Meta-analysis of immune-related adverse events of immune checkpoint inhibitor therapy in cancer patients
Topic: Immunotherapy

Abstract
Background: Immune checkpoint inhibitors (ICIs) have significant clinical efficacy in the treatment of non-small cell lung cancer (NSCLC); however, the incidence of immune-related adverse events (irAEs) of up to 50% has prevented their widespread use. With the increase in the use of ICIs alone or as combination therapy, clinicians are required to have a better understanding of irAEs and be able to manage them systematically. In this study, we aimed to assess the incidence of irAEs associated with ICIs.

Methods: We searched PubMed, Embase, and the Web of Science databases, and also included relevant literature references to widen our search. The relevant data with inclusion criteria were performed using RevMan 3.6.0 for meta-analysis. We undertook a systematic literature search which included published data up to December 2019.

Results: Overall, 147 articles and 23 761 cancer patients with 11 different ICI treatment-related (grade 1-5 and 3-5) irAEs were included in the study. There were 46 articles on pembrolizumab (6598 patients), 27 on nivolumab (3576 patients), 13 on atezolizumab (2787 patients), 12 on avelumab (3213 patients), 10 on durvalumab (1780 patients), 22 on ipilimumab (4067 patients), eight on tremelimumab (1158 patients), three on JS001 (223 patients), four on camrelizumab (SHR-1210) (178 patients), one on sintilimab (96 patients), and one on cemiplimab (85 patients). Grade 1-5 irAEs were: cytotoxic T lymphocyte antigen 4 (CTLA-4) (82.87%), programmed cell death 1 (PD-1) (71.89%), and programmed cell death ligand-1 (PD-L1) (58.95%). Subgroup analysis was: Avelumab (44.53%), durvalumab (66.63%), pembrolizumab (67.25%), atezolizumab (68.77%), nivolumab (76.25%), Ipilimumab (82.18%), and tremelimumab (86.78%). Grade 3-5 irAEs were: CTLA-4 (27.22%), PD-1(17.29%), and PD-L1(17.29%). Subgroup analysis was: Avelumab (5.86%), durvalumab (13.43%), atezolizumab (14.45%), nivolumab (15.72%), pembrolizumab (16.58%), tremelimumab (22.04%), and ipilimumab (28.27%).

Conclusions: This meta-analysis confirmed that anti-PD-1 and anti-PD-L1 inhibitors had a lower incidence of irAEs compared with anti-CTLA-4 inhibitors.

Keywords: Cancer; immune checkpoint inhibitor (ICI); immune-related adverse events (irAEs).

PICO
Population: Cancer patients receiving immune checkpoint inhibitor therapy
Intervention: Immune checkpoint inhibitor (ICI) therapy
Comparison: Different types of ICI therapies, including pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, ipilimumab, tremelimumab, JS001 (toripalimab), camrelizumab (SHR-1210), sintilimab, and cemiplimab
Outcomes: Incidence of immune-related adverse events (irAEs)

Included studies:
title: Pembrolizumab versus Ipilimumab in advanced melanoma
title: Pembrolizumab for the treatment of non–small‐cell lung cancer
title: Phase 1 study of pembrolizumab (MK‐3475; anti‐PD‐1 monoclonal antibody) in patients with advanced solid tumors
title: PD‐1 blockade in tumors with mismatch‐repair deficiency
title: Pembrolizumab versus investigator‐choice chemotherapy for ipilimumab‐refractory melanoma (KEYNOTE‐002): A randomised, controlled, phase 2 trial
title: Pembrolizumab versus docetaxel for previously treated, PD‐L1‐positive, advanced non‐small‐cell lung cancer (KEYNOTE‐010): A randomised controlled trial
title: Phase 1 study of pembrolizumab (MK‐3475; anti‐PD‐1 monoclonal antibody) in Japanese patients with advanced solid tumors
title: Pembrolizumab for patients with PD‐L1‐positive advanced gastric cancer (KEYNOTE‐012): A multicentre, open‐label, phase 1b trial
title: Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE‐012): An open‐label, multicentre, phase 1b trial
title: A phase II trial of pembrolizumab for patients with melanoma or non‐small cell lung cancer and untreated brain metastases
title: Pembrolizumab versus chemotherapy for PD‐L1–positive non–small‐cell lung cancer
title: Safety and antitumor activity of the anti‐PD‐1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal
title: Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE‐012): A non‐randomised, open‐label, phase 1b study
