Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Issue 7 (July 2015)

• Record Type: Journal Article
• Authors: Yang, James C-H; Sequist, Lecia V; Geater, Sarayut Lucien; Tsai, Chun-Ming; Mok, Tony Shu Kam; Schuler, Martin; Yamamoto, Nobuyuki; Yu, Chong-Jen; Ou, Sai-Hong I; Zhou, Caicun; Massey, Daniel; Zazulina, Victoria; Wu, Yi-Long
• Is Part Of: Lancet oncology. Volume 16:Issue 7(2015:Jul.)
• Page Start: 830
• Page End: 838
• Publication Date: 2015-07
• Subjects: Oncology -- Periodicals; Neoplasms -- Periodicals; Cancérologie -- Périodiques; Oncologie; Oncology; Periodicals; Electronic journals; 616.994005
• DOI: 10.1016/S1470-2045(15)00026-1
• 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="spara130">Most patients with non-small-cell lung cancer tumours that have <italic>EGFR</italic> mutations have deletion mutations in exon 19 or the Leu858Arg point mutation in exon 21, or both (ie, common mutations). However, a subset of patients (10%) with mutations in <italic>EGFR</italic> have tumours that harbour uncommon mutations. There is a paucity of data regarding the sensitivity of these tumours to EGFR inhibitors. Here we present data for the activity of afatinib in patients with advanced non-small-cell lung cancer that have tumours harbouring uncommon <italic>EGFR</italic> mutations.</p> </sec> <sec> <title id="cestitle30">Methods</title> <p id="spara140">In this post-hoc analysis, we used prospectively collected data from tyrosine kinase inhibitor-naive patients with <italic>EGFR</italic> mutation-positive advanced (stage IIIb–IV) lung adenocarcinomas who were given afatinib in a single group phase 2 trial (LUX-Lung 2), and randomised phase 3 trials (LUX-Lung 3 and LUX-Lung 6). Analyses were done in the intention-to-treat population, including all randomly assigned patients with uncommon <italic>EGFR</italic> mutations. The type of <italic>EGFR</italic> mutation (exon 19 deletion [del19], Leu858Arg point mutation in exon 21, or other) and ethnic origin (LUX-Lung 3 only; Asian <italic>vs</italic> non-Asian) were pre-specified stratification factors in the randomised trials. We categorised all uncommon mutations as: point mutations or duplications in exons 18–21 (group 1); de-novo Thr790Met mutations in exon 20 alone or in combination with other mutations (group 2); or exon 20 insertions (group 3). We also assessed outcomes in patients with the most frequent uncommon mutations, Gly719Xaa, Leu861Gln, and Ser768Ile, alone or in combination with other mutations. Response was established by independent radiological review. These trials 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:NCT00525148" xmlns:xlink="http://www.w3.org/1999/xlink">NCT00525148</ext-link>, <ext-link ext-link-type="unknown" id="interrefs30" 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="interrefs40" 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="spara150">Of 600 patients given afatinib across the three trials, 75 (12%) patients had uncommon <italic>EGFR</italic> mutations (38 in group 1, 14 in group 2, 23 in group 3). 27 (71·1%, 95% CI 54·1–84·6) patients in group 1 had objective responses, as did two (14·3%, 1·8–42·8) in group 2 and two (8·7%, 1·1–28·0) in group 3. Median progression-free survival was 10·7 months (95% CI 5·6–14·7) in group 1, 2·9 months (1·2–8·3) in group 2; and 2·7 months (1·8–4·2) in group 3. Median overall survival was 19·4 months (95% CI 16·4–26·9) in group 1, 14·9 months (8·1–24·9) in group 2, and 9·2 months (4·1–14·2) in group 3. For the most frequent uncommon mutations, 14 (77·8%, 95% CI 52·4–93·6) patients with Gly719Xaa had an objective response, as did nine (56·3%, 29·9–80·2) with Leu861Gln, and eight (100·0%, 63·1–100·0) with Ser768Ile.</p> </sec> <sec> <title id="cestitle50">Interpretation</title> <p id="spara160">Afatinib was active in non-small-cell lung cancer tumours that harboured certain types of uncommon <italic>EGFR</italic> mutations, especially Gly719Xaa, Leu861Gln, and Ser768Ile, but less active in other mutations types. Clinical benefit was lower in patients with de-novo Thr790Met and exon 20 insertion mutations. These data could help inform clinical decisions for patients with non-small-cell lung cancer harbouring uncommon <italic>EGFR</italic> mutations.</p> </sec> <sec> <title id="cestitle60">Funding</title> <p id="spara170">Boehringer Ingelheim.</p> </sec> </abstract>