Results from the Phase III FLAURA trial which provide data for osimertinib use in the 1st-line treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) have been published in the New England Journal of Medicine.1
The trial showed a statistically significant, clinically meaningful progression-free survival (PFS) advantage for osimertinib, a third-generation, irreversible EGFR tyrosine kinase inhibitor (TKI), compared with current 1st-line EGFR-TKIs, erlotinib or gefitinib.
Among the international FLAURA research team was Professor Siow-Ming Lee, from the UCL Cancer Institute and University College London Hospitals, who acted as UK Chief Investigator for the trial. Professor Lee co-leads the Clinical Trials theme for the Cancer Research UK Lung Cancer Centre of Excellence. He said: “This is a practice-changing study, which will now establish Osimertinib as the new standard of care as first line TKI treatment to treat advanced EGFR-mutant NSCLC. We are proud to be associated with this drug as our Centre was also involved in the pilot dose-finding study, co-led by Professor Malcolm Ranson from the Christie Hospital2“
Osimertinib has already been granted approval as a breakthrough therapy by the US FDA.
Dr. Suresh S. Ramalingam, Principal Investigator of the FLAURA trial, from the Winship Cancer Institute of Emory University, Atlanta, USA, said: “The results of the FLAURA trial may herald a shift in how we treat patients with EGFR-mutated NSCLC. The data demonstrate superiority of osimertinib compared to current standard EGFR-TKIs in the 1st-line setting.”
In the Phase III FLAURA trial, osimertinib significantly improved PFS compared to erlotinib or gefitinib in previously untreated patients with locally advanced or metastatic EGFR-mutated (EGFRm) NSCLC.
Median PFS was nearly doubled at 18.9 months for osimertinib compared with 10.2 months for the EGFR-TKI comparator arm (PFS, hazard ratio [HR] 0.46; 95% confidence interval [CI] 0.37-0.57; p<0.001).
Preliminary overall survival (OS) data favoured osimertinib with a 37% reduction in the risk of death (HR 0.63, 95% CI 0.45-0.88; p=0.007 [not significant]) at the interim OS analysis (25% maturity).
The FLAURA safety data for osimertinib were in line with those observed in prior clinical trials. The phase I trial of the drug took place in Manchester, also part of the CRUK Lung Cancer Centre of Excellence.
Osimertinib was well tolerated, with less frequent grade 3 or higher adverse events (AEs) than with standard EGFR-TKIs (34% vs. 45%).
In all patients, the most common AEs were rash or acne (58% [1% Grade ≥3] for osimertinib vs. 78% [7% Grade ≥3] for the comparator arm), diarrhoea (58% [2% Grade ≥3] for osimertinib vs. 57% [2% Grade ≥3] for the comparator arm), and dry skin (36% [<1% Grade ≥3] for osimertinib vs. 36% [1% Grade ≥3] for the comparator arm).
Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: “EGFR-mutated NSCLC patients need new therapies that improve outcomes. The data published in NEJM today further emphasise the potential of osimertinib as a new treatment standard in this patient population.”
Notes for editors
1Paper entitled “Osimertinib in Untreated EGFR-Mutated Advanced Non-small-cell Lung Cancer” J-C Soria et al. New England Journal of Medicine 378(2); 113-125 (2018)
2AZD9291 in EGFR inhibitor-Resistant Non-Small-Cell Lung Cancer PA Janne et al. New England Journal of Medicine 372(18); 1689-1699 (2015)
Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-quarter of all cancer deaths, more than breast, prostate and colorectal cancers combined.2 Approximately 10-15% of patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.3,4,5 These patients are particularly sensitive to treatment with currently available EGFR-TKIs, which block the cell-signaling pathways that drive the growth of tumour cells.6 However, tumours almost always develop resistance to EGFR-TKI treatment leading to disease progression.7 Approximately half of patients develop resistance to approved EGFR-TKIs such as gefitinib and erlotinib due to the resistance mutation, EGFR T790M. Osimertinib also targets this secondary mutation that leads to disease progression.7,8 There is also a need for medicines with improved CNS efficacy, since approximately 25% of patients with EGFR-mutated NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis.9
Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI designed to inhibit both EGFR-sensitising and EGFR T790M-resistance mutations, with clinical activity against CNS metastases.10 Osimertinib 40mg and 80mg once-daily oral tablets have been approved in more than 60 countries, including the US, EU, Japan and China, for patients with EGFR T790M mutation-positive advanced NSCLC. Osimertinib is also being investigated in the adjuvant setting and in combination with other treatments.11,12
The FLAURA trial assessed the efficacy and safety of osimertinib 80mg once daily vs. standard-of-care EGFR-TKIs (either erlotinib [150mg orally, once daily] or gefitinib [250mg orally, once daily]) in previously untreated patients with locally advanced or metastatic EGFR-mutated NSCLC.13 The trial was a double-blinded, randomised study, with 556 patients across 29 countries.13
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