title: Pembrolizumab as first‐line therapy for patients with PD‐L1‐positive advanced non‐small cell lung cancer: A phase 1 trial
title: Phase II study of the efficacy and safety of Pembrolizumab for relapsed/refractory classic Hodgkin lymphoma
title: Mismatch‐repair deficiency predicts response of solid tumors to PD‐1 blockade
title: Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival results of a multicentre, randomised, open‐label phase 3 study (KEYNOTE‐006)
title: First‐line pembrolizumab in cisplatin‐ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE‐052): A multicentre, single‐arm, phase 2 study
title: Phase II trial of pembrolizumab in patients with platinum refractory germ‐cell tumors: A Hoosier cancer research network study GU14‐206
title: Pembrolizumab in patients with thymic carcinoma: A single‐arm, single‐centre, phase 2 study
title: Pembrolizumab for the treatment of advanced salivary gland carcinoma findings of the phase 1b KEYNOTE‐028 study
title: Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and Gastroesophageal junction cancer phase 2 clinical KEYNOTE‐059 trial
title: Safety and antitumor activity of Pembrolizumab in patients with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer
title: Adjuvant Pembrolizumab versus placebo in resected stage III melanoma
title: Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE‐224): A non‐randomised, open‐label phase 2 trial
title: Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro‐oesophageal junction cancer (KEYNOTE‐061): A randomised, open‐label, controlled, phase 3 trial
title: Pembrolizumab for advanced prostate adenocarcinoma: Findings of the KEYNOTE‐028 study
title: Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head‐and‐neck squamous cell carcinoma (KEYNOTE‐040): A randomised, open‐label, phase 3 study
title: Pembrolizumab in patients with programmed death ligand 1‐positive advanced ovarian cancer: Analysis of KEYNOTE‐028
title: Efficacy and safety of Pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of the esophagus the phase 2 KEYNOTE‐180 study
title: Randomised phase 2 study of pembrolizumab plus CC‐486 versus pembrolizumab plus placebo in patients with previously treated advanced non‐small cell lung cancer
title: Pembrolizumab versus chemotherapy for previously untreated, PD‐L1‐expressing, locally advanced or metastatic non‐small‐cell lung cancer (KEYNOTE‐042): A randomised, open‐label, controlled, phase 3 trial
title: Pembrolizumab alone or in combination with chemotheration as first‐line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: Results from the phase II nonrandomized KEYNOTE‐059 study
title: A phase Ib study of pembrolizumab as second‐line therapy for Chinese patients with advanced or metastatic melanoma (KEYNOTE‐151)
title: Efficacy and safety of Pembrolizumab in previously treated advanced cervical cancer: Results from the phase II KEYNOTE‐158 study
title: Randomized phase III KEYNOTE‐045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: Results of > 2 years of follow‐up
title: Pembrolizumab in patients with advanced triple‐negative breast cancer: Phase Ib KEYNOTE‐012 study
title: Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE‐028): Preliminary results from a non‐randomised, open‐label, phase 1b trial
title: Pembrolizumab for platinum‐ and Cetuximab‐refractory head and neck cancer: Results from a single‐arm, phase II study
title: Safety and antitumor activity of Pembrolizumab in patients with programmed death‐ligand 1‐positive nasopharyngeal carcinoma: Results of the KEYNOTE‐028 study
title: Safety and efficacy of Pembrolizumab in advanced, programmed death ligand 1‐positive cervical cancer: Results from the phase Ib KEYNOTE‐028 trial
title: Safety and antitumor activity of the anti‐programmed death‐1 antibody Pembrolizumab in patients with advanced esophageal carcinoma
title: Pembrolizumab monotherapy for previously untreated, PD‐L1‐positive, metastatic triple‐negative breast cancer: Cohort B of the phase II KEYNOTE‐086 study
title: Survival, durable tumor remission, and Long‐term safety in patients with advanced melanoma receiving Nivolumab
title: Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with Ipilimumab in small‐cell lung cancer
