Receiving Immune Checkpoint Inhibitors Therapy Research Articles

Ophthalmic immune-related adverse events associated with immune checkpoint inhibitors.

To investigate the incidence of immune-related adverse events (irAEs) of immune checkpoint inhibitor (ICI) therapy and to report the clinical features, management, and outcomes of ophthalmic irAEs. We retrospectively reviewed the medical records of patients who received ICI therapy from January 2016 to September 2022 at Peking Union Medical College Hospital and analyzed the incidence of systemic and ophthalmic adverse effects of this therapy. Of 962 patients, 248 (25.8%) experienced irAEs. The first-year incidences of total irAEs and ophthalmic irAEs were 23.5% and 1.1%. The most common ICI received by the patients was pembrolizumab (373; 38.8%). Nearly half of the patients (477; 49.6%) had lung cancer. Combination therapy was associated with an increased incidence of irAEs without statistical significance. Patients with lung cancer presented with an increased incidence of total irAEs (p = 0.003) and ophthalmic irAEs (p = 0.032). Eleven patients had ophthalmic manifestations, including ophthalmoplegia (6/11), conjunctivitis (3/11), reactive cutaneous capillary endothelial proliferation (RCCEP) (1/11), and orbital inflammation (1/11). Eight patients had concomitant extra-ophthalmic irAEs. Furthermore, ICIs were discontinued in nine patients, and most ophthalmic manifestations were well controlled with topical and systemic steroids. Ten patients were treated with intravenous or oral steroids. However, cancer progression occurred in five out of eleven patients after the interruption of ICIs. IrAEs are correlated with ICI regimens and underlying neoplasia. In our Chinese cohort, patients have a higher risk of ophthalmoplegia than uveitis. Early recognition and multidisciplinary consultation are crucial for optimal treatment of ophthalmic irAEs.

Increased risk of cutaneous immune-related adverse events in patients treated with talimogene laherparepvec and immune checkpoint inhibitors: A multi-hospital cohort study

Previous studies have shown that combining immune checkpoint inhibitors (ICIs) with talimogene laherparepvec (TVEC) may improve antitumor responses. However, the risk of developing cutaneous immune-related adverse events (cirAEs) in patients treated with ICI and TVEC has not been studied. To evaluate the differences in cirAE development between patients treated with ICI alone and both ICI and TVEC (ICI+TVEC). Patients with cutaneous malignancy receiving ICI with or without TVEC therapy at the Massachusetts General Brigham healthcare system were included. CirAE development, time from ICI initiation to cirAE, cirAE grade, cirAE morphology, and survival were analyzed. Pearson's χ2 test or Fisher's exact test for categorical variables and t test or Kruskal-Wallis test for continuous variables were used. To account for immortal time bias, we performed adjusted time-varying Cox proportional hazards modeling. The rate of cirAE development was 32.3% and 38.7% for ICI only and ICI+TVEC, respectively. After adjusting for covariates, ICI+TVEC was associated with a 2-fold increased risk of cirAE development (hazard ratio: 2.03, P=.006) compared to patients receiving ICI therapy alone. The retrospective nature and limited sample size from a tertiary-level academic center. These findings underscore potential opportunities for dermatologists and oncologists incounseling and monitoring patients.

A retrospective cohort study on the cardiotoxicity incidence rates of immune checkpoint inhibitors for oncology patients.

