UPDATED SEPTEMBER 10, 2017 // MADRID, Spain — Osimertinib (Tagrisso, Astra-Zeneca), a third-generation EGFR tyrosine kinase inhibitor (TKI), provided significant improvement in progression-free survival (PFS) over current standard-of-care (SOC) therapies in advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations in the first-line setting. Compared with SOC, patients receiving osimertinib were at a 54% reduced risk for progression.
The results come from the phase 3 FLAURA (NCT02296125) study presented here at the European Society for Medical Oncology (ESMO) 2017 Congress.
At this time, osimertinib is approved to treat patients with advanced NSCLC with the EGFR T790M mutation who have progressed while receiving prior EGFR tyrosine kinase inhibitor therapies. These new data from FLAURA provide strong support for its use in the first-line setting across other sensitizing EGFR mutations as well.
"The FLAURA data for osimertinib are likely to result in a major paradigm shift in the treatment of patients with EGFR mutation-positive advanced lung cancer," lead author Suresh S. Ramalingam, MD, director of the lung cancer program at Winthrop Cancer Institute, Emory University, Atlanta, Georgia, said in a statement.
"Not only did the trial demonstrate a robust improvement in efficacy with osimertinib when compared to other commonly-used EGFR inhibitors, the side effects profile was also more favorable with osimertinib," he said.
"The progression-free survival benefit for patients with and without brain metastases was almost identical, suggesting that osimertinib is active in the brain as well as in systemic sites. This is important because brain metastasis is a common problem in EGFR mutated patients," he said.
Commenting on the results for ESMO, Enriqueta Felip, MD, PhD, from the Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain, said: "Based on these results, osimertinib should be considered a new first-line treatment option for patients with EGFR mutations."
AstraZeneca said it is in discussions with global health authorities regarding regulatory submissions for osimertinib based on the FLAURA data.
In the FLAURA trial, osimertinib was compared with gefitinib (Iressa, Astra-Zeneca) or erlotinib (Tarceva, Roche/Genentech), both of which are considered SOC, in patients with locally advanced or metastatic NSCNC with sensitizing mutations (exon 19 deletion or L858R mutation) in EGFR (EGFR+).
Patients were required to be treatment-naive and eligible for first-line treatment with an EGFR tyrosine kinase inhibitor. Osimertinib was dosed at 80 mg orally, once daily; gefitinib 250 mg orally, once daily; and erlotinib 150 mg orally, once daily. Patients continued to receive treatment until disease progression.
Patients receiving SOC therapy were allowed to crossover to receive open-label osimertinib on central confirmation of progression and EGFR T790M positivity.
In this global study, 556 patients from Asia, Europe, and North America were randomly assigned to receive osimertinib (n = 279) or SOC (n = 277). Baseline characteristics were balanced across the two groups with respect to patient demographics and disease characteristics. Sixty-two percent of patients in each group were Asians. More than half the patients had exon 19 deletion (57% vs 56% for SOC), and a third had the L858R mutation (35% vs 32% for SOC). The study also included patients with central nervous system (CNS) metastases (19% vs 23% for SOC).
At data cut-off on June 12, 2017, median PFS for patients receiving osimertinib was 18.9 months compared with 10.2 months for patients receiving SOC therapies (P < .0001). Consistent PFS benefits were reported across all subgroups, including Asian/non-Asian patients, patients with or without prior smoking history, patients with exon deletion/EGFR L858 R mutation, and patients with or without CNS metastases at study entry.
For patients with CNS metastases (n = 116), median PFS was 15.2 months vs 9.6 months for patients receiving osimertinib vs SOC, respectively. Correspondingly, for patients without CNS metastases (n = 440), median PFS was 19.1 vs 10.1 months.
Dr Ramalingam also noted that at progression, 6% of patients receiving osimertinib and 15% of patients receiving SOC showed CNS metastases. These data are encouraging for clinical practice and provide evidence for using osimertinib even in patients with brain metastases, he pointed out.
Median survival was not reached for both groups, but patients receiving osimertinib were at a 37% reduced risk for death or progression (P = .0068). "Overall survival data is not yet mature, and there is a clear need to continue follow-up to see if those treated with osimertinib live longer," Dr Felipe said. Although survival data are immature, at 25%, Dr Ramalingam indicated there was a strong and promising survival trend.
Overall response rates were numerically higher for patients receiving osimertinib, at 80% vs 76% for SOC. Median duration of response was almost double for patients receiving osimertinib, at 17.2 months vs 8.5 months for SOC.
With a median duration of treatment of 16.2 months, patients receiving osimertinib were treated longer than patients receiving SOC (median, 11.5 months). Adverse events were reported in approximately 98% of patients in each treatment group. Grade 3/4 adverse events were reported for 34% of patients receiving osimertinib and 45% receiving SOC therapy. Treatment discontinuation rates resulting from adverse events were similar, at 13% for osimertinib and 18% for SOC.
