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ESMO 2017: Front-Line Osimertinib Poised to Become Standard of Care in EGFR-Mutation Positive NSCLC

The risk of progression was reduced with osimertinib compared to SoC in patients with advanced NSCLC and EGFR mutations
09 Sep 2017
Lung and other thoracic tumours;  Personalised medicine;  Anticancer agents & Biologic therapy

First-line oral osimertinib significantly prolonged progression-free survival (PFS) compared to the standard of care (SoC) among patients with Ex19del/L858R EGFR mutated advanced non–small cell lung cancer (NSCLC), according to results from the phase III FLAURA study that were reported during ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.

The FLAURA trial, which compared SoC to osimertinib as the initial treatment in patients with EGFR mutated advanced NSCLC met its primary endpoint of improved PFS with osimertinib. The PFS was improved with osimertinib over SoC in patients both with and without central nervous system (CNS) metastasis.

Osimertinib is a third-generation, irreversible, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that was designed to inhibit both EGFR sensitising and EGFR T790M resistance mutations. Although EGFR-TKIs are an effective SoC for patients with NSCLC and EGFR activating mutations, nearly 50 to 60% of patients that are initially responsive to this treatment eventually acquire resistance by developing a T790M mutation. Since osimertinib crosses the blood-brain barrier, it also has the potential to be active against CNS lesions.

Suresh S. Ramalingam, a professor of medical oncology and deputy director of the Winship Cancer Institute of Emory University in Atlanta, Georgia, USA reported results on behalf of an international team from the phase III double-blind, randomised FLAURA (NCT02296125) study that evaluated the efficacy and safety of osimertinib compared to a SoC EGFR-TKI in the first-line in patients with Ex19del/L858R EGFR mutated advanced NSCLC.

The trial enroled adult patients who had not received previous EGFR-TKI/systemic anticancer therapy for advanced disease and included neurologically stable patients with CNS metastases with the caveat that definitive treatment or steroids had been completed for ≥2 weeks. The patients were randomly assigned to oral osimertinib (n=279) at 80 mg once daily orally or SoC EGFR-TKI (n=277) with gefitinib at 250 mg or erlotinib at 150 mg orally per day. Patients had been stratified by mutation status (Ex19del versus L858R) and race (Asian versus non-Asian). Patient characteristics across the osimertinib and SoC arms were well balanced with 57% versus 56% and 35% versus 32% of patients in the respective arms having Ex19del, and L858R mutation.

The primary endpoint was PFS by investigator per RECIST v1.1.

The primary endpoint of progression-free survival was met in FLAURA

As of data cut-off on 12 June 2017, a consistent PFS benefit was demonstrated across all subgroups, including patients having CNS metastasis at study entry.

Median PFS with osimertinib was 18.9 months; 95% confidence interval [CI] 15.2, 21.4) compared to 10.2 months; 95% CI 9.6, 11.1 with SoC, hazard ratio [HR] 0.46; 95% CI 0.37, 0.57 (p < 0.0001). A total of 136 (49%) versus 206 (74%) patients had a PFS event with osimertinib versus SoC, respectively.

Median overall survival (OS) was not reached in either arm and will be calculated at approximately 60% maturity; for the current OS comparison of osimertinib versus SoC, the HR was 0.63; 95% CI 0.45, 0.88 (p = 0.0068) at 21% data maturity.

The objective response rate (ORR) was 80% with osimertinib compared to 76% with SoC; However, the duration of response (DoR) was doubled with osimertinib, where the median DoR was 17.2 (95% CI 13.8, 22.0) versus 8.5 (95% CI 7.3, 9.8) with SoC.

Fewer adverse events occurred with osimertinib

The median total treatment duration was 16.2 (range 0.1, 27.4) months with osimertinib compared to 11.5 (range 0, 26.2) months with SoC.

The incidence of adverse events (AEs) of any cause by investigator was 98% with both osimertinib and SoC. Despite a higher median duration of exposure to osimertinib, grade ≥3 AEs was lower with osimertinib at 34% versus 45% with SoC. The most commonly occurring all causality AEs with osimertinib were diarrhoea in 58% and dry skin in 32% of patients, whereas 57% of patients on SoC had diarrhoea, and 48 had dermatitis acneiform. Grade ≥3 diarrhoea occurred in 2% versus 3% of osimertinib and SoC patients, respectively.

Thirteen percent of osimertinib patients discontinued the trial due to an AE compared to 18% of patients receiving SoC.

During the study 58 (21%) of patients receiving osimertinib and 83 (30%) of patients receiving SoC died.

Osimertinib regulatory agency approvals

The European Medicines Agency (EMA) and US Food and Drug Administration (FDA) granted approval for osimertinib 80 mg once-daily tablets for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC.

EMA approval concerns the treatment of adult patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC. The summary of product characteristics states that it is important that the EGFR T790M mutation status is determined. A validated test should be performed using either tumour DNA derived from a tissue sample or circulating tumour DNA (ctDNA) obtained from a plasma sample.

In March 2017, FDA granted regular approval to osimertinib for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR TKI therapy.


The investigators concluded that osimertinib demonstrated a superior risk/benefit over SoC as first-line therapy in patients with advanced EGFR mutated advanced NSCLC.

These findings support frontline use of osimertinib in all EGFR mutated NSCLC.


The FLAURA trial was sponsored by AstraZeneca.


LBA2_PR - Ramalingam SS, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA.

Last update: 09 Sep 2017

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