The New England Journal of Medicine NOVEMBER 23, 2023

Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC (FLAURA2)

David Planchard, Pasi A. Jänne, Ying Cheng, et al.

Bottom Line

In patients with previously untreated EGFR-mutated advanced non-small cell lung cancer, the addition of platinum-based chemotherapy to osimertinib significantly improved both progression-free survival and overall survival compared to osimertinib monotherapy.

Key Findings

1. Progression-free survival was significantly improved with the addition of chemotherapy to osimertinib, with a median of 25.5 months compared to 16.7 months for osimertinib alone (hazard ratio 0.62; 95% CI 0.49–0.79; P < 0.001).

2. Final overall survival analysis demonstrated a statistically significant benefit for the combination, with a median overall survival of 47.5 months in the combination arm versus 37.6 months with monotherapy (hazard ratio 0.77; 95% CI 0.61–0.96; P = 0.02).

3. The 36-month survival rate was 63% in the combination arm compared to 51% in the monotherapy arm.

4. The safety profile of the combination was consistent with the known toxicity profiles of the individual treatments; however, grade 3 or higher adverse events were more common in the combination arm, largely driven by expected myelosuppression.

Study Design

Design

RCT

Open-Label

Sample

557

Patients

Duration

Variable (final OS median follow-up ~57% maturity)

Median

Setting

Multicenter, International

Population Patients with previously untreated, EGFR-mutated (exon 19 deletions or L858R mutations) locally advanced or metastatic non-small cell lung cancer.

Intervention Osimertinib (80 mg once daily) plus pemetrexed (500 mg/m2) and either cisplatin (75 mg/m2) or carboplatin (AUC 5) every 3 weeks for four cycles, followed by maintenance pemetrexed.

Comparator Osimertinib monotherapy (80 mg once daily).

Outcome Investigator-assessed progression-free survival.

Study Limitations

• The open-label study design may have introduced investigator bias in the assessment of progression-free survival.

• The combination regimen is associated with higher rates of grade 3 or higher adverse events, which may impact patient quality of life and treatment tolerance.

• While statistically significant, the absolute survival benefit must be weighed against the increased toxicity and logistical burden of administering concurrent chemotherapy.

• The study did not restrict subsequent therapies, which may have influenced the final overall survival outcomes.

Clinical Significance

These results support the use of the combination of osimertinib and platinum-based chemotherapy as a standard-of-care first-line treatment for patients with EGFR-mutated advanced NSCLC, offering a survival advantage over osimertinib monotherapy in this setting.

Historical Context

Osimertinib monotherapy established itself as the standard-of-care first-line treatment for EGFR-mutated NSCLC following the original FLAURA trial. Given the eventual development of resistance to EGFR-TKIs, the FLAURA2 trial was designed to investigate whether upfront combination with chemotherapy could delay resistance and further extend survival.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the mechanism of action of osimertinib distinguish it from first-generation EGFR tyrosine kinase inhibitors (TKIs) like erlotinib, and how does this relate to its efficacy in the FLAURA2 trial?

Key Response

Osimertinib is a third-generation, irreversible EGFR TKI that selectively targets both EGFR-sensitizing mutations and the T790M resistance mutation while sparing wild-type EGFR, leading to a better safety profile. Its superior blood-brain barrier penetration compared to earlier generations makes it an ideal backbone for combination therapies like those tested in FLAURA2, especially for patients with CNS involvement.

Resident

In the context of the FLAURA2 trial results, which specific patient subgroups might derive the most significant clinical benefit from the addition of chemotherapy to osimertinib, and what are the primary toxicity trade-offs?

Key Response

While FLAURA2 showed a broad benefit, patients with central nervous system (CNS) metastases and those with high tumor burden (e.g., L858R mutations which historically underperform compared to Exon 19 deletions) appeared to derive substantial benefit. The trade-off includes significantly higher rates of Grade 3 or higher adverse events, primarily hematologic toxicities (neutropenia, anemia) and gastrointestinal issues associated with platinum-pemetrexed.

