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. Issue 2 (February 2015)

• Record Type: Journal Article
• Authors: Yang, James Chih-Hsin; Wu, Yi-Long; Schuler, Martin; Sebastian, Martin; Popat, Sanjay; Yamamoto, Nobuyuki; Zhou, Caicun; Hu, Cheng-Ping; O'Byrne, Kenneth; Feng, Jifeng; Lu, Shun; Huang, Yunchao; Geater, Sarayut L; Lee, Kye Young; Tsai, Chun-Ming; Gorbunova, Vera; Hirsh, Vera; Bennouna, Jaafar; Orlov, Sergey; Mok, Tony; Boyer, Michael; Su, Wu-Chou; Lee, Ki Hyeong; Kato, Terufumi; Massey, Dan; Shahidi, Mehdi; Zazulina, Victoria; Sequist, Lecia V
• Is Part Of: Lancet oncology. Volume 16:Issue 2(2015:Feb.)
• Page Start: 141
• Page End: 151
• Publication Date: 2015-02
• Subjects: Oncology -- Periodicals; Neoplasms -- Periodicals; Cancérologie -- Périodiques; Oncologie; Oncology; Periodicals; Electronic journals; 616.994005
• DOI: 10.1016/S1470-2045(14)71173-8
• Languages: English
• ISSNs: 1470-2045

Abstract

<abstract abstract-type="author" id="ceab10"> <title id="cestitle10">Summary</title> <sec> <title id="cestitle20">Background</title> <p id="spara140">We aimed to assess the effect of afatinib on overall survival of patients with <italic>EGFR</italic> mutation-positive lung adenocarcinoma through an analysis of data from two open-label, randomised, phase 3 trials.</p> </sec> <sec> <title id="cestitle30">Methods</title> <p id="spara150">Previously untreated patients with <italic>EGFR</italic> 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 <italic>EGFR</italic> 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 <ext-link ext-link-type="unknown" id="interrefs10" xlink:type="simple" xlink:href="http://ClinicalTrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">ClinicalTrials.gov</ext-link>, numbers <ext-link ext-link-type="unknown" id="interrefs20" xlink:type="simple" xlink:href="ctgov:NCT00949650" xmlns:xlink="http://www.w3.org/1999/xlink">NCT00949650</ext-link> and <ext-link ext-link-type="unknown" id="interrefs30" xlink:type="simple" xlink:href="ctgov:NCT01121393" xmlns:xlink="http://www.w3.org/1999/xlink">NCT01121393</ext-link>.</p> </sec> <sec> <title id="cestitle40">Findings</title> <p id="spara160">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 <italic>EGFR</italic> 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%]).</p> </sec> <sec> <title id="cestitle50">Interpretation</title> <p id="spara170">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 <italic>EGFR</italic> mutations. The absence of an effect in patients with Leu858Arg <italic>EGFR</italic> mutations suggests that <italic>EGFR</italic> del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials.</p> </sec> <sec> <title id="cestitle60">Funding</title> <p id="spara180">Boehringer Ingelheim.</p> </sec> </abstract>