Elsevier

The Lancet Oncology

Volume 16, Issue 2, February 2015, Pages 141-151
The Lancet Oncology

Articles
Afatinib 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

https://doi.org/10.1016/S1470-2045(14)71173-8Get rights and content

Summary

Background

We aimed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, randomised, phase 3 trials.

Methods

Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in LUX-Lung 3 (n=345) and LUX-Lung 6 (n=364). These patients were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy (pemetrexed-cisplatin [LUX-Lung 3] or gemcitabine-cisplatin [LUX-Lung 6]), stratified by EGFR mutation (exon 19 deletion [del19], Leu858Arg, or other) and ethnic origin (LUX-Lung 3 only). We planned analyses of mature overall survival data in the intention-to-treat population after 209 (LUX-Lung 3) and 237 (LUX-Lung 6) deaths. These ongoing studies are registered with ClinicalTrials.gov, numbers NCT00949650 and NCT01121393.

Findings

Median follow-up in LUX-Lung 3 was 41 months (IQR 35–44); 213 (62%) of 345 patients had died. Median follow-up in LUX-Lung 6 was 33 months (IQR 31–37); 246 (68%) of 364 patients had died. In LUX-Lung 3, median overall survival was 28·2 months (95% CI 24·6–33·6) in the afatinib group and 28·2 months (20·7–33·2) in the pemetrexed-cisplatin group (HR 0·88, 95% CI 0·66–1·17, p=0·39). In LUX-Lung 6, median overall survival was 23·1 months (95% CI 20·4–27·3) in the afatinib group and 23·5 months (18·0–25·6) in the gemcitabine-cisplatin group (HR 0·93, 95% CI 0·72–1·22, p=0·61). However, in preplanned analyses, overall survival was significantly longer for patients with del19-positive tumours in the afatinib group than in the chemotherapy group in both trials: in LUX-Lung 3, median overall survival was 33·3 months (95% CI 26·8–41·5) in the afatinib group versus 21·1 months (16·3–30·7) in the chemotherapy group (HR 0·54, 95% CI 0·36–0·79, p=0·0015); in LUX-Lung 6, it was 31·4 months (95% CI 24·2–35·3) versus 18·4 months (14·6–25·6), respectively (HR 0·64, 95% CI 0·44–0·94, p=0·023). By contrast, there were no significant differences by treatment group for patients with EGFR Leu858Arg-positive tumours in either trial: in LUX-Lung 3, median overall survival was 27·6 months (19·8–41·7) in the afatinib group versus 40·3 months (24·3–not estimable) in the chemotherapy group (HR 1·30, 95% CI 0·80–2·11, p=0·29); in LUX-Lung 6, it was 19·6 months (95% CI 17·0–22·1) versus 24·3 months (19·0–27·0), respectively (HR 1·22, 95% CI 0·81–1·83, p=0·34). In both trials, the most common afatinib-related grade 3–4 adverse events were rash or acne (37 [16%] of 229 patients in LUX-Lung 3 and 35 [15%] of 239 patients in LUX-Lung 6), diarrhoea (33 [14%] and 13 [5%]), paronychia (26 [11%] in LUX-Lung 3 only), and stomatitis or mucositis (13 [5%] in LUX-Lung 6 only). In LUX-Lung 3, neutropenia (20 [18%] of 111 patients), fatigue (14 [13%]) and leucopenia (nine [8%]) were the most common chemotherapy-related grade 3–4 adverse events, while in LUX-Lung 6, the most common chemotherapy-related grade 3–4 adverse events were neutropenia (30 [27%] of 113 patients), vomiting (22 [19%]), and leucopenia (17 [15%]).

Interpretation

Although afatinib did not improve overall survival in the whole population of either trial, overall survival was improved with the drug for patients with del19 EGFR mutations. The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials.

Funding

Boehringer Ingelheim.

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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