Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis

Abstract

Objective: To provide a complete toxicity profile, toxicity spectrum, and a safety ranking of immune checkpoint inhibitor (ICI) drugs for treatment of cancer.

Design: Systematic review and network meta-analysis.

Data sources: Electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) were systematically searched to include relevant studies published in English between January 2007 and February 2018.

Review methods: Only head-to-head phase II and III randomised controlled trials comparing any two or three of the following treatments or different doses of the same ICI drug were included: nivolumab, pembrolizumab, ipilimumab, tremelimumab, atezolizumab, conventional therapy (chemotherapy, targeted therapy, and their combinations), two ICI drugs, or one ICI drug with conventional therapy. Eligible studies must have reported site, organ, or system level data on treatment related adverse events. High quality, single arm trials and placebo controlled trials on ICI drugs were selected to establish a validation group.

Results: 36 head-to-head phase II and III randomised trials (n=15 370) were included. The general safety of ICI drugs ranked from high to low for all adverse events was as follows: atezolizumab (probability 76%, pooled incidence 66.4%), nivolumab (56%, 71.8%), pembrolizumab (55%, 75.1%), ipilimumab (55%, 86.8%), and tremelimumab (54%, not applicable). The general safety of ICI drugs ranked from high to low for severe or life threatening adverse events was as follows: atezolizumab (49%, 15.1%), nivolumab (46%, 14.1%), pembrolizumab (72%, 19.8%), ipilimumab (51%, 28.6%), and tremelimumab (28%, not applicable). Compared with conventional therapy, treatment-related adverse events for ICI drugs occurred mainly in the skin, endocrine, hepatic, and pulmonary systems. Taking one ICI drug was generally safer than taking two ICI drugs or one ICI drug with conventional therapy. Among the five ICI drugs, atezolizumab had the highest risk of hypothyroidism, nausea, and vomiting. The predominant treatment-related adverse events for pembrolizumab were arthralgia, pneumonitis, and hepatic toxicities. The main treatment-related adverse events for ipilimumab were skin, gastrointestinal, and renal toxicities. Nivolumab had a narrow and mild toxicity spectrum, mainly causing endocrine toxicities. Integrated evidence from the pooled incidences, subgroup, and sensitivity analyses implied that nivolumab is the best option in terms of safety, especially for the treatment of lung cancer.

Conclusions: Compared with other ICI drugs used to treat cancer, atezolizumab had the best safety profile in general, and nivolumab had the best safety profile in lung cancer when taking an integrated approach. The safety ranking of treatments based on ICI drugs is modulated by specific treatment-related adverse events.

Systematic review registration: PROSPERO CRD42017082553.

Fig 1

Flowchart of study selection and design

Fig 2

Network plots of comparisons for dose (A) and drug (B) based network meta-analyses. Each circular node represents a type of treatment. The circle size is proportional to the total number of patients (in parentheses). The width of lines is proportional to the number of studies performing head-to-head comparisons in the same study. ICI=immune checkpoint inhibitor

Fig 3

Safety profile (A) and ranking curves (B) according to the drug based network meta-analysis (NMA) in the consistency model. Each cell of the safety profile contains the pooled odds ratios and 95% credibility intervals for grade 1-5 adverse events and grade 3 or 4 adverse events; significant results are in bold. The pooled odds ratios and 95% credibility intervals indicate the result of the top treatment compared with the bottom treatment. Ranking curves indicate the probability of the highest risk of grade 1-5 adverse events and grade 3 or 4 adverse events, the second highest, the third highest, and so on. ICI=immune checkpoint inhibitor

Fig 4

Forest plots depicting the direct and indirect results of head-to-head comparisons. ICI=immune checkpoint inhibitor; NA=not applicable. *Values in brackets are 95% CrIs.

Fig 5

Toxicity spectra and rankings in the subgroup analysis based on each specific grade 1-5 adverse event and cancer type. Immune checkpoint inhibitor (ICI) drugs are shown with a dark background. The number in each parenthesis represents the probability of risk to rank; values with the same rank are underlined.

Fig 6

Safety profiles in the subgroup analysis based on lung cancer (A) and melanoma (B). Each cell contains the pooled odds ratios and 95% credibility intervals for grade 1-5 adverse events or grade 3 or 4 adverse events; significant results are in bold. ICI=immune checkpoint inhibitor