This present study investigated the incidence rates of cardiotoxicity among cancer patients treated with immune checkpoint inhibitors (ICIs) plus other anticancer drugs. This was a retrospective hospital-based cohort study using the medical records and the Cancer Registry records from the Taipei Veterans General Hospital. We enrolled patients diagnosed with cancer between 2011 and 2017, who were over 20 years old and had received ICI therapy, including pembrolizumab, nivolumab, atezolizumab, and ipilimumab. Cardiotoxicity was defined by the diagnosis of myocarditis, pericarditis, arrhythmia, heart failure, and Takotsubo syndrome. We identified 407 patients who were eligible to participate in this study. We defined the three treatment groups as follows: ICI therapy, ICI combined with chemotherapy, and ICI combined with targeted therapy. Using ICI therapy as a reference group, the cardiotoxicity risk was not significantly higher compared to the ICI combined with chemotherapy group (adjusted hazard ratio 2.1, 95% confidence interval 0.2-21.1, p = 0.528] or to the ICI combined with targeted therapy group (adjusted hazard ratio 1.2, 95% confidence interval 0.1-9.2, p = 0.883). The total incidence rate of cardiotoxicity was 3.6 of 100 person-years, indicating an average incidence time of 1.0 ± 1.3 years (median: 0.5 years; range: 0.1-4.7 years) for 18 cardiotoxicity patients. The incidence rate of ICI-related cardiotoxicity is low. Combination of ICI with either chemotherapy or targeted therapy might not significantly increase the risk of cardiotoxicities among cancer patients. Nevertheless, it is recommend being careful in patients treated high-risk cardiotoxicity medications to avoid drug-related cardiotoxicity with a combination of ICI therapy.

The Impact of Concomitant Proton Pump Inhibitors Therapy on Clinical Outcome of Cancer Patients Treated With Immune Checkpoint Inhibitors: A Meta-analysis.

In patients with advanced cancer receiving immune checkpoint inhibitors (ICIs) therapy, there are conflict perspectives about the influence of concomitant use of proton pump inhibitors (PPIs). We are aimed at exploring the influence of concomitant PPIs exposure on clinical outcome among cancer patients receiving ICIs treatment. We searched relevant literatures in PubMed, EMBASE, and the Cochrane Library without language restrictions. We extracted the data from selected studies and calculated the pooled hazard ratios (HRs) with 95% CIs through professional software for overall survival and progression-free survival among cancer patients undergoing ICIs therapy exposed to PPIs. Fourteen studies including 6716 advanced cancer patients receiving ICIs treatment were appropriate for analysis judging by pre-set inclusion and exclusion criteria. The result indicated that concomitant PPIs exposure was significantly related to shorter overall survival (HR=1.388; 95% CI: 1.278-1.498, P <0.001) and progression-free survival (HR=1.285; 95% CI: 1.193-1.384, P <0.001) among multiple cancer patients receiving ICIs therapy. Our meta-analysis showed that concomitant PPIs exposure had an adverse impact on clinical outcome among patients receiving ICIs therapy. Clinical oncologists must be cautious of PPIs delivery during ICIs treatment.

Circulating tumor DNA-based molecular residual disease detection for treatment monitoring in advanced melanoma patients.

Immune checkpoint inhibitors (ICIs) have substantially improved overall survival in patients with advanced melanoma; however, the lack of biomarkers to monitor treatment response and relapse remains an important clinical challenge. Thus, a reliable biomarker is needed that can risk-stratify patients for disease recurrence and predict response to treatment. A retrospective analysis using a personalized, tumor-informed circulating tumor DNA (ctDNA) assay on prospectively collected plasma samples (n=555) from 69 patients with advanced melanoma was performed. Patients were divided into three cohorts: cohort A (N=30), stage III patients receiving adjuvant ICI/observation; cohort B (N=29), unresectable stage III/IV patients receiving ICI therapy; and cohort C (N=10), stage III/IV patients on surveillance after planned completion of ICI therapy for metastatic disease. In cohort A, compared to molecular residual disease (MRD)-negative patients, MRD-positivity was associated with significantly shorter distant metastasis-free survival (DMFS; hazard ratio [HR], 10.77; p=.01). Increasing ctDNA levels from the post-surgical or pre-treatment time point to after 6weeks of ICI were predictive of shorter DMFS in cohort A (HR, 34.54; p<.0001) and shorter progression-free survival (PFS) in cohort B (HR,22; p=.006). In cohort C, all ctDNA-negative patients remained progression-free for a median follow-up of 14.67months, whereas ctDNA-positive patients experienced disease progression. Personalized and tumor-informed longitudinal ctDNA monitoring is a valuable prognostic and predictive tool that may be used throughout the clinical course of patients with advanced melanoma.

Thyroid dysfunction after immune checkpoint inhibitor treatment in a single-center Chinese cohort: a retrospective study.