Fellow

How do the FLAURA2 findings impact the choice between frontline osimertinib-chemotherapy and the amivantamab-lazertinib combination (MARIPOSA), specifically regarding resistance mechanisms and subsequent line sequencing?

Key Response

Fellows must weigh the PFS benefit of FLAURA2 against the MARIPOSA regimen. FLAURA2 uses a well-understood chemotherapy backbone that might delay the emergence of heterogeneous resistance clones. However, the choice involves anticipating whether resistance will be MET-driven or target-site driven (like C797S), as frontline chemotherapy may change the molecular landscape at the time of progression, potentially complicating the use of subsequent targeted agents.

Attending

As we move toward a 'one-size-fits-most' intensive frontline approach with FLAURA2, how do we justify the increased treatment intensity to a patient who values 'chemo-free' time, and does the OS data support a mandated shift in practice?

Key Response

The attending must balance the statistically significant 8.8-month improvement in PFS with the patient's quality of life. While the OS trend favors the combination, the clinical decision often hinges on whether 'front-loading' chemotherapy improves the tail of the curve or if sequential therapy (chemo at progression) provides equivalent lifetime survival with better early-stage quality of life.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The FLAURA2 trial utilized investigator-assessed PFS as the primary endpoint in an open-label design. To what extent could 'assessment bias' or 'differential censoring' have influenced the hazard ratio, and how do the BICR (Blinded Independent Central Review) sensitivity analyses mitigate these concerns?

Key Response

In open-label trials, investigators may be more likely to maintain patients on the experimental arm or prematurely stop the control arm. PhD-level critique examines the concordance between investigator-assessed PFS and BICR-assessed PFS; in FLAURA2, the BICR results closely mirrored the investigator assessments (HR 0.62), which strongly validates the robustness of the efficacy signal against potential observer bias.

Journal Editor

Does the FLAURA2 trial provide sufficient evidence of a synergistic effect between osimertinib and chemotherapy, or is the observed PFS benefit merely an additive effect of two active agents being used simultaneously?

Key Response

Editors evaluate the scientific contribution of the study. A critical appraisal asks if the combination significantly shifts the bar beyond what would be expected from sequential use. If the PFS1 of the combination is significantly longer than the sum of PFS1 (TKI) + PFS2 (Chemo) in historical cohorts, it suggests a synergistic 'clonogenic extinction' effect that warrants high-impact publication.

Guideline Committee

Given that NCCN guidelines currently list osimertinib as a Category 1 preferred frontline option, should FLAURA2 prompt a distinction in 'Preferred' status based on CNS status or mutation subtype (Exon 19 vs. L858R)?

Key Response

Guideline committees must decide if the combination should be the new universal standard or a niche recommendation. While FLAURA2 is practice-changing, current guidelines (e.g., NCCN) now include the combination as a preferred option but acknowledge the toxicity. The committee must evaluate if the evidence is strong enough to prioritize the combination specifically for patients with L858R or CNS disease, where monotherapy hazard ratios were less impressive in previous trials.

Clinical Landscape

Noteworthy Related Trials

2017

AURA3 Trial

n = 419 · NEJM

Tested

Osimertinib

Population

T790M-positive advanced NSCLC with progression on first-line EGFR-TKI

Comparator

Platinum-based doublet chemotherapy

Endpoint

Progression-free survival

Key result: Osimertinib significantly improved progression-free survival compared to platinum-pemetrexed chemotherapy in patients with T790M-positive disease.

2018

FLAURA Trial

n = 556 · NEJM

Tested

Osimertinib

Population

Untreated EGFR-mutated advanced NSCLC

Comparator

Gefitinib or Erlotinib

Endpoint

Progression-free survival

Key result: Osimertinib demonstrated superior progression-free survival compared to first-generation EGFR tyrosine kinase inhibitors.

2019

NEJ009 Trial

n = 345 · Lancet Oncol

Tested

Gefitinib plus chemotherapy

Population

Untreated EGFR-mutated advanced NSCLC

Comparator

Gefitinib monotherapy

Endpoint

Progression-free survival and overall survival

Key result: The addition of chemotherapy to gefitinib resulted in significantly longer progression-free and overall survival than gefitinib alone.

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