scholarly journals The quality of reporting general safety parameters and immune-related adverse events in clinical trials of FDA-approved immune checkpoint inhibitors

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Zahra Karimian ◽  
Sandra Mavoungou ◽  
Joe-Elie Salem ◽  
Florence Tubach ◽  
Agnès Dechartres
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Safety Information ◽  
Safety Data ◽  
Phase Iii ◽  
Quality Of Reporting ◽  
Link Type

Abstract Background While immune-checkpoint inhibitors (ICIs) have transformed the field of oncology for advanced-stage cancers, they can lead to serious immune toxicities. Several systematic reviews have evaluated the risk of immune-related adverse events (irAEs); however, most have focused on published articles without evaluating trial registries. The objective of this methodological review was to compare the quality of reporting of safety information and in particular, serious irAEs (irSAEs), in both publications and ClinicalTrials.gov for all current FDA-approved ICIs. Methods PubMed was searched to retrieve all published phase III randomized controlled trials (RCTs) evaluating ICIs. For each eligible trial, we searched for corresponding registration on ClinicalTrials.gov and extracted relevant safety data from both the publication and results posted on registry. We then compared the quality of reporting and the value of safety data between both sources. Results Of 42 eligible published trials, 34 had results posted on ClinicalTrials.gov. Considerable variability was noted in the reporting of safety in both sources. SAEs were reported for all trial results in ClinicalTrials.gov compared to 23.5% of publications. An overall incidence for irAEs and irSAEs was reported in 58.8 and 8.8% of publications respectively, compared to 11.8 and 5.9% in registry results. Comparing the value of specific irSAEs was not possible between the two sources in 32/34 trials either due to different reporting formats (61.8%) or data not being reported in one or both sources (32.4%). From the 2 studies with compatible irSAE format, only 1 had matching data in both sources. Conclusions The reporting of irAEs / irSAEs varies considerably in publications and registries, which outlines the importance of standardizing the terminologies and methodologies for reporting safety information relevant to ICIs.

scholarly journals The quality of reporting general safety parameters and immune-related adverse events in clinical trials of FDA-approved immune checkpoint inhibitors

2020 ◽  
Author(s):  
Zahra Karimian ◽  
Sandra Mavoungou ◽  
Joe-Elie Salem ◽  
Florence Tubach ◽  
Agnes Dechartres
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Safety Information ◽  
Safety Data ◽  
Phase Iii ◽  
Quality Of Reporting ◽  
Safety Parameters

Abstract Background – While immune-checkpoint inhibitors (ICIs) have transformed the field of oncology for advanced-stage cancers, they can lead to serious immune toxicities. Several systematic reviews have evaluated the risk of immune-related adverse events (irAEs); however, most have focused on published articles without evaluating trial registries. The objective of this methodological review was to compare the quality of reporting of safety information and in particular, serious irAEs (irSAEs), in both publications and ClinicalTrials.gov for all current FDA-approved ICIs. Methods – PubMed was searched to retrieve all published phase III randomized controlled trials (RCTs) evaluating ICIs. For each eligible trial, we searched for corresponding registration on ClinicalTrials.gov and extracted relevant safety data from both the publication and results posted on registry. We then compared the quality of reporting and the value of safety data between both sources. Results – Of 42 eligible published trials, 34 had results posted on ClinicalTrials.gov. Considerable variability was noted in the reporting of safety in both sources. SAEs were reported for all trial results in ClinicalTrials.gov compared to 23.5% of publications. An overall incidence for irAEs and irSAEs was reported in 58.8% and 8.8% of publications respectively, compared to 11.8% and 5.9% in registry results. Comparing the value of specific irSAEs was not possible between the two sources in 32/34 trials either due to different reporting formats (61.8%) or data not being reported in one or both sources (32.4%). From the 2 studies with compatible irSAE format, only 1 had matching data in both sources. Conclusions – The reporting of irAEs / irSAEs varies considerably in publications and registries, which outlines the importance of standardizing the terminologies and methodologies for reporting safety information relevant to ICIs.

scholarly journals The quality of reporting general safety parameters and immune-related adverse events in clinical trials of FDA-approved immune checkpoint inhibitors