Thyroid dysfunction is a common adverse event after immune checkpoint inhibitor (ICI) therapy. The clinical manifestations of thyroid immune-related adverse events (irAEs) are variable and the underlying mechanisms remain unclear. To identify the clinical and biochemical characteristics of Chinese patients with ICI-related thyroid dysfunction. We retrospectively reviewed patients with carcinoma who received ICI therapy and underwent evaluation of thyroid function during hospitalization at Peking Union Medical College Hospital between January 1, 2017 and December 31, 2020. Clinical and biochemical features were analyzed in patients who developed ICI-related thyroid dysfunction. Survival analyses were performed to determine the effect of thyroid autoantibodies on thyroid abnormalities and the impact of thyroid irAEs on clinical outcomes. The cohort included 270 patients with a median follow-up of 17.7 months; 120 (44%) of these patients developed thyroid dysfunction on immunotherapy. The most common thyroid irAE was overt hypothyroidism (with/without transient thyrotoxicosis), which occurred in 38% of patients (n = 45), followed by subclinical thyrotoxicosis (n = 42), subclinical hypothyroidism (n = 27), and isolated overt thyrotoxicosis (n = 6). The median time to first clinical presentation was 49 days (interquartile range 23, 93) for thyrotoxicosis and 98 days (interquartile range 51, 172) for hypothyroidism. In patients treated with PD-1 inhibitors, hypothyroidism was strongly associated with younger age (odds ratio [OR] 0.44, 95% confidence interval [CI] 0.29-0.67; P < 0.001), previous thyroid disease (OR 4.30, 95% CI 1.54-11.99; P = 0.005), and a higher baseline thyroid-stimulating hormone level (OR 2.76, 95% CI 1.80-4.23; P < 0.001). Thyrotoxicosis was only associated with the baseline thyroid-stimulating hormone (TSH) level (OR 0.59, 95% CI 0.37-0.94; P = 0.025). Thyroid dysfunction after initiation of ICI therapy was associated with better progression-free survival (hazard ratio [HR] 0.61, 95% CI 0.44-0.86; P = 0.005) and overall survival (hazard ratio 0.67, 95% CI 0.45-0.99; P = 0.046). Anti-thyroglobulin antibody positivity increased the risk of thyroid irAEs. The occurrence of thyroid irAEs with diverse phenotypes is common. Distinct clinical and biochemical characteristics suggest heterogeneity among different subgroups of thyroid dysfunction, which requires further research to explore the under mechanism.

Development and validation of a novel defined mutation classifier based on Lasso logistic regression for predicting the overall survival of immune checkpoint inhibitor therapy in renal cell carcinoma.

Currently, immune checkpoint inhibitor (ICI)-based therapy has become the first-line treatment for advanced renal cell carcinoma (RCC). However, few biomarkers have been identified to predict the response to ICI therapy in RCC patients. Herein, our research aimed to build a gene mutation prognostic indicator for ICI therapy. This multi-cohort study explored the mutation patterns in 2 publicly available advanced RCC ICI therapy cohorts, the Memorial Sloan Kettering Cancer Center (MSKCC) advanced RCC ICI therapy cohort and the CheckMate ICI therapy cohort. A total of 261 patients in the CheckMate ICI therapy cohort were randomly assigned to either the training or validation set. Least absolute shrinkage and selection operator (Lasso) logistic regression analysis was subsequently used to develop a mutation classifier utilizing the training set. The classifier was then validated internally in the validation set and externally in 2 ICI therapy cohorts and 2 non-ICI therapy cohorts. Survival analysis, receiver operator characteristic curves and Harrell's concordance index were performed to assess the prognostic value of the classifier. Function and immune microenvironment analysis in each subgroup defined by the classifier were performed. A 10-gene mutation classifier was constructed based on the CheckMate ICI therapy cohort to separate patients into 2 risk groups, with patients in the high-risk group showing significantly lower overall survival probability than those in the low-risk group [the training set (HR: 1.791; 95% CI: 1.207-2.657; P=0.003), the validation set (HR: 1.842; 95% CI: 1.133-2.996; P=0.012) and combination set (HR: 1.819; 95% CI: 1.339-2.470; P<0.001)]. Further validation confirmed that the mutation classifier only showed predictive value for patients receiving ICI therapy instead of non-ICI therapy. Combined with the clinical characteristics, the risk score was proven to be an independent prognostic factor for overall survival in ICI therapy by multivariate Cox regression analysis. Functional and immune infiltration analysis demonstrated that lower risk scores tended to associate with immunologically "hot" status in RCC. Our 10-gene mutation classifier was found to be a biomarker for predicting the overall survival of patients with advanced RCC to ICI therapy.

