scholarly journals Eosinophil Count as Predictive Biomarker of Immune-Related Adverse Events (irAEs) in Immune Checkpoint Inhibitors (ICIs) Therapies in Oncological Patients

Immuno ◽  
2021 ◽  
Vol 1 (3) ◽  
pp. 253-263
Author(s):  
Elisa Giommoni ◽  
Roberta Giorgione ◽  
Agnese Paderi ◽  
Elisa Pellegrini ◽  
Elisabetta Gambale ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Eosinophil Count ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Predictive Biomarker ◽  
Response To Treatment ◽  
Analysis Model

Background: To date, no biomarkers are effective in predicting the risk of developing immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors (ICIs). This study aims to evaluate the association between basal absolute eosinophil count (AEC) and irAEs during treatment with ICIs for solid tumors. Methods: We retrospectively evaluated 168 patients with metastatic melanoma (mM), renal cell carcinoma (mRCC), and non-small cell lung cancer (mNSCLC) receiving ICIs at our medical oncology unit. By combining baseline AEC with other clinical factors, we developed a mathematical model for predicting the risk of irAEs, which we validated in an external cohort of patients. Results: Median baseline AEC was 135/µL and patients were stratified into two groups accordingly; patients with high baseline AEC (>135/µL) were more likely to experience toxicity (p = 0.043) and have a better objective response rate (ORR) (p = 0.003). By constructing a covariance analysis model, it emerged that basal AEC correlated with the risk of irAEs (p < 0.01). Finally, we validated the proposed model in an independent cohort of 43 patients. Conclusions: Baseline AEC could be a predictive biomarker of ICI-related toxicity, as well as of response to treatment. The use of a mathematical model able to predict the risk of developing irAEs could be useful for clinicians for monitoring patients receiving ICIs.

scholarly journals Identification and validation of tissue or ctDNA PTPRD phosphatase domain deleterious mutations as prognostic and predictive biomarkers for immune checkpoint inhibitors in non-squamous NSCLC

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yiting Sun ◽  
Jianchun Duan ◽  
Wenfeng Fang ◽  
Zhijie Wang ◽  
Xinyang Du ◽  
...  
Keyword(s):  
Clinical Data ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Validation Cohort ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Predictive Biomarker ◽  
Deleterious Mutations ◽  
Phosphatase Domain ◽  
Nsclc Patients

Abstract Background With the revolutionary progress of immune checkpoint inhibitors (ICIs) achieved in non-small cell lung cancers (NSCLC), identifying patients benefiting from ICIs becomes critical and urgent. The associations of genomic alterations in protein tyrosine phosphatase receptor-type (PTPRs) and ICIs responses are unknown. Methods Whole-exome sequencing (WES) of 73 advanced NSCLC tumors sampled before anti-PD-(L)1 therapy was carried out with corresponding clinical data collected as a discovery cohort to find the associations of PTPR mutations and ICI responses. Three validation cohorts consolidated by 7 public cohorts of 1920 NSCLC patients with WES or target sequencing data of tumor tissue-derived DNA or circulating tumor DNA (ctDNA) and relevant clinical data were applied as validation cohorts. The lung adenocarcinoma (LUAD) cohort (n=586) in The Cancer Genome Atlas (TCGA) database was used for analyzing the potential anti-tumor immunologic mechanisms. Results With the highest mutation frequency among all PTPRs, PTPRD mutations in non-squamous NSCLC (ns-NSCLC) were linked to longer progression-free survivals (PFS, 324 vs 63 days, hazard ratio (HR)=0.36, p= 0.0152) and higher objective response rate (ORR, p=0.0099). In validation cohort 1 (n=377), ns-NSCLC patients with tissue PTPRD mutations had favorable PFS (9.10 vs 4.33 months, HR=0.62, p=0.0184) and ORR (p=0.013). In validation cohort 2 (n=406), ns-NSCLC patients with tissue PTPRD mutations had favorable overall survivals (OS, over 40 vs 11.94 months, HR=0.57, p=0.011). In validation cohort 3 (n=1137), ns-NSCLC patients with ctDNA PTPRD mutations had longer PFS (6.97 vs 2.73 months, HR=0.63, p=0.028) and higher ORR (p=0.047). Moreover, it was deleterious mutations in phosphatase domains (phosphatase-mut), rather than other mutations (other-mut), that were responsible of PTPRD’s prediction efficiency. In addition, in validation cohort 3, ctDNA phosphatase-mut also functioned as a predictive biomarker helping identify patients benefiting more from ICIs than chemotherapy (interaction P for PFS=0.0506, for OS=0.04). Univariate and multivariate regression analysis revealed that phosphatase-mut was independent on PD-L1 expression and tumor mutation burden (TMB) to predict. In silico analysis based on TCGA LUAD cohort discovered enhanced anti-tumor immunity in phosphatase-mut patients. Conclusions Tissue or ctDNA PTPRD phosphatase domain deleterious mutations might function as a both prognostic and predictive biomarker predicting clinical outcomes of ICIs in ns-NSCLC patients, independent on TMB or PD-L1 expression.