2020 ◽  
Author(s):  
Zahra Karimian ◽  
Sandra Mavoungou ◽  
Joe-Elie Salem ◽  
Florence Tubach ◽  
Agnes Dechartres
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Safety Information ◽  
Safety Data ◽  
Phase Iii ◽  
Quality Of Reporting ◽  
Safety Parameters

Abstract Background – While immune-checkpoint inhibitors (ICIs) have transformed the field of oncology for advanced-stage cancers, they can lead to serious immune toxicities. Several systematic reviews have evaluated the risk of immune-related adverse events (irAEs); however, most have focused on published articles without evaluating trial registries. The objective of this methodological review was to compare the quality of reporting of safety information and in particular, serious irAEs (irSAEs), in both publications and ClinicalTrials.gov for all current FDA-approved ICIs.Methods – PubMed was searched to retrieve all published phase III randomized controlled trials (RCTs) evaluating ICIs. For each eligible trial, we searched for corresponding registration on ClinicalTrials.gov and extracted relevant safety data from both the publication and results posted on registry. We then compared the quality of reporting and the value of safety data between both sources.Results – Of 42 eligible published trials, 34 had results posted on ClinicalTrials.gov. Considerable variability was noted in the reporting of safety in both sources. SAEs were reported for all trial results in ClinicalTrials.gov compared to 23.5% of publications. An overall incidence for irAEs and irSAEs was reported in 58.8% and 8.8% of publications respectively, compared to 11.8% and 5.9% in registry results. Comparing the value of specific irSAEs was not possible between the two sources in 32/34 trials either due to different reporting formats (61.8%) or data not being reported in one or both sources (32.4%). From the 2 studies with compatible irSAE format, only 1 had matching data in both sources.Conclusions – The reporting of irAEs / irSAEs varies considerably in publications and registries, which outlines the importance of standardizing the terminologies and methodologies for reporting safety information relevant to ICIs.

scholarly journals Evaluation of the Reporting of Safety and Immune-Related Adverse Events in Clinical Trials of FDA-Approved Immune Checkpoint Inhibitors in Oncology

2020 ◽  
Author(s):  
Zahra Karimian ◽  
Sandra Mavoungou ◽  
Joe-Elie Salem ◽  
Florence Tubach ◽  
Agnes Dechartres
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Safety Information ◽  
Safety Data ◽  
Phase Iii ◽  
Considerable Variability ◽  
Methodological Review ◽  
Randomized Controlled

Abstract Background – While immune-checkpoint inhibitors (ICIs) have transformed the field of oncology for advanced stage cancers, they can lead to serious immune toxicities. Several systematic reviews have evaluated the risk of immune-related adverse events (irAEs); however, most have focused on published articles without evaluating trial registries. The objective of this methodological review was to compare the reporting of safety information and in particular, serious irAEs (irSAEs), in both publications and ClinicalTrials.gov for all current FDA-approved ICIs. Methods – MEDLINE was searched via PubMed to retrieve all published phase III randomized controlled trials (RCTs) evaluating ICIs. For each eligible trial, we searched for corresponding registration on ClinicalTrials.gov and extracted relevant safety data from both the publication and results posted on registry. We then compared reporting and evaluated concordance in reported safety data between both sources. Results – Of 42 eligible published trials, 34 had results posted on ClinicalTrials.gov. Considerable variability was noted in the reporting of safety in both sources. SAEs were reported for all trial results in ClinicalTrials.gov compared to 23.5% of publications. An overall incidence for irAEs and irSAEs was reported in 58.8% and 8.8% of published trials respectively, compared to 11.8% and 5.9% of registry results. Evaluating the concordance of specific irSAEs was not possible between the two sources in 32/34 trials either due to different reporting formats (61.8%) or data not being reported in one or both sources (32.4%). From the 2 studies with compatible irSAE format, only 1 had concordant data between both sources.Conclusions – The reporting of irAEs / irSAEs varies considerably in publications and registries, which outlines the importance of standardizing the terminologies and methodologies for reporting safety information relevant to ICIs.

