A Network Comparison on Safety Profiling of Immune Checkpoint Inhibitors in Advanced Lung Cancer

Yi-Dan Yan,Jie Fu,Zhi-Chun Gu,Hou-Wen Lin,Xiao-Yu Chen,Ying-Jie Su,Jiu-Jie Cui

doi:10.3389/fimmu.2021.760737

Abstract

BackgroundImmune checkpoint inhibitors (ICIs) have become one of the standard treatment options for advanced lung cancer. However, adverse events (AEs), particularly immune–related AEs (irAEs), caused by these drugs have aroused public attention. The current network meta-analysis (NMA) aimed to compare the risk of AEs across different ICI–based regimens in patients with advanced lung cancer.MethodsWe systematically searched the PubMed, EMBASE, and Cochrane Library databases (from inception to 19 April 2021) for relevant randomized controlled trials (RCTs) that compared two or more treatments, with at least one ICI administered to patients with advanced lung cancer. The primary outcomes were treatment–related AEs and irAEs, including grade 1–5 and grade 3–5. The secondary outcomes were grade 1–5 and grade 3–5 irAEs in specific organs. Both pairwise and network meta-analyses were conducted for chemotherapy, ICI monotherapy, ICI monotherapy + chemotherapy, dual ICIs therapy, and dual ICIs + chemotherapy for all safety outcomes. Node–splitting analyses were performed to test inconsistencies in network. Sensitivity analyses were adopted by restricting phase III RCTs and studies that enrolled patients with non–small cell lung cancer.ResultsOverall, 38 RCTs involving 22,178 patients with advanced lung cancer were enrolled. Both pooled incidence and NMA indicated that treatments containing chemotherapy increased the risk of treatment–related AEs when compared with ICI-based regimens without chemotherapy. As for grade 1–5 irAEs, dual ICIs + chemotherapy was associated with the highest risk of irAEs (probability in ranking first: 50.5%), followed by dual-ICI therapy (probability in ranking second: 47.2%), ICI monotherapy (probability in ranking third: 80.0%), ICI monotherapy + chemotherapy (probability in ranking fourth: 98.0%), and finally chemotherapy (probability in ranking fifth: 100.0%). In grade 3–5 irAEs, subtle differences were observed; when ranked from least safe to safest, the trend was dual ICIs therapy (60.4%), dual ICIs + chemotherapy (42.5%), ICI monotherapy (76.3%), ICI monotherapy + chemotherapy (95.0%), and chemotherapy (100.0%). Furthermore, detailed comparisons between ICI–based options provided irAE profiles based on specific organ/system and severity.ConclusionsIn consideration of overall immune–related safety profiles, ICI monotherapy + chemotherapy might be a better choice among ICI–based treatments for advanced lung cancer. The safety profiles of ICI–based treatments are various by specific irAEs and their severity.Systematic Review Registration https://www.crd.york.ac.uk/prospero, identifier CRD42021268650

Highlights

Lung cancer remains the leading cause of global cancer mortality, with approximately 1.8 million deaths annually (18% of the total cancer deaths) [1]
A series of immune checkpoint Inhibitor (ICI) [pembrolizumab, nivolumab, ipilimumab, atezolizumab, and durvalumab registered by the U.S Food and Drug Administration (FDA); camrelizumab, sintilimab, and tislelizumab approved by the National Medical Products Administration (NMPA)] have been successfully introduced for use in patients with advanced lung cancer
As shown in the network map (Figure 2), a total of 22,178 patients with advanced lung cancer were included in five treatment regimens (8,768, 6,057, 4,917, 1,807, and 629 patients received chemotherapy, ICI monotherapy, ICI monotherapy + chemotherapy, dual ICIs therapy, and dual ICIs + chemotherapy, respectively)

Summary

Introduction

Lung cancer remains the leading cause of global cancer mortality, with approximately 1.8 million deaths annually (18% of the total cancer deaths) [1]. Platinum–based chemotherapy has become the cornerstone for managing advanced lung cancer; its use is of concern due to inevitable resistance and intolerable adverse events (AEs) in these fragile patients [2, 3]. A series of ICIs [pembrolizumab, nivolumab, ipilimumab, atezolizumab, and durvalumab registered by the U.S Food and Drug Administration (FDA); camrelizumab, sintilimab, and tislelizumab approved by the National Medical Products Administration (NMPA)] have been successfully introduced for use in patients with advanced lung cancer. ICI monotherapy with or without chemotherapy, dual ICIs combination, even dual ICIs combined with chemotherapy have been clinically applied as standard first–line treatment options for advanced lung cancer. Immune checkpoint inhibitors (ICIs) have become one of the standard treatment options for advanced lung cancer. The current network meta-analysis (NMA) aimed to compare the risk of AEs across different ICI–based regimens in patients with advanced lung cancer

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Results

Discussion

Conclusion