Risk of Treatment-Related Toxicities from EGFR Tyrosine Kinase Inhibitors: A Meta-analysis of Clinical Trials of Gefitinib, Erlotinib, and Afatinib in Advanced EGFR-Mutated Non–Small Cell Lung Cancer
Journal
Journal of Thoracic Oncology
Journal Volume
12
Journal Issue
4
Pages
633-643
Date Issued
2017
Author(s)
Abstract
Introduction Gefitinib, erlotinib, and afatinib are tyrosine kinase inhibitors (TKIs) used for treatment of advanced EGFR-mutated NSCLC. Estimating differences in toxicity between these EGFR TKIs is important for personalizing treatment. Methods We performed a meta-analysis of randomized trials that compared EGFR TKI therapy against chemotherapy or placebo. We extracted data from the EGFR TKI arm for indirect comparisons to estimate the relative risk for toxic death, grade 3 to 4 (G3/4) adverse events (AEs), and discontinuation of treatment because of AE for each EGFR TKI. Results Sixteen trials included 2535 patients with mutated or wild-type EGFR. Toxic deaths were rare (1.7%), with pneumonitis being most frequent cause and no significant differences between EGFR TKIs. Overall, 40% of patients experienced G3/4 AEs. The risk for G3/4 AEs was lower with gefitinib (29.1%) than with erlotinib (54.1%) or afatinib (42.1%) (p < 0.01). Discontinuation of treatment because of AEs occurred in 7.7% of patients, with no significant differences between EGFR TKIs. Diarrhea (in 53.3% of cases) and rash (in 66.5%) were the most frequent AEs.?The risk for rash was higher with afatinib (84.8%) than with erlotinib (62.0%) or gefitinib (62.0%) (p < 0.01). The risk for diarrhea was higher with afatinib (91.7%) than?with erlotinib (42.4%) or gefitinib (44.4%) (p < 0.01). The risk for increased liver enzyme levels was higher with gefitinib (61.7%) than with erlotinib (17.8%) or afatinib (20.1%) (p < 0.01). A risk-benefit contour was used to assess the trade-off between efficacy and toxicity for different EGFR TKIs. Conclusions EGFR TKIs are well tolerated, with less than?10% of patients discontinuing treatment because of AEs. The profile of and risk for toxicities vary between EGFR?TKIs and can be used to inform the selection of treatment. ? 2016 International Association for the Study of Lung Cancer
Subjects
EGFR mutation; Meta-analysis; NSCLC; Tyrosine kinase inhibitors
SDGs
Other Subjects
afatinib; carboplatin; cisplatin; docetaxel; epidermal growth factor receptor; erlotinib; gefitinib; gemcitabine; liver enzyme; paclitaxel; pemetrexed; placebo; vinorelbine tartrate; afatinib; antineoplastic agent; EGFR protein, human; epidermal growth factor receptor; erlotinib; gefitinib; protein kinase inhibitor; quinazoline derivative; adverse drug reaction; Conference Paper; diarrhea; drug efficacy; drug fatality; drug safety; drug tolerability; drug withdrawal; dry skin; EGFR gene; fatigue; gene mutation; human; loss of appetite; nausea; non small cell lung cancer; paronychia; phase 2 clinical trial (topic); phase 3 clinical trial (topic); pneumonia; pruritus; randomized controlled trial (topic); rash; risk assessment; risk benefit analysis; side effect; stomatitis; systematic review; antagonists and inhibitors; cancer staging; chemically induced; diarrhea; genetics; lung tumor; meta analysis; mutation; non small cell lung cancer; pathology; prognosis; risk factor; survival rate; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Diarrhea; Erlotinib Hydrochloride; Humans; Lung Neoplasms; Mutation; Neoplasm Staging; Prognosis; Protein Kinase Inhibitors; Quinazolines; Receptor, Epidermal Growth Factor; Risk Factors; Survival Rate
Publisher
Elsevier Inc
Type
conference paper