MADRID – The EGFR inhibitor osimertinib (Tagrisso) is being hailed as a new standard of care for first-line therapy of advanced, treatment naïve non-small cell lung cancer (NSCLC) with mutations in the epidermal growth factor receptor (EGFR).
Osimertinib cut the risk of disease progression in these patients by 54% compared gefitinib (Iressa) or erlotinib (Tarceva).
Among 279 patients with EGFR-mutated locally advanced or metastatic NSCLC treated with osemirtinib, the median progression-free survival (PFS) was 18.9 months, compared with 10.2 months for 277 patients treated with the standard of care, which translates into a hazard ratio (HR) of 0.46 (P less than .0001).
“We wanted to see if by shutting down a major escape pathway by giving osemirtinib upfront, whether we would be able to improve patient outcomes,” he said at a briefing at the European Society of Medical Oncology (ESMO) Congress.
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) selective for EGFR mutations, including the T790M resistance mutation. It is currently approved in the US for the treatment of patients with EGFR T790M mutation-positive NSCLC whose disease has progressed on or after EGFR TKI therapy.
In the(NCT02296125) investigators stratified patients with previously untreated NSCLC positive for EGFR resistance mutations according to mutation status (exon 19 deletion or the L858R amino acid substitution in exon 21) and race (Asian or non-Asian).
Patients were randomly assigned to treatment with either oral osimertinib 80 mg daily or an EGFR TKI, either oral gefitinib 250 mg or erlotinib 150 mg daily.
The patients were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) every 6 weeks until objective disease progression.
Patients assigned to the standard-of-care arm who had central confirmation of progression and T790M positivity were allowed to cross over to open-label osimertinib.
PFS, the primary endpoint, was also significantly better with osimertinib than with either of the comparator TKIs in patients with and without central nervous system metastases at study entry (HR 0.47, P = .0009 for patients with CNS metastases, HR 0.46, P less than .0001 for patients with no CNS metastases).
For this interim analysis, with OS data at only 25% maturity, median OS had not been reached in either trial arm. The HR for OS with osimertinib was 0.63, with a P value of .0068, but this was not statistically significant, as the statistical method used required a P of less than .0015 for significance, Dr. Ramalingam explained.
The safety profile of osimertinib was comparable to that of the standard of care, with lower rates of grade 3 or greater adverse events, and a lower discontinuation rate, than with either gefitinib or erlotinib.
, the invited commentator at the briefing, said that “based on these results, osimertinib should be considered a new first-line treatment option for patients with EGFR mutations.”
Tony Mok, MD, from the Chinese University of Hong Kong, the invited discussant at the presidential symposium where Dr. Ramalingam presented the study, commented that “there is little doubt that FLAURA is a positive study demonstrating superiority in PFS with first-line osimertinib.”
He questioned, however whether all patients with EGFR mutation-positve NSCLC should receive osimertinib up front.
“I have confidence that patients with CNS metastases at presentation would benefit the most considering osimertinib’s higher CNS penetration, but the optimal sequence for overall survival benefit is controversial,” he said.
Dr. Mok said that he was reserving judgment about elevating osimertinib to standard-of-care status until there were more answers about the final number of patients who are able to crossover to osimertinib, and about the “mechanism and management of osimertinib resistance upon disease progression.”
The study was funded by AstraZeneca, the maker of osimertinib. Dr Ramalingam is on the advisory boards of AstraZeneca and other companies. Dr Mok disclosed honoraria, fees, and research funding from Astra-Zeneca. Dr. Felip disclosed financial relationships with multiple companies not including AstraZeneca.