ArticlesAfatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial
Introduction
Of patients diagnosed with advanced lung adenocarcinoma, those with activating EGFR mutations treated with first-line erlotinib or gefitinib generally have a high objective response rate (complete or partial response) and long progression-free survival and overall survival.1, 2, 3 Nonetheless, all patients' treatment eventually fails. Like other cancers driven by mutant kinases, such as chronic myeloid leukaemia and gastrointestinal stromal tumours, acquired resistance to EGFR tyrosine-kinase inhibitors (TKIs) is most commonly characterised by the so-called gatekeeper mutation, T790M.1, 2, 3
Afatinib (previously called BIBW2992; Boehringer-Ingelheim Pharma GmbH, Ingelheim, Germany)4, 5 is an irreversible ErbB-family blocker, the preclinical in-vitro and in-vivo activity profile of which includes EGFR mutant models with activating EGFR mutations, including the most common mutations, L858R and deletion-19, and the exon 20 gatekeeper T790M mutations, albeit at lower potency.4, 6 Thus, we undertook this phase 2b/3 study of afatinib in patients with lung adenocarcinoma who had received at least one platinum-based chemotherapy regimen, and at least 12 weeks of previous erlotinib or gefitinib treatment, a group for whom few, if any, approved treatment options are available and who we reasoned could potentially benefit from treatment that targets EGFR mutations known to be less sensitive to erlotinib and gefitinib. Patients did not need to have been tested for EGFR mutation status to enter the study, because repeat biopsy was not deemed feasible in this large, international study, and to obtain archival tumour tissue for all patients would be challenging. Instead, the requirement for at least 12 weeks of previous EGFR-TKI treatment served as an enrichment strategy for patients with EGFR mutations and acquired resistance.
Section snippets
Study design and patients
LUX-Lung 1 was a randomised, double-blind, multicentre, phase 2b/3 trial comparing afatinib plus best supportive care with placebo plus best supportive care, done in 86 centres in 15 countries (from three continents: Asia [China, Hong Kong, Korea, Singapore, Taiwan, Thailand], Europe [Belgium, Germany, France, Italy, The Netherlands, UK, Spain], and North America [Canada, USA]). Eligible patients had pathologically confirmed stage IIIB (with pleural effusion) or stage IV adenocarcinoma with
Results
Between May 26, 2008, and Sept 21, 2009, we randomly allocated 585 patients to receive either afatinib plus best supportive care (390 patients) or placebo plus best supportive care (195 patients; figure 1). A summary of best supportive care in this trial is shown in the appendix. Baseline characteristics were much the same between the two groups (table 1). Most patients (361 [62%] of 585) were from Asian countries and around two-thirds (387 of 585) were Asian by ethnic origin. Most patients
Discussion
The lack of effective therapies in patients with EGFR-positive NSCLC after the development of acquired resistance to erlotinib or gefitinib is a major clinical problem.20, 21 This study, in the third-line and fourth-line setting, failed to show a difference between groups in its primary endpoint, overall survival, although our progression-free survival findings were promising (panel). Afatinib had a clear biological effect, with confirmed partial responses seen in about 7–11% of patients and
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