Receiving Immune Checkpoint Inhibitors Therapy Research Articles

Responses to immune checkpoint inhibitor therapy in NF1 mutated cutaneous melanoma.

e21535 Background: NF1 mutations occur in 14% of cutaneous melanoma. Less than 20% of advanced melanoma patients on Immune Checkpoint Inhibitor (ICI) therapy achieve radiographic Complete Response (CR). We present data on radiographic responses to ICI therapy in advanced melanoma patients with tumors harboring NF1 (Neurofibromatosis 1) mutations. Methods: Patients with metastatic or unresectable NF1 mutated melanoma were included in the analysis. Mutation status was identified via NGS and mutation pathogenic status was determined using Genome Oncology Software. All patients received ICI therapy. RECIST 1.1 was used to assess treatment responses with CT scans. CR on PET was defined as disappearance of all metabolically active lesions. Results: 26 metastatic or unresectable melanoma patients met criteria for inclusion. Of these, eight (30.8%) had CNS metastasis. ICI therapy included Ipilimumab-Nivolumab, Pembrolizumab, Nivolumab, or Relatlimab-Nivolumab (24/26 in front-line setting). The 12- and 24-month estimated cumulative incidence of CR were 43.9% and 60.6%, respectively. Altogether, 16 patients achieved CR as their best overall response. Four patients that achieved CR subsequently progressed. Four patients progressed without achieving CR. Six patients achieved a partial response by last follow-up without achieving CR or disease progression. Of the 8 patients with CNS metastasis, five (62.5%) had intra-cranial radiographic responses to ICI therapy, including 1 (12.5%) complete response. Five (62.5%) had multifocal ( > 2 sites of intracranial metastasis) intracranial disease. Five (62.5%) of these patients with intracranial disease received radiation, 2/8 (25.0%) received radiation and surgical resection, and one (12.5%) received neither radiation nor surgery. Three (37.5%) patients with CNS metastasis experienced disease progression while on ICI therapy. Conclusions: NF1 mutated melanoma appears to have high rates of radiographic responses to ICI therapy. Prospective validation of this finding, particularly in patients with CNS metastasis, is warranted.

Changes in Serum Interleukin-8 Levels Predict Response to Immune Checkpoint Inhibitors Immunotherapy in Unresectable Hepatocellular Carcinoma Patients.

Effective biomarkers are needed to predict the efficacy of immune checkpoint inhibitors (ICIs) therapy in hepatocellular carcinoma (HCC). We evaluated the early changes in serum interleukin-8 (IL-8) levels as a biomarker of response to ICIs in patients with unresectable HCC. Eighty patients who received ICIs therapy alone or in combination with other treatments for unresectable HCC were included. Serum was collected at baseline and 2-4 weeks after the first dose. Serum IL-8 levels were measured using by ELISA. In the progressive disease (PD) group, serum IL-8 levels increased significantly before the second dose of ICIs therapy compared with baseline levels (P < 0.001). Early changes in serum IL-8 levels were significantly associated with the response to ICIs therapy (P < 0.001). A cutoff value of 8.1% increase over the baseline most effectively predicted the response to ICIs. Increases in serum IL-8 levels > 8.1% indicated the uselessness of ICIs immunotherapy in patients with unresectable HCC. Patients with increases in serum IL-8 levels > 8.1% had significantly shorter overall survival (OS) and progression-free survival (PFS) than those with increases in serum IL-8 levels ≤ 8.1% (P < 0.001). Increases in serum IL-8 levels > 8.1% were independent prognosticators of worse OS (P = 0.003) and PFS (P < 0.001). Early changes in serum IL-8 levels, measured only 2-4 weeks after starting therapy, could predict the response to ICIs therapy, as well as OS and PFS of patients with unresectable HCC. Increases in serum IL-8 levels > 8.1% indicated the uselessness of ICIs immunotherapy and predicted worse OS and PFS.

Impact of concurrent medications on clinical outcomes of cancer patients treated with immune checkpoint inhibitors: analysis of Health Insurance Review and Assessment data

PurposeMedications regulating immune homeostasis and gut microbiota could affect the efficacy of immune checkpoint inhibitors (ICIs). This study aimed to investigate the impact of concurrent medications on the clinical outcomes of patients with cancer receiving ICI therapy in South Korea.MethodsWe identified patients newly treated with ICI for non-small cell lung cancer (NSCLC), urothelial carcinoma (UC), and malignant melanoma (MM) between August 2017 and June 2020 from a nationwide database in Korea. The effect of concurrent antibiotics (ATBs), corticosteroids (CSs), proton-pump inhibitors (PPIs), and opioids prescribed within 30 days before ICI initiation on the treatment duration and survival was assessed.ResultsIn all, 8870 patients were included in the ICI cohort (NSCLC, 7,128; UC, 960; MM, 782). The patients were prescribed ATBs (33.8%), CSs (47.8%), PPIs (28.5%), and opioids (53.1%) at the baseline. The median overall survival durations were 11.1, 12.2, and 22.1 months in NSCLC, UC, and MM subgroups, respectively, since starting the ICI mostly as second-line (NSCLC and UC) and first-line (MM) therapy. Early progression was observed in 34.2% of the patients. Opioids and CS were strongly associated with poor survival across all cancer types. A high number of concurrent medications was associated with early progression and short survival. Opioid and CS use was associated with poor prognosis in all patients treated with ICIs. However, ATBs and PPIs had a cancer-specific effect on survival.ConclusionA high number of concurrent medications was associated with poor clinical outcomes.

