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
Journal
The Lancet Oncology
Journal Volume
16
Journal Issue
7
Pages
830-838
Date Issued
2015
Author(s)
Sequist L.V.
Geater S.L.
Tsai C.-M.
Mok T.S.K.
Schuler M.
Yamamoto N.
Ou S.H.I.
Zhou C.
Massey D.
Zazulina V.
Wu Y.-L.
Abstract
Background: Most patients with non-small-cell lung cancer tumours that have EGFR 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 EGFR 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 EGFR mutations. Methods: In this post-hoc analysis, we used prospectively collected data from tyrosine kinase inhibitor-naive patients with EGFR 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 EGFR mutations. The type of EGFR mutation (exon 19 deletion [del19], Leu858Arg point mutation in exon 21, or other) and ethnic origin (LUX-Lung 3 only; Asian vs 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 ClinicalTrials.gov, numbers NCT00525148, NCT00949650, and NCT01121393. Findings: Of 600 patients given afatinib across the three trials, 75 (12%) patients had uncommon EGFR 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. Interpretation: Afatinib was active in non-small-cell lung cancer tumours that harboured certain types of uncommon EGFR 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 EGFR mutations. Funding: Boehringer Ingelheim. ? 2015 Elsevier Ltd.
SDGs
Other Subjects
afatinib; cisplatin; epidermal growth factor receptor; gemcitabine; pemetrexed; afatinib; quinazoline derivative; advanced cancer; Article; cancer chemotherapy; dose response; drug dose reduction; ethnic group; exon; gene mutation; human; lung adenocarcinoma; multiple cycle treatment; non small cell lung cancer; overall survival; pharmacogenetics; phase 2 clinical trial (topic); phase 3 clinical trial (topic); point mutation; post hoc analysis; priority journal; progression free survival; randomized controlled trial (topic); recommended drug dose; tumor regression; adult; aged; cancer staging; Carcinoma, Non-Small-Cell Lung; clinical trial; comparative study; confidence interval; controlled study; disease free survival; drug administration; female; gene expression regulation; genetics; Kaplan Meier method; Lung Neoplasms; male; middle aged; mortality; mutation; pathology; phase 2 clinical trial; phase 3 clinical trial; proto oncogene; randomized controlled trial; survival; treatment outcome; tumor invasion; very elderly; Adult; Aged; Aged, 80 and over; Carcinoma, Non-Small-Cell Lung; Confidence Intervals; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Gene Expression Regulation, Neoplastic; Genes, erbB-1; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasm Invasiveness; Neoplasm Staging; Quinazolines; Survival Analysis; Treatment Outcome
Publisher
Lancet Publishing Group
Type
journal article