Immune-related adverse events associated with programmed cell death protein-1 and programmed cell death ligand 1 inhibitors for non-small cell lung cancer: a PRISMA systematic review and meta-analysis

Xiaoying Sun,Shangya Chen,Ting Dai,Bin Fan,Chengqian Yin,Min Zhou,Xin Li,Yaqiong Zhou,Bo Zhu,Bin Li,Hongjin Li,Raheleh Roudi

doi:10.1186/s12885-019-5701-6

Abstract

BackgroundProgrammed cell death protein-1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have remarkable clinical efficacy in the treatment of non-small cell lung cancer (NSCLC); however, the breakdown of immune escape causes a variety of immune-related adverse events (irAEs). With the increasing use of PD-1/PD-L1 inhibitors alone or in combination with other therapies, awareness and management of irAEs have become more important. We aimed to assess the incidence and nature of irAEs associated with PD-1 and PD-L1 inhibitors for NSCLC.MethodsArticles from the MEDLINE, EMBASE, and Cochrane databases were searched through December 2017. The incidence of overall and organ-specific irAEs was investigated in all clinical trials with nivolumab, pembrolizumab, atezolimumab, durvalumab, and avelumab as single agents for treatment of NSCLC. We calculated the pooled incidence using R software with package Meta.ResultsSixteen trials were included in the meta-analysis: 10 trials with PD-1 inhibitors (3734 patients) and 6 trials with PD-L1 inhibitors (2474 patients). The overall incidence of irAEs was 22% (95% confidence interval [CI], 17–28) for all grades and 4% (95% CI, 2–6) for high-grade irAEs. The frequency of irAEs varied based on drug type and organ, and patients treated with PD-1 inhibitors had an increased rate of any grade and high-grade irAEs compared with patients who received PD-L1 inhibitors. Organ-specific irAEs were most frequently observed in, in decreasing order, the endocrine system, skin, pulmonary tract, and gastrointestinal tract. The total number of patients whose death was attributed to irAEs was 14 (0.34%), and most (79%) of these patients died because of pneumonitis. The median time to the onset of irAEs after the initiation of treatment was 10 weeks (interquartile range, 6–19.5 weeks) and varied depending on the organ system involved.ConclusionsThe specificity of irAEs was closely associated with the mechanism of PD-1/PD-L1 antibodies involved in restarting anticancer immune attacks. Comprehensive understanding, timely detection, and effective management could improve the compliance of patients and guide the interruption of treatment.

Highlights

Programmed cell death protein-1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have remarkable clinical efficacy in the treatment of non-small cell lung cancer (NSCLC); the breakdown of immune escape causes a variety of immune-related adverse events
PD-1 inhibitors pembrolizumab and nivolumab as well as the PD-L1 inhibitors atezolizumab, avelumab, and durvalumab have all been approved in succession by the Food and Drug Administration (FDA) for treating patients with metastatic NSCLC
The titles and abstracts were read for these 805 articles, and 643 articles were excluded because they were duplicate articles, included non-NSCLC tumors, or reported the use of the inhibitors in combination with other drugs or were review articles, basic research articles, or off topic

Summary

Introduction

Programmed cell death protein-1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have remarkable clinical efficacy in the treatment of non-small cell lung cancer (NSCLC); the breakdown of immune escape causes a variety of immune-related adverse events (irAEs). In 2002, a study using cloned antibodies in a mouse model showed that local immunosuppression can be abolished by blocking the binding of PD-1 and programmed cell death ligand 1 (PD-L1) [1] This strategy established the basis for using PD-1/PD-L1 monoclonal antibodies to treat tumors. Inhibitors of PD-1 and PD-L1 act as ICIs by relaunching T cell-mediated tumor cell death programs (Fig. 1) These inhibitors have shown promising clinical efficacy in the treatment of non-small cell lung cancer (NSCLC), which remains a leading cause of cancer-related mortality [2]. The use of the same treatment for different diseases signifies a deeper and more comprehensive understanding of cancer and represents an important milestone in precision medicine

Objectives

Methods

Results

Discussion

Conclusion