COVID-19 Outcomes in Patients with Cancer Receiving Immune Checkpoint Inhibitors: A Systematic Review.

Immune checkpoint inhibitors (ICIs) can cause inflammatory and immune-related adverse events (irAEs) that might worsen the course of COVID-19. We conducted a systematic review (PROSPERO ID: CRD42022307545) to evaluate the clinical course and complications of COVID-19 in patients with cancer receiving ICI. We searched Medline and Embase through January 5, 2022. We included studies evaluating patients with cancer who received ICI and developed COVID-19. Outcomes included mortality, severe COVID-19, intensive care unit (ICU) and hospital admissions, irAEs, and serious adverse events. We pooled data with random effects meta-analysis. Twenty-five studies met study eligibility (n = 36,532 patients: 15,497 had COVID-19 and 3220 received ICI). Most studies (71.4%) had a high risk of comparability bias. There were no significant differences in mortality (relative risk [RR] 1.29; 95% CI 0.62-2.69), ICU admission (RR 1.20; 95% CI 0.71-2.00), and hospital admission (RR 0.91; 95% CI 0.79-1.06) when comparing patients treated with ICI with patients without cancer treatment. When pooling adjusted odds ratios (ORs), no statistically significant differences were observed in mortality (OR 0.95; 95% CI 0.57-1.60), severe COVID-19 (OR 1.05; 95% CI 0.45-2.46), or hospital admission (OR 2.02; 95% CI 0.96-4.27), when comparing patients treated with ICIs versus patients with cancer without ICI therapy. No significant differences were observed when comparing clinical outcomes in patients receiving ICIs versus patients receiving any of the other anticancer therapies. Although current evidence is limited, COVID-19 clinical outcomes of patients with cancer receiving ICI therapy appear to be similar to those not receiving oncologic treatment or other cancer therapies.

Predicting survival of NSCLC patients treated with immune checkpoint inhibitors: Impact and timing of immune-related adverse events and prior tyrosine kinase inhibitor therapy.

Immune checkpoint inhibitors (ICIs) produce a broad spectrum of immune-related adverse events (irAEs) affecting various organ systems. While ICIs are established as a therapeutic option in non-small cell lung cancer (NSCLC) treatment, most patients receiving ICI relapse. Additionally, the role of ICIs on survival in patients receiving prior targeted tyrosine kinase inhibitor (TKI) therapy has not been well-defined. To investigate the impact of irAEs, the relative time of occurrence, and prior TKI therapy to predict clinical outcomes in NSCLC patients treated with ICIs. A single center retrospective cohort study identified 354 adult patients with NSCLC receiving ICI therapy between 2014 and 2018. Survival analysis utilized overall survival (OS) and real-world progression free survival (rwPFS) outcomes. Model performance matrices for predicting 1-year OS and 6-month rwPFS using linear regression baseline, optimal, and machine learning modeling approaches. Patients experiencing an irAE were found to have a significantly longer OS and rwPFS compared to patients who did not (median OS 25.1 vs. 11.1 months; hazard ratio [HR] 0.51, confidence interval [CI] 0.39- 0.68, P-value <0.001, median rwPFS 5.7 months vs. 2.3; HR 0.52, CI 0.41- 0.66, P-value <0.001, respectively). Patients who received TKI therapy before initiation of ICI experienced significantly shorter OS than patients without prior TKI therapy (median OS 7.6 months vs. 18.5 months; P-value < 0.01). After adjusting for other variables, irAEs and prior TKI therapy significantly impacted OS and rwPFS. Lastly, the performances of models implementing logistic regression and machine learning approaches were comparable in predicting 1-year OS and 6-month rwPFS. The occurrence of irAEs, the timing of the events, and prior TKI therapy were significant predictors of survival in NSCLC patients on ICI therapy. Therefore, our study supports future prospective studies to investigate the impact of irAEs, and sequence of therapy on the survival of NSCLC patients taking ICIs.

