAURA2 Phase III trial confirms that first-line osimertinib combined with platinum–pemetrexed chemotherapy provides a statistically significant and clinically meaningful improvement in overall survival for patients with advanced EGFR-mutated NSCLC compared to osimertinib alone.

You can read the full article here.

Written by Sona Karamyan, MD