ArticlesAfatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials
Introduction
Patients with lung adenocarcinoma harbouring EGFR mutations are highly responsive to treatment with EGFR tyrosine kinase inhibitors such as gefitinib, erlotinib, or afatinib.1 Findings from seven randomised phase 3 studies done in this genetically selected subset of patients with lung cancer have shown better progression-free survival and responses with gefitinib or erlotinib than with platinum-based chemotherapy.2, 3, 4, 5, 6, 7, 8 However, differences in overall survival were not reported in these studies, irrespective of EGFR mutation type,8, 9, 10, 11, 12, 13, 14, 15 presumably because most patients randomly assigned to first-line chemotherapy were subsequently treated with EGFR tyrosine kinase inhibitors. Findings from a meta-analysis of 13 randomised studies examining first-line gefitinib or erlotinib (monotherapy or combined with chemotherapy) compared with chemotherapy or placebo in patients with EGFR mutation-positive lung cancer showed that overall survival did not differ (hazard ratio [HR] 1·01, 95% CI 0·87–1·18) despite the large progression-free survival advantage among patients receiving EGFR tyrosine kinase inhibitors (HR 0·43, 95% CI 0·38–0·49, p<0·001).16
Afatinib, a second-generation irreversible tyrosine kinase inhibitor that inhibits signalling from all homodimers and heterodimers formed by ERBB receptor family members (including EGFR, HER2, ERBB3, and ERBB4), has shown clinical activity in patients with EGFR mutation-positive lung adenocarcinoma previously untreated with EGFR tyrosine kinase inhibitors.17, 18, 19 First-line afatinib was compared with standard chemotherapy in two large, randomised phase 3 trials in previously untreated patients with EGFR mutation-positive advanced lung adenocarcinoma.18, 19 These two studies, designed to meet the regulatory requirements of different regions, were nearly identical in design with the exception of the platinum-based comparator regimen: pemetrexed-cisplatin was used in LUX-Lung 3, and gemcitabine-cisplatin in LUX-Lung 6. Findings from both studies showed improved progression-free survival (the primary endpoint), objective responses, and patient-reported outcomes for patients receiving first-line afatinib.18, 19, 20 These studies also demonstrated differences in progression-free survival with afatinib on the basis of EGFR mutation type; progression-free survival was most improved in patients with tumours harbouring exon 19 deletion (del19) followed by the exon 21 substitution (Leu858Arg) mutation.18, 19
Here, we report mature overall survival results from the individual LUX-Lung 3 and LUX-Lung 6 studies. Additionally, to provide more accurate estimates of the overall effect of afatinib treatment in these patients (particularly in prespecified subgroups), we combined individual patient data from the two studies for an exploratory analysis of overall survival.
Section snippets
Study design and participants
Detailed study designs, inclusion and exclusion criteria, and methods of the primary analyses of both trials have been previously published.18, 19 In brief, each trial was a randomised, open-label, phase 3 study done either globally18 or in China, South Korea, and Thailand.19 Eligible patients were aged 18 years or older, had previously untreated stage IIIB or IV lung adenocarcinoma (measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1), an Eastern
Results
In LUX-Lung 3, 1269 patients were screened between Aug 17, 2009, and Feb 28, 2011, and 345 patients were randomly assigned to study treatment (figure 1). Of these patients, 340 received at least one dose of study medication. In LUX-Lung 6, 910 patients were screened between April 27, 2010, and Nov 16, 2011, and 364 patients were randomly assigned to study treatment (figure 1). Of these patients, 352 received at least one dose of study medication. Reasons for patient ineligibility for
Discussion
Findings from randomised studies comparing first-line EGFR tyrosine kinase inhibitors with standard chemotherapies suggest that patients with lung adenocarcinoma harbouring EGFR mutations have improved responses, progression-free survival, and quality of life, although no improvements in overall survival have been reported (panel).2, 3, 4, 5, 6, 7, 8, 18, 19 To our knowledge, our analysis of these two independent phase 3 studies shows for the first time that first-line afatinib significantly
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