scholarly journals 540 Baseline mTOR transcriptional signatures in CD8 T cells are associated with immune-related adverse events but not anti-tumor responses in patients receiving immune checkpoint inhibitors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A570-A570
Author(s):  
Chen Zhao ◽  
Matthew Mule ◽  
Andrew Martins ◽  
Iago Pinal Fernandez ◽  
Renee Donahue ◽  
...  
Keyword(s):  
T Cells ◽  
Adverse Events ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Effector Memory ◽  
Link Type ◽  
Anti Tumor Activity

BackgroundImmune checkpoint inhibitors (ICIs) have changed the cancer treatment landscape, but immune-related adverse events (irAEs) can affect a wide range of tissues in patients receiving ICIs. Severe irAEs can be life-threatening or fatal and prohibit patients from receiving further ICI treatment. While the clinical features of irAEs are well documented, the pathological mechanisms and predictive biomarkers are largely unknown. In addition, there is a critical need to preserve ICI-induced anti-tumor immunity while controlling for irAEs, which requires deciphering molecular and cellular signatures associated specifically with irAEs beyond those more generally linked to anti-tumor immunity.MethodsTo unbiasedly identify immune cells and states associated with irAEs, we applied CITE-seq to measure transcripts and surface proteins (83 protein markers) from PBMCs collected from patients with thymic epithelial tumors before and after treatment with an anti-PD-L1 antibody (avelumab, NCT01772004, NCT03076554).ResultsSamples from 9 patients were analyzed. No patient had a history of pre-existing paraneoplastic autoimmune disease. Anti-tumor activity was observed in all cases, and 5 patients had clinical and/or biochemical evidence of immune-related muscle inflammation (myositis with or without myocarditis). Multilevel models applied within highly resolved cell clusters revealed transcriptional states associated with ICI response and more uniquely with irAEs. A total of 190,000 cells were included in the analysis after quality control. Most notably, CD45RA+ effector memory CD8 T cells with an mTOR transcriptional signature were highly enriched at baseline and post treatment in patients with irAEs.ConclusionsOur findings suggest the potential therapeutic avenues by using mTOR inhibitors to dampen autoimmune responses while potentially sparing anti-tumor activity, to prevent treatment discontinuation and improve clinical outcomes for cancer patients treated with ICIs.AcknowledgementsThis research was supported in part by the Intramural Research Program of the NCI (the Center for Cancer Research), NIAID and NIAMS, and through a Cooperative Research and Development Agreement between the National Cancer Institute and EMD Serono.Trial RegistrationNCT01772004, NCT03076554Ethics ApprovalThis study is approved by NCI institutional review board.

scholarly journals Efficacy and immune-related adverse event associations in avelumab-treated patients

2020 ◽  
Vol 8 (2) ◽  
pp. e001427
Author(s):  
Karen Kelly ◽  
Juliane Manitz ◽  
Manish R Patel ◽  
Sandra P D’Angelo ◽  
Andrea B Apolo ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cox Model ◽  
Safety Data ◽  
Time Dependent ◽  
Risk Of Death ◽  
Link Type ◽  
Event Order

BackgroundAdverse events (AEs) of special interest that arise during treatment with immune checkpoint inhibitors, including immune-related AEs (irAEs), have been reported to be associated with improved clinical outcomes. We analyzed patients treated with avelumab from the JAVELIN Solid Tumor and Merkel 200 trials, examining the association between AEs and efficacy while adjusting for confounding factors such as treatment duration and event order.MethodsWe analyzed efficacy and safety data from 1783 patients treated with the programmed death ligand 1 inhibitor avelumab who were enrolled in expansion cohorts of the JAVELIN Solid Tumor and Merkel 200 trials. To analyze the association between irAEs and efficacy with regard to survival, we used a time-dependent Cox model with time-varying indicators for irAEs, as well as multistate models that accounted for competing risks and time inhomogeneity.Results295 patients (16.5%) experienced irAEs and 454 patients (25.5%) experienced infusion-related reactions. There was a reduced risk of death in patients who experienced irAEs compared with those who did not (HR 0.71, 95% CI 0.59 to 0.85) using the time-dependent Cox model. The multistate model did not suggest that the occurrence of irAEs could predict response; however, it predicted a higher chance of irAEs occurring after a response. No association was observed between response and infusion-related reactions.ConclusionsPatients who experience irAEs showed improved survival. Although irAEs are not predictors for response to immune checkpoint inhibitors, increased vigilance for irAEs is needed after treatment with avelumab.Trial registration numbersNCT01772004 and NCT02155647.

