Afatinib in the treatment of EGFR mutation-positive NSCLC – A network meta-analysis☆
Introduction
Worldwide, lung cancer is the most common cause of cancer-related death in men and the second most common cause in women after breast cancer [1]. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for around 85% of all cases and more than 40% of NSCLC is metastatic (Stage IV) disease at diagnosis [2]. There has been considerable progress in the treatment of NSCLC in the past 10 years [3], with improvements in screening, diagnosis and systemic therapy all contributing to gains in survival. One notable advance is the recognition that there are several distinct subgroups of NSCLC that respond differently to treatment. For example, patients whose tumours harbour an epidermal growth factor receptor (EGFR) mutation define a distinct lung cancer subtype that is optimally treated with early use of EGFR tyrosine kinase inhibitors (TKIs) [4].
The current standard of care for the initial treatment of patients with advanced NSCLC whose tumours do not test positive for an EGFR mutation remains platinum-based doublet chemotherapy for four to six cycles [5] and was standard of care in all lung adenocarcinoma before the discovery of EGFR mutations. As such, pivotal trials evaluating the efficacy of the EGFR TKIs for the first-line treatment of EGFR mutation-positive NSCLC used platinum-based doublet chemotherapy as the control. Randomized phase III clinical trials with the reversible EGFR TKIs, gefitinib and erlotinib, have demonstrated that first-line treatment with these EGFR TKIs leads to improvement in progression-free survival (PFS) versus platinum doublet chemotherapy combinations with a taxane or gemcitabine [6], [7], [8], [9].
Afatinib is an oral, irreversible ErbB family blocker, that selectively and potently blocks signalling from all relevant ErbB family receptors (EGFR/ErbB1, human epidermal growth factor receptor-2 [HER2; ErbB2] and ErbB4) [10] and transphosphorylation of ErbB3 [11]. In patients with locally advanced or metastatic lung adenocarcinoma and EGFR mutations, afatinib has been associated with prolonged PFS compared with cisplatin/pemetrexed in LUX-Lung 3, a global, randomized phase III trial [12] and compared to cisplatin/gemcitabine in LUX-Lung 6, a large randomized phase III trial conducted in Asian patients [13].
To date, no head-to-head trials have compared the efficacy of afatinib to the reversible EGFR TKIs, gefitinib or erlotinib, for the first-line treatment of patients with locally advanced or metastatic EGFR mutation-positive NSCLC. Similarly, no prospective randomized studies have compared erlotinib directly with gefitinib in patients with known EGFR mutations. Although a weighted pooled analysis of available studies has been performed comparing these agents [14], this is not a standard approach for assessing relative effectiveness of medical interventions. In the absence of randomized controlled trials (RCTs) involving a direct comparison of all treatments of interest, network meta-analysis (NMA) provides a useful method for judiciously estimating the relative treatment effects of available EGFR TKIs [15]. NMA has advantages over traditional meta-analyses as it enables direct and indirect evidence via a common comparator to be combined to create a network that then allows comparison of treatments based on individual trials. Similar to traditional meta-analysis, an NMA conducted using relative treatment effects, such as hazard ratios (HRs), from RCTs also protects the randomization within each trial [16].
This analysis compared the relative treatment effects of afatinib and erlotinib and gefitinib in the first-line treatment of EGFR mutation-positive NSCLC by conducting an NMA of the available evidence. The analyses were conducted using within-trial estimates of relative treatment effects based on HRs of PFS by investigator assessment and HRs of overall survival (OS).
Section snippets
Literature identification
A systematic literature review was undertaken to identify all relevant RCTs conducted in locally advanced or metastatic NSCLC; due to the nature of the NMA methodology, the search strategy was not limited to trials conducted with afatinib, erlotinib or gefitinib in order to identify trials for inclusion in the network. The following databases were searched using criteria to identify all relevant trials: EMBASE, MedLine, MedLine In-Process and the Cochrane Library. Searches were limited to
Identification of trials for inclusion in the NMA
The search of the published literature identified 246 articles that were assessed for eligibility; 66 studies were identified as being conducted in the first-line treatment setting (Fig. 1). Of the 66 studies identified, 10 publications reported results from 7 trials conducted in an EGFR mutation-positive population (4 trials, 6 publications) [6], [8], [9], [28], [29], [30] or reported outcomes for an EGFR mutation-positive subgroup of the study population (3 trials, 4 publications) [7], [31],
Discussion
Afatinib has demonstrated superior efficacy to chemotherapy (cisplatin/pemetrexed and cisplatin/gemcitabine) in the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR mutations [12], [13]. Although findings from this NMA showed no statistically significant differences between afatinib and erlotinib or gefitinib in terms of PFS, some numerical differences were observed, particularly in patients with common EGFR mutations. All comparisons for PFS versus currently
Conclusions
NMA provides a useful source of information on the comparative benefits of different treatments for healthcare decision-makers when direct head-to-head trials have not been conducted. Afatinib is a viable treatment alternative to erlotinib and gefitinib for first-line treatment in patients with EGFR mutation-positive NSCLC. Direct head-to-head studies are needed and results of LUX-Lung 7 are eagerly awaited.
Conflict of interest statement
Sanjay Popat: Consultancy for Boehringer Ingelheim, AstraZeneca, Roche. Tony Mok: Advisory board and honoraria from AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, BeiGene, AVEO, Pfizer, Taiho, Boehringer Ingelheim, GSK Biologicals; speaker fees from AstraZeneca, Roche, Eli Lilly, Boehringer Ingelheim, Merck Serono, Pfizer; research funding from AstraZeneca. James Chih-Hsin Yang: Consultancy for Novartis, Pfizer, Clovis, AstraZeneca, Roche, Bayer, Merck, Optima, Innopharma;
Acknowledgments
This study was supported by Boehringer Ingelheim. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development and have approved the final version. Medical writing assistance provided by Suzanne Patel of Ogilvy Healthworld and editorial assistance provided by Caroline Allinson of GeoMed, a division of the KnowledgePoint360 Group, was supported financially by Boehringer Ingelheim during the preparation of this article.
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Real-world clinical outcomes of first-generation and second-generation epidermal growth factor receptor tyrosine kinase inhibitors in a large cohort of European non-small-cell lung cancer patients
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Previous publication: Fonseca T, Lungershausen J, Wallenstein G, Stammberger U, Bertwistle D, Griebsch I. Treatments for EGFR mutation positive NSCLC – a network meta-analysis. Poster presented at the ISPOR 16th Annual European Congress, 2013.