Abstract
BackgroundLocally advanced or metastatic non-small cell lung cancer (NSCLC) that has progressed after first-line treatment has a poor prognosis. Recent randomized clinical trials (RCTs) have demonstrated survival benefits of alternative treatments to docetaxel. However, information is lacking on which patients benefit the most and what drug or regimen is optimal. We report a systematic review and network meta-analysis (NMA) of second-line treatments in all subgroup combinations determined by histology, programmed death ligand 1 (PD-L1) expression, and epidermal growth factor receptor (EGFR) mutation.MethodsMEDLINE, PubMed, EMBASE, Biosciences Information Service (using the Dialog Platform), Cochrane Library, and abstracts from scientific meetings were searched for RCTs published up to September 2015. Key outcomes were overall survival (OS) and progression-free survival (PFS). Bayesian hierarchical exchangeable NMAs were conducted to calculate mean survival times and relative differences for eight subgroups, using docetaxel as the reference comparator. For OS, the NMA was based on hazard ratios applied to a first-order fractional polynomial model fitted to the reference treatment. For PFS, a second-order fractional polynomial model was fitted to reconstructed patient-level data for the entire network of evidence.ResultsThe search identified 30 studies containing 17 different treatment regimens. Docetaxel plus ramucirumab was associated with a significant improvement in OS and PFS, relative to docetaxel, regardless of patient type. Docetaxel plus nintedanib showed similar efficacy to docetaxel plus ramucirumab in the nonsquamous populations. EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib showed superior levels of efficacy in EGFR mutation-positive populations and the one PD-1 immunotherapy (nivolumab) studied showed superior efficacy in the populations exhibiting high PD-L1 expression.ConclusionsIn the absence of head-to-head comparisons, we performed a mixed-treatment analysis to synthesize evidence of the efficacy of each treatment. Benefits are optimized by targeting specific treatments to individual patients guided by histology, PD-L1 expression, and EGFR mutation status.Systematic review registrationThis review is registered in PROSPERO (registration number: CRD42014013780 available at www.crd.york.ac.uk/PROSPERO).
Highlights
Advanced or metastatic non-small cell lung cancer (NSCLC) that has progressed after first-line treatment has a poor prognosis
The covariate data from this table shows some differences between studies for the proportion of patients restricted in activity (performance status (ECOG) ≥ 1 = 0.48–0.94), stage of disease, and proportion of Asian patients (0.01–1.0); none of these covariates appeared to improve the fit of the network meta-analysis (NMA)
Results by subgroup Nonsquamous, programmed death ligand 1 (PD-L1) expression < 5% and epidermal growth factor receptor (EGFR) negative For overall survival (OS), docetaxel plus ramucirumab and docetaxel plus nintedanib were the only interventions that showed a significant improvement in mean survival time over docetaxel (75 mg/m2) with gains of 2.3 and 2.6 months, respectively (Fig. 4)
Summary
Advanced or metastatic non-small cell lung cancer (NSCLC) that has progressed after first-line treatment has a poor prognosis. Lung cancer is the most commonly occurring life-threatening cancer in the world, with an estimated 1.8 million new cases diagnosed in 2012 (12.9% of all new cancers) [1]. Lung cancer is estimated to be the leading cause of cancer-related deaths in men in Europe (25% of all cancer-related deaths) and represents the second most common cause of cancer-related deaths in women in Europe (14% of all cancer-related deaths) [2]. 85% of newly diagnosed cases are classified as non-small cell lung cancer (NSCLC), while the remaining 10 to 15% are small cell lung cancer and fewer than 5% are lung carcinoid tumors [4]. Because symptoms of the disease are nonspecific (e.g., cough, dyspnea, fatigue, weight loss) or absent, approximately 65% of patients globally present with advanced-stage disease (i.e., stage IIIB or stage IV) [5, 6]
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