Elsevier

The Lancet Oncology

Volume 13, Issue 5, May 2012, Pages 528-538
The Lancet Oncology

Articles
Afatinib 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

https://doi.org/10.1016/S1470-2045(12)70087-6Get rights and content

Summary

Background

Afatinib, an irreversible ErbB-family blocker, has shown preclinical activity when tested in EGFR mutant models with mutations that confer resistance to EGFR tyrosine-kinase inhibitors. We aimed to assess its efficacy in patients with advanced lung adenocarcinoma with previous treatment failure on EGFR tyrosine-kinase inhibitors.

Methods

In this phase 2b/3 trial, we enrolled patients with stage IIIB or IV adenocarcinoma and an Eastern Cooperative Oncology Group performance (ECOG) performance score of 0–2 who had received one or two previous chemotherapy regimens and had disease progression after at least 12 weeks of treatment with erlotinib or gefitinib. We used a computer-generated sequence to randomly allocate patients (2:1) to either afatinib (50 mg per day) or placebo; all patients received best supportive care. Randomisation was done in blocks of three and was stratified by sex and baseline ECOG performance status (0–1 vs 2). Investigators, patients, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival (from date of randomisation to death), analysed on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00656136.

Findings

Between May 26, 2008, and Sept 21, 2009, we identified 697 patients, 585 of whom were randomly allocated to treatment (390 to afatinib, 195 to placebo). Median overall survival was 10·8 months (95% CI 10·0–12·0) in the afatinib group and 12·0 months (10·2–14·3) in the placebo group (hazard ratio 1·08, 95% CI 0·86–1·35; p=0·74). Median progression-free survival was longer in the afatinib group (3·3 months, 95% CI 2·79–4·40) than it was in the placebo group (1·1 months, 0·95–1·68; hazard ratio 0·38, 95% CI 0·31–0·48; p<0·0001). No complete responses to treatment were noted; 29 (7%) patients had a partial response in the afatinib group, as did one patient in the placebo group. Subsequent cancer treatment was given to 257 (68%) patients in the afatinib group and 153 (79%) patients in the placebo group. The most common adverse events in the afatinib group were diarrhoea (339 [87%] of 390 patients; 66 [17%] were grade 3) and rash or acne (305 [78%] patients; 56 [14%] were grade 3). These events occurred less often in the placebo group (18 [9%] of 195 patients had diarrhoea; 31 [16%] had rash or acne), all being grade 1 or 2. Drug-related serious adverse events occurred in 39 (10%) patients in the afatinib group and one (<1%) patient in the placebo group. We recorded two possibly treatment-related deaths in the afatinib group.

Interpretation

Although we recorded no benefit in terms of overall survival with afatinib (which might have been affected by cancer treatments given after progression in both groups), our findings for progression-free survival and response to treatment suggest that afatinib could be of some benefit to patients with advanced lung adenocarcinoma who have failed at least 12 weeks of previous EGFR tyrosine-kinase inhibitor treatment.

Funding

Boehringer Ingelheim Inc.

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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