Diarrhea and colitis related to immune checkpoint inhibitor and BRAF/MEK inhibitor therapy.

Immune checkpoint inhibitor (ICI) therapy can be complicated by gastrointestinal adverse events (AEs). Similarly, gastrointestinal AEs have been reported with the use of serine/threonine-protein kinase B-Raf (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitor therapy. We investigated the characteristics and management of gastrointestinal AEs related to sequential ICI and BRAF/MEK inhibitor therapy. We identified 255 adult cancer patients who received both BRAF/MEK inhibitor therapy and ICI therapy between 2014 and 2021. Thirty-two eligible patients had gastrointestinal AEs after receiving both therapies and were categorized based on the order of their administration. Their clinical characteristics, evaluation, treatment and outcomes were compared. Of the 32 eligible patients, 18 (56.3%) received ICI therapy followed by BRAF/MEK inhibitors (early ICI group), and 14 (44.8%) received BRAF/MEK inhibitor therapy followed by ICI (early BRAF/MEK inhibitor group). Compared with the early BRAF/MEK inhibitor group, the early ICI group had higher rates of grade 3-4 diarrhea (50.0% vs. 14.3%, P=0.047) and grade 3-4 colitis (38.9% vs. 0%, P=0.010). The early ICI group had a later onset of colitis (347.5 vs. 84.5 days, P=0.011) and a higher rate of hospitalization at initial colitis presentation (100% vs. 71.4%, P=0.028). Patients in the early ICI group were more likely to have diarrhea or colitis recurrence (69.2% vs. 9.1%, P=0.019) and re-hospitalization for colitis (38.9% vs. 0%, P=0.010). The sequential exposure of BRAF/MEK therapy after ICI may contribute to a more aggressive clinical profile of gastrointestinal toxicities that may warrant a more aggressive management strategy.

Inflammatory Cell Infiltration Into Islets Without PD-L1 Expression Is Associated With the Development of Immune Checkpoint Inhibitor-Related Type 1 Diabetes in Genetically Susceptible Patients.

Immune checkpoint inhibitors (ICIs) could cause type 1 diabetes (T1D). However, the underlying mechanism remains unclear. We immunohistochemically analyzed pancreatic specimens from 3 cases with ICI-related T1D, and their histopathological data were compared those from 3 patients who had received ICI therapy but did not develop T1D (non-T1D) and 7 normal glucose-tolerant subjects as controls. All ICI-related T1D patients had susceptible HLA haplotypes. In ICI-related T1D, the β-cell area decreased and the α-cell area increased compared to non-T1D and controls. The number of CD3- positive cells around islets increased in ICI-related T1D and non-T1D compared with controls, while the number of CD68-positive cells around islets increased in ICI-related T1D compared with non-T1D and controls. The expression ratios of PD-L1 on islets decreased in non-T1D and almost completely disappeared in ICI-related T1D, while PD- L1 expression was observed in most cells of pancreatic islets in controls. This study, therefore, indicates that ICI therapy itself could reduce PD-L1 expression on islets in all subjects, which may be related to β cell vulnerability. In addition, we showed that absence of PD-L1 expression on β cells, genetic susceptibility and infiltration of macrophages as well as T lymphocytes around islets might be responsible for T1D onset.

Safety of COVID-19 vaccines in subjects with solid tumor cancers receiving immune checkpoint inhibitors

