Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): A phase 2B, open-label, randomised controlled trial
Journal
The Lancet Oncology
Journal Volume
17
Journal Issue
5
Pages
577-589
Date Issued
2016
Author(s)
Park K
Tan E.-H
O'Byrne K
Zhang L
Boyer M
Mok T
Hirsh V
Lee K.H
Lu S
Shi Y
Kim S.-W
Laskin J
Kim D.-W
Arvis C.D
Kölbeck K
Laurie S.A
Tsai C.-M
Shahidi M
Kim M
Massey D
Zazulina V
Paz-Ares L.
Abstract
Background: The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. Methods: This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660. Findings: Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3-33·9). Progression-free survival (median 11·0 months [95% CI 10·6-12·9] with afatinib vs 10·9 months [9·1-11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57-0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9-15·0] with afatinib vs 11·5 months [10·1-13·1] with gefitinib; HR 0·73 [95% CI 0·58-0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. Interpretation: Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population. Funding: Boehringer Ingelheim. ? 2016 Elsevier Ltd.
SDGs
Other Subjects
afatinib; alanine aminotransferase; arginine; aspartate aminotransferase; bicarbonate; creatinine; epidermal growth factor receptor; gefitinib; leucine; liver enzyme; afatinib; EGFR protein, human; epidermal growth factor receptor; gefitinib; protein kinase inhibitor; quinazoline derivative; acidosis; acne; acute kidney failure; acute respiratory failure; adult; adverse drug reaction; aged; alopecia; anus disease; Article; bacterial skin disease; bicarbonate blood level; bone marrow depression; brain ischemia; brain metastasis; cancer chemotherapy; cancer growth; cancer patient; cancer staging; cancer survival; chemotherapy induced emesis; confusion; conjunctivitis; controlled study; decreased appetite; dehydration; diarrhea; drug dose escalation; drug dose reduction; drug efficacy; drug eruption; drug fatality; drug safety; drug treatment failure; drug withdrawal; dry nose; dry skin; EGFR gene; encephalomyelitis; exon; exploratory research; fatigue; female; follow up; gastrointestinal pain; gene deletion; gene mutation; hand foot syndrome; human; human cell; human tissue; hypoalbuminemia; hypokalemia; interstitial lung disease; intertrigo; kidney failure; liver failure; major clinical study; male; malignant neoplastic disease; mucosa inflammation; multicenter study; nausea; neutropenia; non small cell lung cancer; open study; overall survival; paronychia; phase 2 clinical trial; pneumonia; priority journal; progression free survival; pruritus; randomized controlled trial; rash; respiratory distress; side effect; stomatitis; survival time; toxic hepatitis; treatment response; weight reduction; adverse drug reaction; Carcinoma, Non-Small-Cell Lung; classification; clinical trial; disease free survival; genetics; Kaplan Meier method; middle aged; mutation; pathology; pathophysiology; very elderly; Adult; Aged; Aged, 80 and over; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mutation; Protein Kinase Inhibitors; Quinazolines; Receptor, Epidermal Growth Factor
Publisher
Lancet Publishing Group
Type
journal article