Abstract 3460: Predicting cessation of immune checkpoint inhibitor therapy due to severe adverse events with an integrated autoimmune disease polygenic risk score

Abstract Background: Immune checkpoint inhibitors (ICIs), including anti-PD1/PD-L1 and anti-CTLA4 agents, have changed the landscape of cancer therapy. However, 6-30% of patients treated with ICIs can develop severe immune-related adverse events (irAEs) depending on the type of therapy used, often leading to cessation of treatment. Hundreds of genetic variants have been associated with autoimmune disorders, and recent genetic studies have developed polygenic risk scores (PRS) for composite risk of autoimmune disease (PRSAID). We used data from an ongoing observational study of patients with non-small cell lung cancer (NSCLC) treated with ICIs to evaluate the association between PRSAID and cessation of ICI therapy due to severe irAEs. Methods: Our cohort comprises 1,316 advanced NSCLC patients who received ICI therapy from four institutions between 2009 and 2022. Genotyping was performed using the Affymetrix Precision Medicine Array, and imputation was performed using 1000 Genomes Reference. To evaluate cessation of therapy due to severe irAEs, we conducted a thorough review of electronic health records. We identified permanent discontinuation of ICIs due to irAEs as cessation for at least 6 months without any disease progression. We tested the association of a previously published PRSAID (PMID: 35393596) with cessation of ICI due to any severe irAE. PRSAID was converted to a standard normal distribution. We conducted an unconditional logistic regression model to evaluate the association between a standardized PRSAID and discontinuation of ICI therapy due to severe irAEs. All models were adjusted for age at diagnosis, sex, type of ICI therapy, recruitment site, and 5 ancestry-informative principal components. Results: Of the 1,316 participants with genotype and outcome data, 171 (13.5%) of patients stopped ICI therapy due to severe irAEs. The most common irAEs leading to discontinuation were colitis, hepatitis, and pneumonitis. The PRSAID predicts the cessation of therapy due to severe irAEs with an odds ratio (OR) per standard deviation (SD) of 1.20 (95% confidence intervals [CI]=1.02-1.41, p=0.03). The association was stronger in individuals with high genetic risk (top 25th percentile compared to bottom 75th percentile of the PRSAID) (OR=1.60, 95% CI = 1.11-2.28, p=0.01). When we stratified the analysis by therapy type, we found an OR of 1.17 (95% CI-0.98-1.39, p = 0.08) for the anti-PD1/PD-L1 monotherapy groups and an OR of 1.48 (95% CI=0.94-2.40,p=0.09) for the dual anti-PD1/PD-L1 and anti-CTLA4 therapy group. Conclusions: An integrated PRS for autoimmunity can predict the cessation of ICI therapy due to severe irAEs in patients with advanced cancer. These findings suggest that PRS may help determine which patients may benefit from careful monitoring or even preventative measures for irAEs during ICI therapy. Citation Format: Pooja Middha, Rohit Thummalapalli, Zoe Quandt, Princess Margaret Lung Group, Matthew A. Gubens, Christine M. Lovly, Geoffrey Liu, Melinda C. Aldrich, Adam J. Schoenfeld, Elad Ziv. Predicting cessation of immune checkpoint inhibitor therapy due to severe adverse events with an integrated autoimmune disease polygenic risk score [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3460.

Non-Invasive Predictive Biomarkers for Immune-Related Adverse Events Due to Immune Checkpoint Inhibitors.

Immune-related adverse events (irAEs) are the most common complication of immune checkpoint inhibitor (ICI) therapy. With the widespread use of ICIs in patients with solid tumors, up to 40% of the patients develop irAEs within five months of treatment, and 11% develop severe irAEs requiring interventions. A predictive test for irAEs would be a crucial tool for monitoring for complications during and after ICI therapy. We performed an extensive review of potential predictive biomarkers for irAEs in patients who received ICI therapy. Currently, only thyroid-stimulating hormone is utilized in common clinical practice. This is due to the unavailability of commercial tests and unclear predictive values from various studies. Given the lack of single strong predictive biomarkers, some novel approaches using composite scores using genomic, transcriptomics, cytokine levels, or clinical parameters appear appealing. Still, these have yet to be validated and incorporated into clinical practice. Further research conducted to validate the models before implementing them into real-world settings will be of the utmost importance for irAE prediction.

