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

Abstract

ObjectiveTo provide a complete toxicity profile, toxicity spectrum, and a safety ranking of immune checkpoint inhibitor (ICI) drugs for treatment of cancer.DesignSystematic review and network meta-analysis.Data sourcesElectronic 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 methodsOnly 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.Results36 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.ConclusionsCompared 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 registrationPROSPERO CRD42017082553.

The landscape of immune checkpoint inhibitor plus chemotherapy versus immunotherapy for advanced non‐small‐cell lung cancer: A systematic review and meta‐analysis

“…We found that the anti-PD-1 therapy appeared to illicit greater treatment benefits compared with the anti-PD-L1 therapy, which is consistent with the previous hypothesis that NSCLC patients with anti-PD-1 therapy are more likely to experience prolonged survival and a more tolerable safety prolife than anti-PD-L1 therapy Wei et al, 2017;Xu et al, 2018). Theoretically, the interaction between PD-1 and PD-L1 as the dominant ligand, can be inhibited by both PD-L1 blockers and PD-1 blockers.…”

A Comparative Study of Longitudinal Toxicities of Cytotoxic Drugs, Molecularly Targeted Agents, Immunomodulatory Drugs, and Cancer Vaccines

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“…Recently, some researchers discussed the toxicity profiles of immune checkpoint inhibitors. [26][27][28] Although it is difficult to compare the results between these investigations and our study, findings from this paper should contribute to a deeper understanding of the complete picture of the toxicity profiles for CD, MTA, IMD, and CV, and are consequently expected to be useful for the identification, assessment, and management of toxicities related to these drugs. In addition, the cancer types of the patients enrolled into early-phase trials were heterogenous; however, note that patients with solid and hematologic cancers were included in our analyses when interpreting the results of this study.…”

Treatment- and immune-related adverse events of immune checkpoint inhibitors in advanced lung cancer

“…Traditional chemotherapeutic drugs work by killing rapidly dividing cells, whether they are tumor or healthy. Due to the long-term clinical application, the toxicities of chemotherapy drugs that reduce the quality of life of patients have been clearly demonstrated [47]. In the era of precision medicine, it is proposed that the treatment should not only cure diseases, but also restore patients' health with the maximum quality of life [48].…”