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
Journal
The Lancet Oncology
Journal Volume
16
Journal Issue
2
Pages
141-151
Date Issued
2015
Author(s)
Wu Y.-L
Schuler M
Sebastian M
Popat S
Yamamoto N
Zhou C
Hu C.-P
O'Byrne K
Feng J
Lu S
Huang Y
Geater S.L
Lee K.Y
Tsai C.-M
Gorbunova V
Hirsh V
Bennouna J
Orlov S
Mok T
Boyer M
Su W.-C
Lee K.H
Kato T
Massey D
Shahidi M
Zazulina V
Sequist L.V.
Abstract
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. ? 2015 Elsevier Ltd.
SDGs
Other Subjects
afatinib; cisplatin; epidermal growth factor receptor; gemcitabine; pemetrexed; afatinib; antineoplastic agent; cisplatin; deoxycytidine; EGFR protein, human; epidermal growth factor receptor; gemcitabine; glutamic acid derivative; guanine; pemetrexed; quinazoline derivative; acne; adult; aged; Article; cancer combination chemotherapy; cancer control; cancer staging; cancer survival; computer assisted tomography; controlled study; diarrhea; drug dose increase; drug dose reduction; drug effect; drug response; drug safety; drug withdrawal; EGFR gene; ethnic group; fatigue; female; gene mutation; human; leukopenia; lung adenocarcinoma; major clinical study; male; mucosa inflammation; multiple cycle treatment; neutropenia; nuclear magnetic resonance imaging; overall survival; paronychia; phase 3 clinical trial (topic); progression free survival; randomized controlled trial; randomized controlled trial (topic); rash; stomatitis; vomiting; adenocarcinoma; analogs and derivatives; antagonists and inhibitors; clinical trial; comparative study; follow up; genetics; Lung Neoplasms; middle aged; mortality; mutation; pathology; phase 3 clinical trial; prognosis; survival rate; very elderly; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Deoxycytidine; Female; Follow-Up Studies; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasm Staging; Prognosis; Quinazolines; Receptor, Epidermal Growth Factor; Survival Rate
Publisher
Lancet Publishing Group
Type
journal article