Efficacy and predictors of immune checkpoint inhibitors in patients with gallbladder cancer.

Immune checkpoint inhibitors (ICIs) have shown promising efficacy in multiple cancers including biliary tract cancers (BTCs). However, the data focusing on the efficacy of ICIs in patients with gallbladder cancer (GBC) is still limited. In this study, we aim to assess the efficacy of ICIs in GBC and explore the clinicopathologic and molecular markers associated with ICI benefit. We retrospective analyzed 69 GBC patients who had received ICI therapy between January 2016 and December 2020. Tumor samples were obtained for genomic sequencing and immunohistochemical analysis. The median progression-free survival (PFS) and overall survival (OS) was 4.4 months and 8.5 months, respectively. Multivariate analysis indicated that alcohol intake history, carcinoma embryonic antigen (CEA) level ≥100 U/mL, and cutaneous immune-related adverse events (irAEs) were independent prognostic factors for PFS. CEA level ≥100 U/mL and cutaneous irAEs were independent prognostic factors for OS. The objective response rate and disease control rate (DCR) were 15.9% and 37.7%, respectively. Patients with cutaneous irAEs, high CD8+ T cell infiltrated or immune inflamed GBCs had higher DCR. Patients with high CD8+ T cell infiltrated or immune inflamed GBCs also had a notably improved prognosis. These results suggest that ICIs were effective in patients with GBC. High CEA level, cutaneous irAEs, high CD8+ T cell infiltration, and immune inflamed phenotype could be useful for predicting the efficacy of ICIs in GBC.

Immune Checkpoint Inhibitors and Lupus Erythematosus.

Immune checkpoint inhibitors (ICIs) are the standard of care for a growing number of malignancies. Unfortunately, they are associated with a broad range of unique toxicities that mimic the presentations of primary autoimmune conditions. These adverse events are termed immune-related adverse events (irAEs), of which ICI-lupus erythematosus (ICI-LE) constitutes a small percentage. Our review aims to describe the available literature on ICI-LE and ICI treatment for patients with pre-existing lupus. Most diagnoses of ICI-LE had findings of only cutaneous lupus; four diagnoses of ICI-LE had systemic lupus manifestations. Over 90% (27 of 29) of cases received anti-PD-1/PDL-1 monotherapy, 1 received combination therapy, and 1 received only anti-CTLA-4 treatment. About three-fourths (22 of 29 or 76%) of patients with ICI-lupus were managed with topical steroids, 13 (45%) received hydroxychloroquine, and 10 (34%) required oral corticosteroids. In our case series, none of the patients with pre-existing lupus receiving ICI therapy for cancer had a flare of their lupus, but few had de novo irAE manifestations, all of which were characterized as low-grade. The review of the literature yielded seven ICI-LE flares from a total of 27 patients with pre-existing lupus who received ICI. Most flares were manageable without need for ICI cessation.

Examining crossover and postprotocol therapies in first-line immunotherapy trials in non-small cell lung cancer.

Immune checkpoint inhibitor (ICI) therapy has led to significant improvement in outcomes for patients with nononcogene-driven advanced non-small cell lung cancer (NSCLC). The rate of crossover and receipt of postprotocol ICI in frontline trials for advanced NSCLC has not been systematically evaluated. ClinicalTrials.gov was used to identify phase 3 studies evaluating the use of immunotherapy or combination chemoimmunotherapy against chemotherapy alone in the frontline management of advanced NSCLC. Data on outcomes, rate of crossover and/or subsequent post-protocol receipt of immunotherapy, and the start dates of these clinical trials were then extracted. Twenty-three frontline trials in nononcogene-driven advanced NSCLC were identified. Six trials with ICI monotherapy/dual ICI therapy and 17 trials evaluating chemotherapy/ICI in first-line advanced NSCLC were included in the analysis. The crossover rate ranged 0% to 54% in ICI monotherapy/dual ICI trials and 0% to 52% in chemotherapy/ICI trials. Nineteen of 23 trials provided information on subsequent postprotocol therapies. Among the trials not allowing crossover, postprotocol ICI was administered to 17% to 45.8% of patients. Information regarding the eventual receipt of ICI therapy was available for 22 of 23 trials. Of 6631 patients, 2507 (37.8%) randomized to the control arm eventually received ICI therapy. The rate of crossover and postprotocol ICI use was low in frontline trials for first-line NSCLC incorporating ICI. Given the proven improved overall survival of ICI in a broad population, there is a need to ensure availability of this life-prolonging therapy in future trials, either by crossover treatment or postprotocol administration.