scholarly journals Correlation Between Immune-Related Adverse Events and Prognosis in Hepatocellular Carcinoma Patients Treated With Immune Checkpoint Inhibitors

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuo Xu ◽  
Ruixue Lai ◽  
Qian Zhao ◽  
Pandong Zhao ◽  
Ruili Zhao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Clinical Benefit ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Low Grade ◽  
Better Than

BackgroundImmune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) were associated with clinical benefit in cancer patients of melanoma, a lung cancer. In the present study, we investigated the correlation between irAE and ICI efficacy in hepatocellular carcinoma (HCC) patients.MethodsWe divided the HCC patients who received the anti-PD-1 antibody into two groups as irAE group and non-irAE group according to the National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.03. The treatment efficacy of ICIs was evaluated with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).ResultOf the 65 HCC patients who received the anti-PD-1 antibody (monotherapy or combined with targeted medicine), median PFS in the irAE group was superior to that in the non-irAE group (302 days vs. 148 days, p = 0.004). Median OS in the irAE group was also better than that in the non-irAE group (374 days vs. 279 days, p = 0.038). Although the statistical difference for DCR in the irAE group and non-irAE group was not reached, the DCR of the irAE displayed a trend better than that of the non-irAE group (41.20% vs. 20.80%, p = 0.118). Multivariate analysis also demonstrated that the non-irAE group (HR = 6.410, 95% CI: 1.404 to 29.275) was associated independently with the poor prognosis.ConclusionsDevelopment of irAEs was associated with clinical benefit for HCC patients who were treated with immune checkpoint inhibitors; irAE, particularly low-grade irAE, was a predictable marker for better ICI treatment efficiency in HCC patients.

scholarly journals Immune-Related Adverse Events Predict the Efficacy of Immune Checkpoint Inhibitors in Lung Cancer Patients: A Meta-Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Donghui Wang ◽  
Cen Chen ◽  
Yanli Gu ◽  
Wanjun Lu ◽  
Ping Zhan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Objective Response ◽  
Progression Free Survival ◽  
Lung Cancer Patients