title: A subanalysis of Japanese patients in a randomized, double‐blind, placebo‐controlled, phase 3 trial of nivolumab for patients with advanced gastric or gastro‐esophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO‐4538‐12, ATTRACTION‐2)
title: Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT‐1501 MAPS2): A multicentre, open‐label, randomised, non‐comparative, phase 2 trial
title: Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma
title: Phase I study of Nivolumab, an anti‐PD‐1 antibody, in patients with malignant solid tumors
title: Multicenter phase II study of nivolumab in Japanese patients with relapsed or refractory classical Hodgkin lymphoma
title: Nivolumab in patients with metastatic DNA mismatch repair deficient/microsatellite instability–high colorectal cancer (CheckMate 142): Results of an open‐label, multicentre, phase 2 study
title: Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: A multicentre randomised phase 2 study
title: Efficacy and safety of nivolumab in Japanese patients with previously untreated advanced melanoma: A phase II study
title: Multicentre phase II study of nivolumab in Japanese patients with advanced or recurrent non‐squamous non‐small cell lung cancer
title: Efficacy and safety of nivolumab in Japanese patients with advanced or recurrent squamous non‐small cell lung cancer
title: Nivolumab treatment for oesophageal squamous‐cell carcinoma: An open‐label, multicentre, phase 2 trial
title: Safety and antitumor activity of anti‐PD‐1 antibody, Nivolumab, in patients with platinum‐resistant ovarian cancer
title: Activity and safety of nivolumab, an anti‐PD‐1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non‐small‐cell lung c ancer (CheckMate 063): A phase 2, single‐arm trial.
title: Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): Two open‐label, non‐comparative, randomised, phase 2 trials
title: PD‐1 blockade with Nivolumab in relapsed or refractory Hodgkin's lymphoma
title: Nivolumab versus Docetaxel in advanced nonsquamous non‐small‐cell lung cancer
title: Nivolumab versus Docetaxel in advanced squamous‐cell non‐small‐cell lung cancer
title: Nivolumab versus Everolimus in advanced renal‐cell carcinoma
title: Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti‐CTLA‐4 treatment (CheckMate 037): A randomised, controlled, open‐label, phase 3 trial
title: First‐line Nivolumab in stage IV or recurrent non–small‐cell lung cancer
title: Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma
title: Nivolumab in patients with advanced gastric or gastro‐oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO‐4538‐12, ATTRACTION‐2): A randomised, double‐blind, placebo‐controlled, phase 3 trial
title: Nivolumab for recurrent squamous‐cell carcinoma of the head and neck
title: Serious adverse events and fatal adverse events associated with nivolumab treatment in cancer patients: Nivolumab‐related serious/fatal adverse events
title: Predictive correlates of response to the anti‐PD‐L1 antibody MPDL3280A in cancer patients
title: Atezolizumab, an anti‐programmed death‐ligand 1 antibody, in metastatic renal cell carcinoma: Long‐term safety, clinical activity, and immune correlates from a phase Ia study
title: Atezolizumab as first‐line treatment in cisplatin‐ineligible patients with locally advanced and metastatic urothelial carcinoma: A single‐arm, multicentre, phase 2 trial
title: Atezolizumab versus docetaxel in patients with previously treated non‐small‐cell lung cancer (OAK): A phase 3, open‐label, multicentre randomised controlled trial
title: Phase II trial of Atezolizumab as first‐line or subsequent therapy for patients with programmed death‐ligand 1‐selected advanced non‐small‐cell lung cancer (BIRCH)
title: Atezolizumab versus chemotherapy in patients with platinum‐treated locally advanced or metastatic urothelial carcinoma (IMvigor211): A multicentre, open‐label, phase 3 randomised controlled trial
title: Atezolizumab (MPDL3280A) Monotherapy for patients with metastatic urothelial cancer: Long‐term outcomes from a phase 1 study
title: Efficacy, safety, and biomarker analysis of a phase II open‐label study of Atezolizumab in PD‐L1‐selected patients with NSCLC