ABSTRACT The incidence of severe immune-related adverse events (irAEs) in cancer subjects receiving immune checkpoint inhibitors (ICIs) following COVID-19 vaccination and the relationship between the incidence of severe irAE and the interval between COVID-19 vaccination and ICI dose have not been established. We performed a retrospective study evaluating the incidence of irAEs in solid tumor subjects receiving ICI therapy who received any COVID-19 vaccinations since FDA authorization. irAEs were defined as severe with one or more grade 3 or above events (CTCAE v5.0), multiple organ involvement, or requiring hospitalization for management. Two hundred and eighty-four subjects who received COVID vaccinations from December 2020 and February 2022 were included in this analysis [median age at vaccination 67 years (IQR 59.0–75.0); 67.3% male]. Twenty-nine subjects (10.2%) developed severe irAEs, of which 12 subjects (41.4%) received ICI monotherapy, 10 subjects (34.5%) received combination ICI therapy with nivolumab and ipilimumab, and 7 subjects (24.1%) received ICI plus VEGFR-TKI therapy. Hospitalization occurred in 62% of subjects with severe irAEs, with a median duration of 3 days (IQR: 3.0–7.5 days). Immunosuppressive therapy was required in 79.3%, with a median duration of 103 days (IQR: 42.0–179.0). ICI therapy was discontinued in 51.7% of subjects with severe irAE; dosing was held or interrupted in 34.5%. Among severe irAEs, the median interval between vaccination and ICI treatment closest to the occurrence of severe irAE was 15.5 days (IQR: 10.0–23.0). In solid tumor cancer subjects receiving ICIs, COVID-19 vaccination is not associated with an increased incidence of severe irAEs compared to historical data and may be safely administered during ICI cancer therapy in subjects who lack contraindications.

Celebrating the 15th Anniversary ofImmunotherapy: A Reflection on 2022

Celebrating the 15th Anniversary of<i>Immunotherapy</i>: A Reflection on 2022

Impact of Infections in Patients Receiving Pembrolizumab-Based Therapies for Non-Small Cell Lung Cancer.

Background: Immune checkpoint inhibitor (ICI) therapy has significantly improved outcomes across a range of malignancies. While infections are a well-known contributor to morbidity and mortality amongst patients receiving systemic chemotherapy regimens, little is known about the impact of infections on patients receiving ICI therapy. This study aims to assess incidence, risk factors, and outcomes in patients who develop infections while on pembrolizumab-based therapies for non-small cell lung cancer (NSCLC). Methods: Patients receiving pembrolizumab for stage III/IV NSCLC from 1/1/2017-8/1/2021 across seven hospitals were identified. Incidence and type of infection were characterized. Covariates including baseline demographics, treatment information, treatment toxicities, and immunosuppressive use were collected and compared between infected and non-infected patients. Outcomes included the rate of infections, all-cause hospital admissions, median number of treatment cycles, overall survival (OS), and progression free survival (PFS). Univariable and multivariable analysis with reported odds ratio (OR) and 95% confidence intervals (CI) were utilized to evaluate infection risks. OS and PFS were analyzed by Kaplan−Meier analysis and tested by log-rank test. p-value < 0.05 was considered statistically significant. Results: There were 243 NSCLC patients that met the inclusion criteria. Of these, 111 (45.7%) had one documented infection, and 36 (14.8%) had two or more. Compared to non-infected patients, infected patients had significantly more all-cause Emergency Department (ED) [37 (33.3%) vs. 26 (19.7%), p = 0.016], hospital [87 (78.4%) vs. 53 (40.1%), p < 0.001], and ICU visits [26 (23.4%) vs. 5 (3.8%), p < 0.001], and had poorer median OS (11.53 [95% CI 6.4−16.7] vs. 21.03 [95% CI: 14.7−24.2] months, p = 0.033). On multivariable analysis, anti-infective therapy (OR 3.32, [95% CI: 1.26−8.76], p = 0.015) and ECOG of >1 (OR 5.79, [95% CI 1.72−19.47], p = 0.005) at ICI initiation conferred an increased risk for infections. At last evaluation, 74 (66.7%) infected and 70 (53.0%) non-infected patients died (p = 0.041). Conclusion: Infections occurred in nearly half of patients receiving pembrolizumab-based therapies for NSCLC. Infected patients had frequent hospitalizations, treatment delays, and poorer survival. ECOG status and anti-infective use at ICI initiation conferred a higher infection risk. Infection prevention and control strategies are needed to ameliorate the risk for infections in patients receiving ICIs.

Correlation between immune-related adverse events and treatment efficacy of anti-PD1 immunotherapy in patients with esophageal squamous cell carcinoma.

Immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) are associated with improved treatment efficacy in certain types of cancer. In the present study, we assessed the association between irAEs and ICI efficacy. Patients with esophageal squamous cell carcinoma (ESCC) who received ICI treatment were stratified into irAEs and non-irAE groups. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were used to evaluate the therapeutic efficacy of ICIs. Of the 78 ICI-treated ESCC patients, 39 developed irAEs. The median OS and PFS for all patients were 600 and 300 days, respectively. Median OS (P<0.001) and PFS (P<0.001) times of the patients with irAEs were longer than those in the non-irAE group. In addition, the DCR of the irAE group was higher than that of the non-irAE group (P=0.006). Univariate analysis indicated that the non-irAE group was associated with a relatively shorter OS [hazard ratio (HR)=3.687, 95% CI, 1.974-6.888, P<0.001] and PFS (HR=2.967, 95% CI, 1.691-5.204, P<0.001). The multifactorial analysis demonstrated that irAE status was an independent predictor of PFS (HR=3.564, 95% CI, 1.786-7.114, P<0.001) and OS (HR=3.288, 95% CI, 1.636-6.606, P=0.001). In conclusion, the present study demonstrated that irAEs could be used to predict improved treatment efficacy in patients with ESCC who received ICI therapy.

Analysis of Human Leukocyte Antigen DR Alleles, Immune-Related Adverse Events, and Survival Associated With Immune Checkpoint Inhibitor Use Among Patients With Advanced Malignant Melanoma

Treatment with immune checkpoint inhibitors (ICIs) has increased survival in patients with advanced malignant melanoma but can be associated with a wide range of immune-related adverse events (irAEs). The role of human leukocyte antigen (HLA)-DR alleles in conferring irAE risk has not been well studied. To evaluate the association between irAEs and treatment response, survival, and the presence of HLA-DR alleles after ICI therapy in advanced melanoma. This case-control study used the patient registry and biobanked samples from the tertiary referral University of Colorado Cancer Center. Specimens and clinical data were collected between January 1, 2010, and December 31, 2021. Patients with advanced (stage III unresectable and stage IV) melanoma who received ICI therapy (n = 132) were included in the analysis. Immune checkpoint inhibitors (anti-cytotoxic T-lymphocyte antigen 4, anti-programmed cell death protein 1 or its ligand, or the combination) for the treatment of advanced melanoma. The association between irAEs and response to therapy, survival, and HLA-DR alleles. Among the cohort of 132 patients with advanced melanoma (mean [SD] age, 63.4 [7.2] years; 85 men [64%] and 47 women [36%]) treated with ICIs, 73 patients had at least 1 irAE and 59 did not have an irAE. Compared with patients without an irAE, patients with an irAE had higher treatment response rates (50 of 72 [69%] vs 28 of 57 [49%]; P = .02) and increased survival (median, 4.8 [IQR, 0.2-9.6] vs 3.2 [IQR, 0.1-9.2] years; P = .02). Specific HLA-DR alleles were associated with the type of irAE that developed: 7 of 10 patients (70%) who developed type 1 diabetes had DR4; 6 of 12 (50%) who developed hypothyroidism had DR8; 5 of 8 (63%) who developed hypophysitis had DR15; 3 of 5 (60%) who developed pneumonitis had DR1; and 8 of 15 (53%) who developed hepatitis had DR4. These findings suggest that IrAEs are associated with treatment response rates and increased survival after ICI therapy for advanced melanoma. Because distinct HLA-DR alleles are associated with given adverse events, HLA genotyping before ICI therapy may aid in identifying risk for specific irAEs that could develop with such treatment.

Targeting T-cell metabolism to boost immune checkpoint inhibitor therapy.

Immune checkpoint inhibitors (ICIs) have shown promising therapeutic effects in the treatment of advanced solid cancers, but their overall response rate is still very low for certain tumor subtypes, limiting their clinical scope. Moreover, the high incidence of drug resistance (including primary and acquired) and adverse effects pose significant challenges to the utilization of these therapies in the clinic. ICIs enhance T cell activation and reverse T cell exhaustion, which is a complex and multifactorial process suggesting that the regulatory mechanisms of ICI therapy are highly heterogeneous. Recently, metabolic reprogramming has emerged as a novel means of reversing T-cell exhaustion in the tumor microenvironment; there is increasing evidence that T cell metabolic disruption limits the therapeutic effect of ICIs. This review focuses on the crosstalk between T-cell metabolic reprogramming and ICI therapeutic efficacy, and summarizes recent strategies to improve drug tolerance and enhance anti-tumor effects by targeting T-cell metabolism alongside ICI therapy. The identification of potential targets for altering T-cell metabolism can significantly contribute to the development of methods to predict therapeutic responsiveness in patients receiving ICI therapy, which are currently unknown but would be of great clinical significance.