scholarly journals Pulmonary adverse events due to immune checkpoint inhibitors: A literature review

2021 ◽  
Author(s):  
Vasiliki Epameinondas Georgakopoulou ◽  
Nikolaos Garmpis ◽  
Dimitrios Mermigkis ◽  
Christos Damaskos ◽  
Serafeim Chlapoutakis ◽  
...  
Keyword(s):  
Immune System ◽  
Adverse Events ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Allergic Bronchopulmonary Aspergillosis ◽  
Pulmonary Nodules ◽  
Airway Disease

Cancer immunotherapy aims to stimulate the immune system to fight against tumors, utilizing the presentation of molecules on the surface of the malignant cells that can be recognized by the antibodies of the immune system. Immune checkpoint inhibitors, a type of cancer immunotherapy, are broadly used in different types of cancer, improving patients’ survival and quality of life. However, treatment with these agents causes immune-related toxicities affecting many organs. The most frequent pulmonary adverse event is pneumonitis representing a non-infective inflammation localized to the interstitium and alveoli. Other lung toxicities include airway disease, pulmonary vasculitis, sarcoid-like reactions, infections, pleural effusions, pulmonary nodules, diaphragm myositis and allergic bronchopulmonary aspergillosis. This review aims to summarize these pulmonary adverse events, underlining the significance of an optimal expeditious diagnosis and management.   

scholarly journals FRI0494 RHEUMATIC IMMUNE RELATED ADVERSE EVENTS OF CHECKPOINT INHIBITORS: A RETROSPECTIVE REVIEW OF 70 PATIENTS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 845.2-846
Author(s):  
T. Lenfant ◽  
L. Calabrese ◽  
C. Calabrese
Keyword(s):  
Adverse Events ◽  
Prospective Studies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Clinical Aspects ◽  
Link Type ◽  
Conventional Dmards

Background:Immune Checkpoint inhibitors (ICI) have revolutionized cancer therapy by achieving remarkable survival benefits however, at the cost of a myriad of immune-related adverse events (irAEs)[1]. Rheumatic irAE can develop in 5-10% of patients although the true incidence is unknown given the lack of prospective studies [2]. Symptoms are heterogenous and probably underreported with few data available about their management and outcome [3].Objectives:To describe the clinical, biological, and radiological features of the largest cohort of rheumatic irAEs from ICI along with their therapeutic management, outcome and follow-up in real-world practice.Methods:A referral process for emergent rheumatic irAEs was initiated in February 2016 between the oncology and rheumatology departments at the Cleveland Clinic Foundation. All patients were evaluated by authors CC and/or LHC. Patients’ characteristics were retrospectively collected from medical charts after IRB approval.Results:70 patients referred for one or more rheumatic irAEs between February 2016 and January 2020 were included. 66% were male, median age was 60.8 years. Among them, 24 (34%) had pre-existing rheumatic complaints. Melanoma was the most frequent malignancy (56%). ICI therapy included anti-CTLA4 (40%), anti-PD1/L1 (79%), and dual therapy ipilimumab/nivolumab (41%). Rheumatic irAE occurred in a median 4 months after ICI initiation, with phenotypes including inflammatory arthritis (32 patients), sicca-like symptoms (12), polymyalgia rheumatica-like (7), and myositis (2). Oral, intravenous or intraarticular glucocorticoids (GC) were administered to 54 patients (77%). Of these 54 patients, 22 (41%) required long term GC, 19 had bone density scan and 15 received pneumocystis (PJP) prophylaxis. One PJP case, 1 osteoporotic fracture and 2 avascular necrosis cases were reported. 16 patients received conventional DMARDS (23%) and 9 received biologics (13%). ICI therapy was held for rheumatic irAE in 31% of cases and for another systemic irAE in 29%. Median follow-up was 13.6 months, at end of follow-up 51 patients were still on treatment for rheumatic irAE and 41% of them were still symptomatic despite ongoing treatment.Conclusion:Rheumatic irAEs are heterogeneous and often chronic requiring prolonged immunomodulatory therapy. Prospective studies are required to define optimal management of rheumatic irAEs that maintain long-term oncologic outcomes.References:[1]Suarez-Almazor ME, Kim ST, Abdel-Wahab N, Diab A. Review: Immune-Related Adverse Events With Use of Checkpoint Inhibitors for Immunotherapy of Cancer. Arthritis Rheumatol 2017;69:687–99.https://doi.org/10.1002/art.40043.[2]Abdel-Wahab N, Suarez-Almazor ME. Frequency and distribution of various rheumatic disorders associated with checkpoint inhibitor therapy. Rheumatol (United Kingdom) 2019;58:vii40–8.https://doi.org/10.1093/rheumatology/kez297.[3]Kostine M, Rouxel L, Barnetche T, Veillon R, Martin F, Dutriaux C, et al. Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study. Ann Rheum Dis 2018;77:393–8.https://doi.org/10.1136/annrheumdis-2017-212257.Disclosure of Interests:Tiphaine Lenfant: None declared, Leonard Calabrese Consultant of: AbbVie, GSK, Bristol-Myers Squibb, Genentech, Janssen, Novartis, Sanofi, Horizon, Crescendo, and Gilead, Speakers bureau: Sanofi, Horizon, Crescendo, Novartis, Genentech, Janssen, and AbbVie, cassandra calabrese Consultant of: AbbvieGSK, Speakers bureau: Sanofi-Genzyme