title: Clinical activity and safety of atezolizumab in patients with recurrent glioblastoma
title: Safety and clinical activity of atezolizumab monotherapy in metastatic non‐small‐cell lung cancer: Final results from a phase I study
title: Safety and clinical activity of atezolizumab in head and neck cancer: Results from a phase I trial
title: Atezolizumab versus docetaxel for patients with previously treated non‐small‐cell lung cancer (POPLAR): A multicentre, open‐label, phase 2 randomised controlled trial
title: Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): A multicentre, open‐label, phase 3, randomised, controlled trial
title: Avelumab in patients with chemotherapy‐refractory metastatic Merkel cell carcinoma: A multicentre, single‐group, open‐label, phase 2 trial
title: Avelumab for patients with previously treated metastatic or recurrent non‐small‐cell lung cancer (JAVELIN solid tumor): Dose‐expansion cohort of a multicentre, open‐label, phase 1b trial
title: Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN solid tumor): A phase 1a, multicohort, dose‐escalation trial
title: Avelumab, an anti‐programmed death‐ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: Results from a multicenter, phase Ib study
title: Avelumab, an anti‐PD‐L1 antibody, in patients with locally advanced or metastatic breast cancer: A phase 1b JAVELIN solid tumor study
title: Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN solid tumor): Pooled results from two expansion cohorts of an open‐label, phase 1 trial
title: Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials
title: Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third‐line treatment of patients with advanced gastric or gastro‐oesophageal junction cancer: Primary analysis of JAVELIN gastric 300
title: Avelumab versus docetaxel in patients with platinum‐treated advanced non‐small‐cell lung cancer (JAVELIN lung 200): An open‐label, randomised, phase 3 study
title: Avelumab in patients with previously treated metastatic adrenocortical carcinoma: Phase 1b results from the JAVELIN solid tumor trial
title: Efficacy and safety of Avelumab treatment in patients with advanced unresectable mesothelioma: Phase 1b results from the JAVELIN solid tumor trial
title: Avelumab in patients with previously treated metastatic melanoma: Phase 1b results from the JAVELIN solid tumor trial
title: Efficacy and safety of Avelumab for patients with recurrent or refractory ovarian cancer: Phase 1b results from the JAVELIN solid tumor trial
title: Avelumab (anti‐PD‐L1) as first‐line switch‐maintenance or second‐line therapy in patients with advanced gastric or gastroesophageal junction cancer: Phase 1b results from the JAVELIN solid tumor trial
title: Safety and efficacy of Durvalumab (MEDI4736), an anti‐programmed cell death ligand‐1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer
title: Durvalumab after chemoradiotherapy in stage III non‐small‐cell lung cancer
title: Durvalumab as third‐line or later treatment for advanced non‐small‐cell lung cancer (ATLANTIC): An open‐label, single‐arm, phase 2 study
title: Efficacy and safety of Durvalumab in locally advanced or metastatic urothelial carcinoma: Updated results from a phase 1/2 open‐label study
title: Safety and Efficacy of Durvalumab (MEDI4736) in Various Solid Tumors
title: 'DURVIT': A phase‐I trial of single low‐dose durvalumab (Medi4736) intratumourally injected in cervical cancer: Safety, toxicity and effect on the primary tumour‐ and lymph node microenvironment
title: Safety and efficacy of Durvalumab with or without Tremelimumab in patients with PD‐L1‐low/negative recurrent or metastatic HNSCC: The phase 2 CONDOR randomized clinical trial
title: Durvalumab for recurrent or metastatic head and neck squamous cell carcinoma: Results from a single‐arm, phase II study in patients with ≥25% tumour cell PD‐L1 expression who have progressed on platinum‐based chemotherapy
title: Safety and efficacy of durvalumab in patients with head and neck squamous cell carcinoma: Results from a phase I/II expansion cohort
title: A pilot trial of CTLA‐4 blockade with human anti‐CTLA‐4 in patients with hormone‐refractory prostate cancer
title: Ipilimumab alone or in combination with radiotherapy in metastatic castration‐resistant prostate cancer: Results from an open‐label, multicenter phase I/II study