SA79 Association Between Antibiotic Exposure and Survival Among Patients Diagnosed With Advanced Melanoma or Advanced Non-Small Cell Lung Cancer (NSCLC) Treated With Immune Checkpoint Inhibitor (ICI) Therapy

Previous studies suggest worse outcomes for patients with cancer exposed to antibiotics who are treated with ICI. This study investigates the association between antibiotic exposure and survival among patients diagnosed with advanced melanoma or NSCLC receiving ICI therapy in an electronic health records (EHR)-claims linked dataset.

Abstract 9343: Predictive Value of Baseline Serum High-Sensitivity Troponin I and NT-proBNP for Cardiac Immunotoxicity Risk During Immune Checkpoint Inhibitor Therapy

Introduction: Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment, but rarely and unpredictably cause fulminant myocarditis. It is unknown if circulating cardiac biomarkers can predict immunotoxicity in a real-world patient population. Aim: To evaluate the predictive value of baseline levels of high-sensitivity troponin-I (hs-TnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) for myocardial injury (hs-TnI&gt;50ng/L) or potential heart failure (NT-proBNP&gt;300pg/mL) risk during ICI therapy. Methods: An institutional multidisciplinary working group developed a monitoring protocol for immune-related adverse events due to ICI. Data recorded during clinical treatment plans over 12 months starting 5/1/2021 were analyzed. Results: 621 patients received ICI therapy, and 6 developed myocarditis requiring hospitalization. Of 317 patients initiated on ICI after the start of this protocol, baseline and at least one follow-up hs-TnI and NT-proBNP values were measured in 183 and 126 patients, respectively. In 110 patients hs-TnI was undetectable (&lt;5ng/L) at baseline. In 66% of these patients hs-TnI remained undetectable on follow-up. Of 88 patients with baseline NT-proBNP below the diagnosis limit for heart failure (&lt;300 pg/mL), 75% had values below this limit on follow-up. The baseline value of the biomarkers was used as a predictor of increase in biomarkers during follow-up. Area under receiver operator curve for predicting an increase from baseline during ICI treatment was 0.67 for hs-TnI, 0.87 for NT-proBNP, and 0.86 combined (Figure). Conclusions: This single-center, prospectively protocolled, retrospectively-analyzed study indicates that hs-TnI and NT-proBNP values obtained at baseline and at least at one immunotherapy cycle can be used to categorize patients at risk or not for potential immunotoxicity during ICI treatment, thus may offer a helpful strategy in the monitoring and prevention of fulminant myocarditis.

Clinical Outcomes in Fibrolamellar Hepatocellular Carcinoma Treated with Immune Checkpoint Inhibitors.

Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of liver cancer primarily affecting children and young adults. Although considered a subset of hepatocellular carcinoma (HCC), FLC has unique molecular and pathologic characteristics, suggesting that it may require different treatment. Immune checkpoint inhibitors (ICIs) are used in the treatment of HCC, but efficacy and safety in FLC has not been characterized. We performed a multicenter retrospective analysis of patients with FLC to determine responses to ICI therapy. Response rates were assessed based on RECIST 1.1 criteria, and Kaplan-Meier statistics were used for progression-free survival (PFS) and overall survival (OS). FLC tumors were characterized by low tumor mutational burden (TMB) and absent PD-L1 expression. We identified 19 patients who received ICIs, including 15 who received ICI therapy alone [programmed death receptor 1 (PD-1) inhibitor, +/- cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor]. Objective tumor responses were observed in 3/19 patients (15.8%), including 2/15 patients (13.3%) who received ICIs alone, all partial responses. Median PFS and OS were 5.5 and 26.0 months, respectively. Grade 3-4 immune related adverse events were observed in 4/19 (21.1%) patients. ICI therapy has modest clinical activity in FLC, and novel therapeutic combinations are needed.