Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: Post hoc analyses of the randomized LUX-Lung 3 and 6 trials
Journal
Annals of Oncology
Journal Volume
27
Journal Issue
11
Pages
2103-2110
Date Issued
2016
Author(s)
Sequist L.V
Zhou C
Schuler M
Geater S.L
Mok T
Hu C.-P
Yamamoto N
Feng J
O'Byrne K
Lu S
Hirsh V
Huang Y
Sebastian M
Okamoto I
Dickgreber N
Shah R
Märten A
Massey D
Wind S
Wu Y.-L.
Abstract
Background: Afatinib 40 mg/day is approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). In the case of drug-related grade ?3 or selected prolonged grade 2 adverse events (AEs), the dose can be reduced by 10 mg decrements to a minimum of 20 mg. Here, we evaluate the influence of afatinib dose reduction on AEs, pharmacokinetics and progression-free survival (PFS) in the phase III LUX-Lung 3 and 6 (LL3/6) trials. Patients and methods: Treatment-na?ve patients with advanced EGFR mutation-positive NSCLC in LL3 (global) and LL6 (China, Thailand, South Korea) were randomized to afatinib or chemotherapy. All afatinib-treated patients (LL3, n = 229; LL6, n = 239) were included in the post hoc analyses. Incidence and severity of common AEs before and after afatinib dose reduction were assessed. Afatinib plasma concentrations were compared in patients who reduced to 30 mg versus those remaining at 40 mg. PFS was compared between patients who dose reduced within the first 6 months of treatment and those who did not. Results: Dose reductions occurred in 53.3% (122/229) and 28.0% (67/239) of patients in LL3 and LL6, respectively; most (86.1% and 82.1%) within the first 6 months of treatment. Dose reduction led to decreases in the incidence of drug-related AEs, and was more likely in patients with higher afatinib plasma concentrations. On day 43, patients who dose reduced to 30 mg (n = 59) had geometric mean afatinib plasma concentrations of 23.3 ng/ml, versus 22.8 ng/ml in patients who remained on 40 mg (n = 284). The median PFS was similar in patients who dose reduced during the first 6 months versus those who did not (LL3: 11.3 versus 11.0 months [hazard ratio (HR) 1.25]; LL6: 12.3 versus 11.0 months (HR 1.00)). Conclusions: Tolerability-guided dose adjustment is an effective measure to reduce afatinib-related AEs without affecting therapeutic efficacy. ? The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
Subjects
Afatinib; Dose; EGFR; First-line; NSCLC; Phase III
SDGs
Other Subjects
afatinib; epidermal growth factor receptor; afatinib; antineoplastic agent; EGFR protein, human; epidermal growth factor receptor; protein kinase inhibitor; quinazoline derivative; acne; adult; aged; Article; blood level; controlled study; decreased appetite; diarrhea; disease severity; dose response; drug blood level; drug dose comparison; drug dose escalation; drug dose reduction; drug dose regimen; drug efficacy; drug safety; drug tolerability; dry skin; fatigue; female; human; incidence; lung adenocarcinoma; major clinical study; male; multiple cycle treatment; nail disease; nausea; priority journal; progression free survival; pruritus; randomized controlled trial (topic); rash; stomatitis; treatment duration; vomiting; adenocarcinoma; adverse drug reaction; China; clinical trial; disease free survival; dose response; genetics; lung tumor; middle aged; mutation; pathology; phase 3 clinical trial; randomized controlled trial; South Korea; Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; China; Disease-Free Survival; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Protein Kinase Inhibitors; Quinazolines; Receptor, Epidermal Growth Factor; Republic of Korea
Publisher
Oxford University Press
Type
journal article