title: Phase I/II study of Ipilimumab for patients with metastatic melanoma
title: Phase II study of ipilimumab monotherapy in Japanese patients with advanced melanoma
title: Prolonged survival in stage III melanoma with Ipilimumab adjuvant therapy
title: Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: A randomised, double‐blind, multicentre, phase 3 trial
title: Randomized, double‐blind, phase III trial of Ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy‐naïve castration‐resistant prostate cancer
title: Randomized, open‐label phase II study evaluating the efficacy and safety of Talimogene laherparepvec in combination with Ipilimumab versus Ipilimumab alone in patients with advanced, unresectable melanoma
title: Adjuvant Nivolumab versus Ipilimumab in resected stage III or IV melanoma
title: Efficacy of sequential Ipilimumab monotherapy versus best supportive care for unresectable locally advanced/metastatic gastric or gastroesophageal junction cancer
title: Open‐label, multicenter, single‐arm phase II DeCOG‐study of ipilimumab in pretreated patients with different subtypes of metastatic melanoma
title: Randomized phase I pharmacokinetic study of ipilimumab with or without one of two different chemotherapy regimens in patients with untreated advanced melanoma
title: Phase II study of ipilimumab in adolescents with unresectable stage III or IV malignant melanoma
title: A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy‐naïve patients with advanced melanoma
title: A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma
title: Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma
title: Combined Nivolumab and Ipilimumab or monotherapy in previously untreated melanoma
title: Sargramostim plus Ipilimumab vs Ipilimumab alone for treatment of metastatic melanoma: A randomized clinical trial
title: Improved survival with Ipilimumab in patients with metastatic melanoma
title: A Randomized, Double‐Blind, Placebo‐Controlled, Phase II Study Comparing the Tolerability and Efficacy of Ipilimumab Administered with or without Prophylactic Budesonide in Patients with Unresectable Stage III or IV Melanoma
title: Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma
title: Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double‐blind, multicentre, phase 2, dose‐ranging study
title: Phase I/II trial of Tremelimumab in patients with metastatic melanoma
title: Phase II trial of Tremelimumab (CP‐675,206) in patients with advanced refractory or relapsed melanoma
title: Phase II study of the anti‐cytotoxic T‐lymphocyte–associated antigen 4 monoclonal antibody, Tremelimumab, in patients with refractory metastatic colorectal cancer
title: Phase III randomized clinical trial comparing Tremelimumab with standard‐of‐care chemotherapy in patients with advanced melanoma
title: Tremelimumab for patients with chemotherapy‐resistant advanced malignant mesothelioma: An open‐label, single‐arm, phase 2 trial
title: A phase 2 study of tremelimumab in patients with advanced uveal melanoma
title: Tremelimumab as second‐line or third‐line treatment in relapsed malignant mesothelioma (DETERMINE): A multicentre, international, randomised, double‐blind, placebo‐controlled phase 2b trial
title: Safety and clinical activity with an anti‐PD‐1 antibody JS001 in advanced melanoma or urologic cancer patients
title: Promising efficacy of SHR‐1210, a novel anti‐programmed cell death 1 antibody, in patients with advanced gastric and gastroesophageal junction cancer in China
title: Addition of low‐dose Decitabine to anti‐PD‐1 antibody Camrelizumab in relapsed/refractory classical Hodgkin lymphoma
title: Camrelizumab (SHR‐1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: Results from two single‐arm, phase 1 trials
title: Safety, anti‐tumour activity, and pharmacokinetics of fixed‐dose SHR‐1210, an anti‐PD‐1 antibody in advanced solid tumours: A dose‐escalation, phase 1 study
title: Safety and activity of sintilimab in patients with relapsed or refractory classical Hodgkin lymphoma (ORIENT‐1): A multicentre, single‐arm, phase 2 trial
title: PD‐1 blockade with Cemiplimab in advanced cutaneous squamous‐cell carcinoma