BackgroundImmune-related adverse events (irAEs) have been reported to be associated with the efficacy of immunotherapy. Herein, we conducted a meta-analysis to demonstrate that irAEs could predict the efficacy of immune checkpoint inhibitors (ICIs) in lung cancer patients.MethodsLiterature on the correlation between irAEs and the efficacy of immunotherapy in lung cancer patients were searched to collect the data on objective response rate (ORR), overall survival (OS), or progression-free survival (PFS) of the patients. These data were incorporated into the meta-analysis.ResultsA total of 34 records encompassing 8,115 patients were examined in this study. The irAEs occurrence was significantly associated with higher ORR {risk ratio (RR): 2.43, 95% confidence interval (CI) [2.06–2.88], p &lt; 0.00001} and improved OS {hazard ratio (HR): 0.51, 95% CI [0.43–0.61], p &lt; 0.00001}, and PFS (HR: 0.50, 95% CI [0.44–0.57], p &lt; 0.00001) in lung cancer patients undergoing ICIs. Subgroup analysis revealed that OS was significantly longer in patients who developed dermatological (OS: HR: 0.53, 95%CI [0.42–0.65], p &lt; 0.00001), endocrine (OS: HR: 0.55, 95%CI [0.45–0.67], p &lt; 0.00001), and gastrointestinal irAEs (OS: HR: 0.58, 95%CI [0.42–0.80], p = 0.0009) than in those who did not. However, hepatobiliary, pulmonary, and high-grade (≥3) irAEs were not correlated with increased OS and PFS.ConclusionThe occurrence of irAEs in lung cancer patients, particularly dermatological, endocrine, and gastrointestinal irAEs, is a predictor of enhanced ICIs efficacy.

scholarly journals Correlation of Peripheral Blood Parameters and Immune-Related Adverse Events with the Efficacy of Immune Checkpoint Inhibitors

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Rilan Bai ◽  
Lingyu Li ◽  
Xiao Chen ◽  
Naifei Chen ◽  
Wei Song ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Proportional Hazards Model ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Characteristic Curve ◽  
Objective Response ◽  
Cox Proportional Hazards Model ◽  
Monocyte Count

Objective. We aimed to retrospectively analyze the predictors of immune checkpoint inhibitors (ICIs)-efficacy in patients with advanced pancancer who were treated with various ICIs in the real world and focused on the correlation between ICIs-efficacy and immune-related adverse events (irAEs). Methods. We retrospectively analyzed data from 103 patients with advanced pancancer treated receiving various ICIs in the First Hospital of Jilin University from January 1, 2016 to August 1, 2020. Survival probabilities of progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan–Meier curves and log-rank tests and the multivariate Cox proportional hazards model. Receiver-operating characteristic curve was used to determine a cutoff value for parameters and area under the curve. Correlations between the two variables were analyzed by logistic regression. Results. All patients were analyzed for survival predictors of OS, while 87 of 103 patients experienced evaluable disease progression of immunotherapy and were included in the analysis of predictors of PFS. First, we found that lower platelet (cutoff = 201.5 × 109/L) and lactate dehydrogenase (LDH) (cutoff = 227 U/L) were independently associated with significantly improved PFS, while lower platelet-lymphocyte ratio (cutoff = 206.5), absolute monocyte count (cutoff = 0.62 × 109/L), and LDH (cutoff = 194.5 U/L) were significantly and independently associated with better OS. In the analysis of the immune cell subgroup, a lower absolute countof CD8+CD28−suppressor T cells was an independent factor associated with better PFS (6.60 vs.4.13 months (mo), hazard ratios (HR) = 3.17, p  = 0.0038), and OS (29.4 vs. 9.57 mo, HR = 3.05, p  = 0.03). Second, the results of the analysis for irAEs showed that patients with any grade irAEs had higher objective response rate (30% vs. 10%, HR = 4.34, p  = 0.009), disease control rate (69.7% vs. 50%, HR = 2.3, p  = 0.028), PFS (8.37 vs. 3.77 mo, HR = 2.02, p  = 0.0038), and OS (24.77 vs.13.83 mo, HR = 1.84, p  = 0.024). Moreover, the groups with irAEs of grade ≥2 and with “multi-site” irAEs had significantly better PFS and OS ( p  < 0.05) compared with the other groups. We also proved that endocrine irAEs (usually thyroid dysfunction) were significantly associated with better mPFS ( p  = 0.01), and hepatic irAEs were significantly associated with better mOS ( p  = 0.023). Conclusions. This retrospective study explored the availability and effectiveness of some cost-effective and readily available blood biochemical parameters in routine clinical practice to predict the ICIs-efficacy and demonstrated the predictive role of different categories of irAEs on efficacy.

