Clinical trialPhase 3Lung cancer

Osimertinib in Untreated EGFR -Mutated Advanced Non–Small-Cell Lung Cancer

N Engl J Med · 2018556 patients

Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. N Engl J Med. 2018. 378:113-125

A newer report of this study has been published: Overall Survival with Osimertinib in Untreated, EGFR -Mutated Advanced NSCLC (2020)

Study type: Clinical trial
Study name: FLAURA
Phase: Phase 3
Design: Randomised, double-blind phase 3 trial with 1:1 randomisation
Sample size: 556 patients
Source: N Engl J Med · 2018
Trial registration: NCT02296125

In plain words

In this study, a tablet called osimertinib was compared with the standard targeted drugs (gefitinib or erlotinib) in patients with advanced lung cancer with an EGFR mutation who had not yet had any treatment. Patients who took osimertinib went longer on average without the disease growing (18.9 months versus 10.2 months). Serious side effects were also less common in the osimertinib group (34% versus 45%).

Key results

18.9 months vs 10.2 months

Median progression-free survival

HR for progression or death 0.46 (95% CI 0.37 to 0.57); P<0.001

80% vs 76%

Objective response rate

Odds ratio 1.27 (95% CI 0.85 to 1.90); P=0.24

17.2 months vs 8.5 months

Median duration of response

95% CI 13.8 to 22.0 vs 7.3 to 9.8

83% vs 71%

Survival rate at 18 months

HR for death 0.63 (95% CI 0.45 to 0.88); P=0.007 (not significant at the interim analysis); overall survival data immature (25% maturity)

34% vs 45%

Grade 3 or higher adverse events

Osimertinib vs standard EGFR-TKI

Median 38.6 months vs 31.8 months

Final overall survival (separate FLAURA-OS paper)

HR 0.80 (95.05% CI 0.64 to 1.00); P=0.046 — Ramalingam SS et al., N Engl J Med 2020

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

Primary endpoint: investigator-assessed progression-free survival. Secondary endpoints reported in the abstract included objective response rate, duration of response, overall survival and adverse events.

Safety and side effects

Grade 3 or higher adverse events were less frequent with osimertinib than with standard EGFR-TKIs (34% versus 45%).

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 study showed that osimertinib is superior to standard EGFR-TKIs in first-line treatment of advanced EGFR-mutated NSCLC (exon 19 deletion or L858R) and has fewer serious adverse events. Overall survival data were still immature at the interim analysis. The status of approvals and clinical guideline recommendations should be checked separately.

Limitations

Overall survival data were immature at the interim analysis (25% maturity), and the survival difference was not considered statistically significant at that analysis. The primary endpoint was investigator-assessed. The trial was funded by AstraZeneca.

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.