Data from the FLAURA study mirror those reported for treatment-naive cohorts in the AURA study, a phase 1/2 dose ascending study (NCT01802632). In that study, median PFS of 20 months and objective response rate of 77% were reported for patients receiving osimertinib.
Given its safety profile, Dr Ramalingam pointed out that osimertinib lends itself to combination with other therapies and provides a platform on which newer therapies can be built.
FLAURA/Osimertinib: Should the Winner Take It All?
Discussant Tony Mok, MD, Li Shu Fan Professor of Clinical Oncology, Chinese University of Hong Kong, viewed the data on osimertinib in FLAURA with the lens of an expert who had command of the treatment landscape for patients with EGFR mutant advanced NSCLC.
Highlighting the significant difference in PFS between the treatment and SOC groups at 8.7 months, "FLAURA was undoubtedly a positive study, with a similar if not better toxicity profile than SOC" he said. While the preclinical evidence supported its reasons for being a winner, should the winner take it all? Which translates to, should all patients with advanced NSCLC with EGFR-positive mutations receive osimertinib first line?
Dr Mok provided a spirited counterpoint on why this should not be the case by discussing three broad questions.
The first question related to the significance of the CNS data in FLAURA. He pointed out several shortcomings of FLAURA yet conceded that osimertinib was a winner for patients with CNS metastases at baseline. With 19% of patients receiving osimertinib and 23% of patients receiving SOC showing CNS metastases at baseline, FLAURA did not stratify patients according to CNS metastases, Dr Mok noted.
He explained that the PFS data shown for FLAURA were with respect to systemic CNS and not CNS PFS. "With no mandatory CNS imaging, FLAURA did not prospectively evaluate intracranial responses," he said. Yet, according to data from other trials of osimertinib (eg, AURA, AURA2, AURA3), which support CNS activity, he said that "osimertinib is the optimal first-line option for patients with CNS metastases at presentation."
Second, Dr Mok noted that osimertinib was compared with first-generation TKIs in the study. However, with respect to toxicities associated with afatinib and dacomitinib, osimertinib was a winner also with respect to the second-generation TKIs, he acknowledged.
Finally, his most cogent argument against universally using osimertinib first line in all patients with advanced EGFR mutation–positive NSCLC was with respect to overall survival (OS).
Dr Mok provided insights into OS based on whether patients were provided EGFR TKI followed by chemotherapy, EGFR TKI followed by osimertinib, or osimertinib first line.
Examining all the available OS data, he pointed out that osimertinib in FLAURA would have to show a median OS greater that 30 months to make it significant as first-line therapy. At the 25% level of maturity, OS was not significant based on what was projected to be significant at this level of data. Is that enough to consider osimertinib first line for all patients?
"The optimal sequencing for OS remains unclear and is pending OS data from AURA3 and FLAURA," he said. "Should we change practice based on these survival data?" he asked.
With respect to progression following first-line treatment with osimertinib, Dr Mok highlighted data from FLAURA wherein patients receiving SOC were allowed to cross over to osimertinib if they showed the T790M mutation. He pointed out that only 62 of the 213 patients had received osimertinib after progression and 27 received chemotherapy; 64 patients were still receiving SOC therapy.
Dr Mok also highlighted data the AURA treatment-naive cohorts recently published. This study identified resistance mechanisms on progression from osimertinib. Putative resistance mechanisms included amplification of MET, EGFR, and KRAS; mutations in MEK1, KRAS, PIK3CA, and EGFRC797S; and HER2 exon 20 insertion.
Although acquired EGFR T790M — the mutation that osimertinib is approved to treat — was not detected, he explained that not all emerging mutations have targeted agents that patients might use. Moreover, he observed that postdose plasma mutations in RB and TP53 were also reported for some patients. "Early clonal loss of RB and TP53 are associated with transformation to small cell lung cancer," he said.
The discussion struck a cautionary note on providing blanket first-line therapy with osimertinib in all patients with advanced NSCLC who have EGFR-positive mutations.
"Only for love should the winner take it all," Dr Mok concluded.
The study was funded by AstraZeneca. Dr Ramalingam is on the advisory boards of AstraZeneca, Bristol-Myers Squibb, Genentech, and Boehringer Ingelheim. Dr Mok disclosed he received honoraria, fees, and research funding from Astra-Zeneca, Roche/Genentech, Eli Lilly, Bristol-Myers Squibb, Boehringer-Ingelheim, Novartis, Pfizer, Merck Serono, Clovis Oncology, Vertex, SJF, ACEA BioSciences, MSD, geneDecode, Oncogenex, Celgene, Ignyta, Taiho Pharmaceutical Co, and Eisai Co. He holds stock in Sanomics Ltd.
European Society for Medical Oncology (ESMO) 2017 Congress: Abstract LBA2. Presented September 8, 2017.
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