Endocrinopathies associated with immune checkpoint inhibitors: Standard of care at veterans administration medical centers.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14148-e14148
Author(s):  
Brett Johnson ◽  
David P. Tuck ◽  
Spyridon Ganas ◽  
Nicholas Bayless ◽  
Nikesh Kotecha ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
Response To Treatment ◽  
Health Administration ◽  
Medical Centers ◽  
The Impact

e14148 Background: Multiple different immune checkpoint inhibitors (ICI) have now received FDA approval for nearly 70 separate indications covering 14 different tumor types. Patients treated with these agents in clinical trials have an observed incidence of immune related adverse events (irAEs), including endocrinopathies, which may increase morbidity and mortality. Limited information describes the incidence and impact of these events outside of clinical trials. Methods: Retrospective data from the Veterans Health Administration (VA) of patients treated with ICI has been aggregated to understand the impact of these events in a standard of care setting, with a goal of improving patient care through predictive models and contributing to the understanding of the mechanisms and response to treatment. Results: Between October 2015 and December 2018, 10,280 patients were prescribed ICI at VA medical centers, with an average age of 70 years (range 20-99). A total of 11098 ICI orders, allowing for combinations or sequential treatments. Overall, nivolumab was prescribed 6024 times (54.3%), pembrolizumab 3976 (35.8%), ipilimumab 565 (5.1%) and atezolizumab 519 (4.6%). Avelumab (13) and durvalumab (1) had limited use. A candidate set of potential endocrine adverse events was estimated based on selected ICD10 codes recorded for the first time after treatment with ICI (Table). Conclusions: The frequency of endocrine immune related adverse events has been reported to be 5-10%. Here we have identified a cohort of ICI treated patients who may have developed endocrine adverse events. This cohort will be used to evaluate phenotyping, potential biomarkers and models of predictive risk.[Table: see text]

scholarly journals The efficacy and safety of combined immune checkpoint inhibitors (nivolumab plus ipilimumab): a systematic review and meta-analysis

2020 ◽  
Author(s):  
Lihu Gu ◽  
Shengnan Li ◽  
Nannan Du ◽  
Qigu Yao ◽  
Xiaojun Fu ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Objective Response ◽  
Cochrane Library ◽  
Effect Estimate ◽  
Grade 3 ◽  
Combined Immunotherapy

Abstract Background: Currently, nivolumab and ipilimumab are the most widely used immune checkpoint inhibitors. We performed a meta-analysis to evaluate the efficacy and treatment-related adverse events (TRAEs) of nivolumab-ipilimumab combination therapy in cancer treatment. Methods: We examined data from PubMed, Web of science, EBSCO and Cochrane library. Eleven articles fulfilled our criteria, which we divided into 3 groups; nivolumab and ipilimumab versus ipilimumab, nivolumab and ipilimumab versus ipilimumab and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3) versus nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1). We measured the complete response (CR), partial response (PR), objective response rate (ORR) and TRAEs in any grade and grade 3 or higher. Results: Compared with ipilimumab alone, the combined immunotherapy had better CR (RR: 4.89, p <0.001), PR (RR: 2.75, p <0.001), and ORR (RR: 3.31, p <0.001). The overall effect estimate favored the combined immunotherapy group in terms of the ORR (RR: 1.40, p <0.001) and PR (RR: 1.50, p <0.001) than nivolumab alone. Finally, N1I3 showed better PR (RR: 1.35, p =0.006) and ORR (RR: 1.21, p =0.03) than N3I1. The incidence of any TRAEs was similar between the both groups (RR: 1.05, p =0.06). However, the incidence of serious adverse events (grade 3 or higher) were lower in group N3I1 than group N1I3 (RR: 1.51, p <0.001). Conclusion: This meta-analysis showed that the curative effect of nivolumab plus ipilimumab was better than that of ipilimumab or nivolumab monotherapy. In the combination group, N1I3 combination was more effective than N3I1. Although the side effects were slightly increased in group N1I3, the overall safety was acceptable.

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 &lt; 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 &lt; 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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