Comparative efficacy and safety of licensed treatments for previously treated non-small cell lung cancer: A systematic review and network meta-analysis

Abstract

Purpose: This systematic review with network meta-analysis compared the efficacy and safety of currently licensed second-line treatments in patients with late stage non-small cell lung cancer (NSCLC).

Methods: Randomised controlled trials (RCTs) of participants with advanced/metastatic NSCLC receiving second/third line treatments were screened. We searched electronic databases (MEDLINE; EMBASE; Web of Science) from January, 2000 to July, 2017. Two reviewers screened bibliographic records, extracted data, and assessed risk of bias of included studies. The outcomes were overall survival (OS), progression-free survival (PFS), and drug-related grade 3-5 adverse-events (AEs). We pooled study-specific hazard ratios (HR; for OS and PFS) and risk ratios (RR; for AEs) using conventional and network-meta-analyses, and ranked interventions by the surface under the cumulative ranking curve.

Findings: We included 11 RCTs (7,581 participants) comparing nine drugs. All drugs except for erlotinib significantly improved OS compared to docetaxel. Nivolumab was the highest ranking drug followed by atezolizumab and pembrolizumab. There was no significant difference in OS across these three drugs (HR = 0.98, 95% CI 0.79, 1.21 for nivolumab vs atezolizumab; HR = 0.98, 95% CI 0.77, 1.25 for nivolumab vs pembrolizumab). For PFS, ramucirumab + docetaxel and nivolumab were the drugs with the highest ranking. All interventions except ramucirumab + docetaxel had a reduced risk for severe drug-related AEs vs. docetaxel. Of the drugs with the highest ranking on AEs, nivolumab was significantly safer compared to atezolizumab (RR = 0.55, 95% CI 0.38, 0.79) or pembrolizumab (RR = 0.52, 95% CI 0.34, 0.81).

Implications: Nivolumab, pembrolizumab and atezolizumab exhibited superior benefit/risk balance compared to other licensed drugs used late stage NSCLC. Our results indicate that the use of immunotherapies in people diagnosed with non-specific late stage NSCLC should be promoted. The use of docetaxel may now be judged irrelevant as a comparator intervention for approval of new drugs for second line treatment of NSCLC.

Study registration number: PROSPERO CRD42017065928.

Fig 1. PRISMA flowchart for study selection.

Fig 2. Network of studies comparing effectiveness (OS, PFS) and safety (grade 3–5 drug-related AE) outcomes in all-histology NSCLC.

Fig 3. Pairwise meta-analyses, OS in all-histology NSCLC.

Fig 4. Clustered ranking plot on effectiveness (OS) and safety (grade 3–5 drug-related AE) both expressed as SUCRAS.

Note: Y and X axes represent the cumulative ranking curve (SUCRA) to rank each intervention (i.e., probability between 0 to 1 of an intervention being superior in effectiveness or in safety compared to DOC); the plot guides a reader with respect to the trade-off between safety (measured drug-related grade 3–5 AE) and effectiveness (measures as OS) across the interventions: interventions in the right upper corner tend to be safer (higher SUCRA for AEs) and more effective (SUCRAs for OS) than those in the left lower corner of the plot (with lower SUCRAs on both factors). Thus, the Fig 3 supports a superior efficacy and safety for NIVO, ATEZO, and PEMBRO as opposed to DOC or ERLO. Also although NIVO compared to ATEZO and PEMBRO had similar effectiveness it appeared safer than the latter two.