Relative efficacy of interventions in the treatment of second-line non-small cell lung cancer: a systematic review and network meta-analysis

Abstract

Background Locally 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. Methods MEDLINE, 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. Results The 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. Conclusions In 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 registration This review is registered in PROSPERO (registration number: CRD42014013780 available at www.crd.york.ac.uk/PROSPERO ). Electronic supplementary material The online version of this article (10.1186/s12885-019-5569-5) contains supplementary material, which is available to authorized users.

Real-world effectiveness and safety of nivolumab in patients with non-small cell lung cancer: A multicenter retrospective observational study in Japan

“…The antitumor effect of nivolumab was associated with PD-L1 expression, and the result was comparable to that of previous studies [5][6][7]. OS in the PD-L1 1-49 % subgroup was numerically longer than that in the PD-L1 ≥ 50 % subgroup.…”

“…In all patients, the median OS, one-year survival rate, median PFS, and ORR were comparable to results from clinical trials [5][6][7][8][9], as summarized in Table S4.…”

“…Approval of nivolumab use for patients with advanced NSCLC was based on two Phase 3 trials (CheckMate 017 and CheckMate 057 [5,6]), which showed survival benefit over docetaxel across histology [7] (median overall survival (OS) in nivolumab vs docetaxel: 9.2 vs 6.0 months for squamous cell carcinoma (SQ) and 12.2 vs 9.4 months for non-SQ), and two Phase 2 studies (ONO-4538-05 and ONO-4538-06 [8,9]) which demonstrated the safety and efficacy of nivolumab in the Japanese population (median OS: 16.3 months for SQ and 17.1 months for non-SQ). Long-term follow-up of these clinical trial results showed that a fraction of the NSCLC patients continued to sustain a durable response [10,11].…”

An Evaluation of Survival Curve Extrapolation Techniques Using Long-Term Observational Cancer Data

“…Improvements in standard of care over time are likely to be considerable in oncology and other disease areas. If there is more than 1 source of external data, sensitivity analyses could be conducted, or a meta-survival model could be used such as that described by Vickers et al 41…”

“…Improvements in standard of care over time are likely to be considerable in oncology and other disease areas. If there is more than 1 source of external data, sensitivity analyses could be conducted, or a meta-survival model could be used such as that described by Vickers et al 41 The data used in this study were from elderly patients (!80 years old), in whom general age-related mortality was a factor, which was not detectable in the short-term data. This resulted in methods that did not use long-term external data and general population data producing biased predictions.…”