Early Use of Osimertinib with Chemotherapy Significantly Boosts Survival in Advanced NSCLC with EGFR Mutations

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Osimertinib Plus Chemo Improves Survival in Advanced EGFR-Mutated Lung Cancer

Osimertinib (Tagrisso) combined with chemotherapy led to a statistically significant and clinically meaningful overall survival (OS) improvement compared to single-agent osimertinib in patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC), according to data from the phase 3 FLAURA2 trial (NCT04035486) presented at the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer.

At a median follow-up of 51.2 months, the median OS was 47.5 months (95% CI, 41.0-not calculable) with osimertinib plus chemotherapy, versus 37.6 months (95% CI, 33.2-43.2) with osimertinib alone. This translates to a 23% reduction in the risk of death (HR, 0.77; 95% CI, 0.61-0.96; P = .02). The 24-, 36-, and 48-month OS rates were 80%, 63%, and 49%, respectively, in the combination arm, compared to 72%, 51%, and 41% in the monotherapy arm. 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,” said 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.

What Did the FLAURA2 Study Examine?

The phase 3 study enrolled treatment-naive patients with locally advanced or metastatic EGFR-mutated NSCLC, aged 18 years or older, with pathologically confirmed nonsquamous disease and an EGFR exon 19 deletion or L858R mutation. Patients had 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 performed at baseline.

A total of 557 patients were randomized 1:1 to receive either:

Osimertinib 80 mg daily plus pemetrexed 500 mg/m² and carboplatin or cisplatin every 3 weeks for 4 cycles,followed by maintenance osimertinib 80 mg daily.
Osimertinib 80 mg daily alone.

Treatment continued at the investigator’s discretion. Patients were stratified by race (asian vs non-Asian), EGFR mutation status, and WHO performance status.

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Keywords: NSCLC, EGFR, Osimertinib, Chemotherapy, Lung Cancer, FLAURA2, Overall Survival, Cancer Treatment

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Further Resources:

* International Association for the Study of Lung Cancer

Disclaimer: This article provides general data and should not be considered medical advice. Consult with a healthcare professional for personalized guidance.

What specific EGFR mutations does osimertinib target, beyond the initial mutations addressed by first-generation TKIs?

early Use of Osimertinib with chemotherapy Considerably Boosts Survival in Advanced NSCLC with EGFR Mutations

Understanding EGFR-Mutated NSCLC

Non-small cell lung cancer (NSCLC) is the moast common type of lung cancer, and epidermal growth factor receptor (EGFR) mutations are present in approximately 10-15% of NSCLC patients, notably those of east Asian descent. These mutations drive cancer growth, making EGFR a crucial target for therapy. Historically, first-line treatment involved EGFR tyrosine kinase inhibitors (TKIs) like erlotinib, gefitinib, or afatinib. Though, resistance inevitably develops, frequently enough due to the T790M mutation.Osimertinib, a third-generation EGFR TKI, specifically targets both common EGFR mutations and the T790M resistance mutation.

The FLAURA trial: A Landmark Study

The FLAURA (Fluorouracil, Leucovorin, and Osimertinib) trial, published in the New England Journal of Medicine in 2018, fundamentally changed the treatment paradigm for EGFR-mutated NSCLC. This Phase III randomized controlled trial compared first-line osimertinib to standard-of-care EGFR TKIs (gefitinib or erlotinib) in patients with treatment-naive, metastatic NSCLC harboring EGFR exon 19 deletions or the L858R mutation.

Key findings from FLAURA included:

Progression-Free Survival (PFS): Osimertinib demonstrated a statistically significant and clinically meaningful improvement in PFS, with a median PFS of 18.9 months compared to 10.1 months with gefitinib or erlotinib.

overall Survival (OS): Updated OS data, presented at major oncology conferences, showed a significant OS benefit with osimertinib. The median OS was 38.8 months with osimertinib versus 31.8 months with earlier-generation TKIs – a considerable improvement.

Central Nervous System (CNS) Metastases: Osimertinib exhibited superior CNS penetration, leading to a 54% reduction in the risk of CNS progression or death. This is particularly important as brain metastases are common in EGFR-mutated NSCLC.

Objective Response Rate (ORR): The ORR was higher with osimertinib (76%) compared to gefitinib/erlotinib (66%).

Integrating Chemotherapy: Recent Advances & the ADAURA Trial

While osimertinib alone showed remarkable efficacy, recent research has explored the potential benefits of combining it with chemotherapy. The ADAURA trial (Osimertinib plus Chemotherapy in EGFR-Mutated NSCLC) investigated the addition of platinum-based chemotherapy to first-line osimertinib in patients with advanced or metastatic EGFR-mutated NSCLC.

ADAURA’s key results demonstrate:

Enhanced PFS: Adding chemotherapy to osimertinib resulted in a median PFS of 25.8 months, a significant improvement over osimertinib alone (19.4 months).

Improved OS (Interim Analysis): An interim analysis of overall survival showed a trend towards improved OS with the osimertinib-chemotherapy combination, even though the results are still maturing.

Higher response Rates: The combination therapy achieved a higher objective response rate compared to osimertinib monotherapy.

Patient Selection & Biomarker Analysis

Identifying patients most likely to benefit from osimertinib, with or without chemotherapy, is crucial.

EGFR Mutation Testing: Thorough EGFR mutation testing is essential for all patients diagnosed with advanced NSCLC. This includes identifying exon 19 deletions, the L858R mutation, and less common mutations.

Liquid Biopsy: Liquid biopsies (ctDNA analysis) can detect EGFR mutations and monitor for the emergence of resistance mutations, like T790M, in a non-invasive manner.

PD-L1 Expression: While PD-L1 expression doesn’t directly dictate osimertinib eligibility, it can influence subsequent treatment decisions if resistance develops.

Performance Status: A patient’s overall health and performance status are important considerations when determining the suitability of chemotherapy.

Managing Side Effects: Osimertinib & Chemotherapy

Osimertinib is generally well-tolerated, but common side effects include:

Diarrhea

Rash

Fatigue

Nail toxicity

When combined with chemotherapy, the side effect profile is more complex and may include:

Neutropenia (low white blood cell count)

Anemia (low red blood cell count)

Peripheral neuropathy

Nausea and vomiting

Proactive management of side effects, including dose modifications and supportive care, is essential to optimize treatment outcomes.

Real-World Implications & Future Directions

The data from FLAURA and ADAURA have led to significant changes in clinical practice. National Comprehensive Cancer Network (NCCN) guidelines now recommend osimertinib as the preferred first-line treatment for patients with advanced NSCLC harboring EGFR exon 19 deletions or the L858R mutation. The addition of chemotherapy is increasingly being considered, particularly for patients with a high tumor burden or aggressive disease.

Ongoing research is focused on:

Identifying biomarkers to predict response to osimertinib-chemotherapy combinations.

* developing