scholarly journals IMMU-04. IMMUNE-RELATED ADVERSE EVENTS STRONGLY PREDICT SUPERIOR OUTCOMES IN BRAIN METASTASES PATIENTS RECEIVING LOCAL TREATMENT AND IMMUNE CHECKPOINT INHIBITORS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii105-ii105
Author(s):  
Alexander Hulsbergen ◽  
Asad Lak ◽  
Yu Tung Lo ◽  
Nayan Lamba ◽  
Steven Nagtegaal ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Adverse Events ◽  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Local Treatment ◽  
Sensitivity Analyses ◽  
Immortal Time Bias ◽  
The Brain

Abstract INTRODUCTION In several cancers treated with immune checkpoint inhibitors (ICIs), a remarkable association between the occurrence of immune-related adverse events (irAEs) and superior oncological outcomes has been reported. This effect has hitherto not been reported in the brain. This study aimed to investigate the relation between irAEs and outcomes in brain metastases (BM) patients treated with both local treatment to the brain (LT; i.e. surgery and/or radiation) and ICIs. METHODS This study is a retrospective cohort analysis of patients treated for non-small cell lung cancer (NSCLC) BMs in a tertiary institution in Boston, MA. Outcomes of interest were overall survival (OS) and intracranial progression-free survival (IC-PFS), measured from the time of LT. Sensitivity analyses were performed to account for immortal time bias (i.e., patients who live longer receive more cycles of ICIs and thus have more opportunity to develop an irAE). RESULTS A total of 184 patients were included; 62 (33.7%) were treated with neurosurgical resection and 122 (66.3%) with upfront brain radiation. irAEs occurred in 62 patients (33.7%). After adjusting for lung-Graded Prognostic Assessment, type of LT, type of ICI, newly diagnosed vs. recurrent BM, BM size and number, targetable mutations, and smoking status, irAEs were strongly associated with better OS (HR 0.33, 95% CI 0.19 – 0.58, p < 0.0001) and IC-PFS (HR 0.41; 95% CI 0.26 – 0.65; p = 0.0001). Landmark analysis including only patients who received more than 3 cycles of ICI (n = 133) demonstrated similar results for OS and IC-PFS, as did sensitivity analysis adjusting for the number of cycles administered (HR range 0.36 – 0.51, all p-values < 0.02). CONCLUSIONS After adjusting for known prognostic factors, irAEs strongly predict superior outcomes after LT in NSCLC BM patients. Sensitivity analysis suggests that this is unlikely due to immortal time bias.

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