Clinical trialPhase 3Lung cancer

Overall Survival with Osimertinib in Untreated, EGFR -Mutated Advanced NSCLC

N Engl J Med · 2020556 patients

Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, et al. N Engl J Med. 2020. 382:41-50

Study type: Clinical trial
Study name: FLAURA
Phase: Phase 3
Design: Randomised phase 3 trial with 1:1 allocation (final overall survival analysis; overall survival was a secondary endpoint)
Sample size: 556 patients
Source: N Engl J Med · 2020
Trial registration: NCT02296125

In plain words

This study looked at patients with advanced lung cancer with an EGFR mutation who had not yet had any treatment. Patients who took osimertinib lived for a median of about 38.6 months, compared with 31.8 months for patients who took gefitinib or erlotinib. Serious side effects were roughly similar in the two groups (42% versus 47%). The decision about the right treatment should be made with your treating doctor.

Key results

38.6 months vs 31.8 months

Median overall survival

Osimertinib (95% CI 34.5 to 41.8) vs comparator (95% CI 26.6 to 36.0)

0.80

Hazard ratio for death

95.05% CI 0.64 to 1.00; P=0.046

79 of 279 patients (28%) vs 26 of 277 patients (9%)

Still on treatment at 3 years

Osimertinib vs comparator

20.7 months vs 11.5 months

Median duration of treatment exposure

Osimertinib vs comparator

42% vs 47%

Grade 3 or higher adverse events

Osimertinib vs comparator

Drugs in this study:Osimertinib (Tagrisso)

Dose and schedule cards

Osimertinib monotherapy (FLAURA)

Metastatic NSCLC with an EGFR exon 19 deletion or L858R (tissue or plasma sample); first-line. Also the T790M mutation after older-generation inhibitorsCycle length: ContinuousOn the page “Lung cancer” · Advanced NSCLC with an EGFR mutation or ALK rearrangement

Metastatic NSCLC with an EGFR exon 19 deletion or L858R (tissue or plasma sample); first-line. Also the T790M mutation after older-generation inhibitors

Drug	Dose	Route	Schedule
Osimertinib	80 mg	Oral, with or without food (can be dispersed in water)	Once daily, continuous

Cycle length: Continuous
Duration: Until disease progression or intolerable toxicity

Source: FDA label; trial. Monitoring and dose modifications as for the adjuvant osimertinib regimen (ADAURA) (QTc, LVEF in patients with cardiac risk factors, permanent discontinuation for interstitial lung disease, 160 mg with a strong CYP3A4 inducer).

On the page “Lung cancer” · Advanced NSCLC with an EGFR mutation or ALK rearrangement

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Osimertinib

Osimertinib 80 mg orally once daily, continuously (21-day cycles), with gefitinib or erlotinib placebo (double-blind design), for as long as the patient derived clinical benefit and met no discontinuation criterion. Dose reduction under protocol-defined conditions: from 80 to 40 mg once daily. (279 patients)

FDA label notes (Tagrisso): 80 mg once daily with or without food until disease progression or unacceptable toxicity (the tablet can be dispersed in water or given via a nasogastric tube). ILD/pneumonitis: permanently discontinue. QTc above 500 ms on at least 2 ECGs: withhold until QTc is below 481 ms (or back to baseline), then resume at 40 mg; QTc prolongation with signs of life-threatening arrhythmia or symptomatic congestive heart failure: permanently discontinue. Grade 3 or higher adverse event: withhold for up to 3 weeks and, if improved to grade 0 to 2, resume at 80 or 40 mg. ECG and electrolyte monitoring in patients prone to QTc prolongation, and LVEF assessment if cardiac symptoms occur.

2Standard EGFR-TKI (gefitinib or erlotinib)

At the centre's choice: gefitinib 250 mg orally once daily (dose reduction not allowed) or erlotinib 150 mg orally once daily (could be reduced to 100 mg), continuously in 21-day cycles with osimertinib placebo; patients on these two drugs were pooled into one comparator group. After disease progression (RECIST 1.1), open-label osimertinib (crossover) was possible; according to the FDA label, this was for patients whose tumour sample was positive for the T790M mutation. (277 patients)

Source of the regimen details: ClinicalTrials.gov NCT02296125 (arms, 21-day cycle, dose reduction and crossover) and the FDA label for Tagrisso (DailyMed, 2026 version); the full text was not available in PMC

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with locally advanced or metastatic lung adenocarcinoma (not amenable to curative surgery or radiotherapy) with one of the two common EGFR mutations (exon 19 deletion or L858R) confirmed in tissue; no prior systemic therapy for advanced disease and no prior EGFR-TKI (prior adjuvant or neoadjuvant therapy was allowed); WHO performance status 0 to 1; measurable disease per RECIST 1.1. Stable brain metastases that had received definitive treatment, with no need for corticosteroids and stable neurological status for at least 2 weeks, were allowed.

Key exclusion criteria: QTc above 470 ms or risk factors for arrhythmia, history of ILD, drug-induced ILD or radiation pneumonitis requiring steroids, spinal cord compression or unstable brain metastases, use of strong CYP3A4 inducers, and active hepatitis B, hepatitis C or HIV infection.

Endpoints

Overall survival was a secondary endpoint. Progression-free survival results had been reported previously (hazard ratio for disease progression or death: 0.46).

Safety and side effects

Grade 3 or higher adverse events were reported in 42% of patients in the osimertinib group and 47% in the comparator group. The safety profile of osimertinib was similar to that of other EGFR tyrosine kinase inhibitors, despite longer exposure in the osimertinib group (median 20.7 versus 11.5 months).

According to the FDA label (FLAURA data, 279 patients receiving osimertinib; median exposure 16.2 months): interstitial lung disease (ILD) 3.9%, QTcF prolongation above 500 ms 1.1% and keratitis 0.4%; most common serious adverse events: pneumonia 2.9%, ILD/pneumonitis 2.1% and pulmonary embolism 1.8%. Dose reduction occurred in 2.9% and permanent discontinuation because of adverse events in 13% of patients (most common cause: ILD/pneumonitis 3.9%); the most common causes of dose reduction or interruption were QT prolongation (4.3%), diarrhoea (2.5%) and lymphopenia (1.1%).

Clinical significance and place in guidelines

This final analysis showed that osimertinib as first-line treatment in advanced EGFR-mutated NSCLC (exon 19 deletion or L858R) is associated with longer overall survival than gefitinib or erlotinib, in addition to the previously reported progression-free survival benefit. These findings support osimertinib as a first-line option. The status of drug approvals and clinical guideline recommendations should be checked in up-to-date sources.

Limitations

Overall survival was a secondary endpoint of the trial. The upper limit of the confidence interval for the hazard ratio for death (1.00) reached the null value, and the P value was 0.046. The comparator group comprised two drugs (gefitinib and erlotinib) pooled into one group. The trial was funded by AstraZeneca. Other methodological details are available in the full text.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.