A novel investigation into the negative impact of opioid use on the efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer patients

ObjectiveImmune checkpoint inhibitors (ICIs) have effectively improved the clinical outcome of advanced non-small cell lung cancer (NSCLC). Opioids are commonly used for pain relief in cancer patients. This study aims to clarify the prognostic impact of opioid use in advanced NSCLC patients receiving ICI therapy. MethodsA systematic literature review was carried out using online databases before July 2023. The meta-analysis was used to clarify the correlation of opioid use with the overall survival (OS) or progression-free survival (PFS) of ICI-treated NSCLC patients, both of which were determined using hazard ratios (HRs) coupled with 95 % confidence intervals (CIs). Then, an independent cohort enrolling 181 NSCLC patients was utilized for validation. Finally, a comprehensive bioinformatics analysis based on TCGA cohort was performed to investigate the prognostic significance of opioid target genes (OTGs) and their correlation with immune infiltration in NSCLC patients. ResultsA total of 8 studies enrolling 1174 patients were included in the meta-analysis. Opioid use was negatively associated with worse PFS (HR = 2.16, 95 %CI: 1.26–3.71) and OS (HR = 2.02, 95 %CI: 1.54–2.63) in ICI-treated NSCLC patients. The retrospective validation confirmed the above result and identified opioid use as an independent unfavorable predictor for PFS and OS in both the entire cohort and ICI subgroup. The bioinformatic analysis identified 14 prognostic OTGs (CYP17A1, PDYN, PYCARD, FGA, NTSR1, FABP1, HPCA, PENK, PDGFB, LIN7A, FKBP5, TYMS, CACNA1H and LDHA), most of which were correlated with immune infiltration in NSCLC. A risk model was constructed based on 14 OTGs and found to effectively stratify the clinical outcome in both the training and validation set, independent of age, gender and TNM staging system. The model was also significantly correlated with infiltration of activated dendritic cells, neutrophils and tumor infiltrating lymphocytes. Finally, a nomogram was constructed based on the model, age, gender and TNM stage, which could predict well the 1-, 3- and 5-year survival of NSCLC patients. ConclusionOpioid use is correlated with the poor clinical outcome in ICI-treated NSCLC patients. Precise pain management is highly advocated and opioids are recommended to be cautiously used in these patients. OTGs have the potential to be prognostic biomarkers for NSCLC patients and their role in tumor immunity needs to be further investigated.

Safety and efficacy of immune checkpoint inhibitor rechallenge in advanced non-small cell lung cancer: a retrospective study

We conducted a retrospective study to evaluate the efficacy of immune checkpoint inhibitor (ICI) rechallenge in patients with advanced non-small cell lung cancer (NSCLC). The study included 111 patients who had previously received ICI therapy and experienced disease progression. The primary endpoints assessed were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Our findings revealed that the ICI rechallenge showed promising results in improving patient outcomes. OS (r) is the time from rechallenging with immune checkpoint inhibitors to the last follow-up or death from any cause. The median OS (r) was 14.3 months (95% CI 11.3–17.3 months), with a median PFS (r) of 5.9 months (95% CI 4.1–7.7 months). The ORR was 17.1%; the DCR was 82.3%. Subgroup analysis demonstrated that patients without brain or liver metastases had a longer OS (r) compared to those with metastases (21.6 vs. 13.8 months, χ2 = 3.873, P = 0.046; 20.8 vs. 9.1 months, χ2 = 10.733, P = 0.001, respectively). Moreover, patients without driver gene mutations exhibited significantly longer OS than those with mutations or wild-type patients (22.9 vs. 16.1 vs. 7.5 months, χ2 = 10.710, P = 0.005). Notably, patients who switched to a different ICI during the rechallenge had shorter OS than those who did not change medications (10.4 vs. 21.1 months, χ2 = 9.014, P = 0.003). The incidence of immune-related adverse events did not significantly differ between the two treatment phases. These findings suggest that ICI rechallenge may be a viable therapeutic strategy for select NSCLC patients. Further prospective studies are needed to validate these results and guide treatment decisions for advanced NSCLC.

TG468: a text graph convolutional network for predicting clinical response to immune checkpoint inhibitor therapy.

Enhancing cancer treatment efficacy remains a significant challenge in human health. Immunotherapy has witnessed considerable success in recent years as a treatment for tumors. However, due to the heterogeneity of diseases, only a fraction of patients exhibit a positive response to immune checkpoint inhibitor (ICI) therapy. Various single-gene-based biomarkers and tumor mutational burden (TMB) have been proposed for predicting clinical responses to ICI; however, their predictive ability is limited. We propose the utilization of the Text Graph Convolutional Network (GCN) method to comprehensively assess the impact of multiple genes, aiming to improve the predictive capability for ICI response. We developed TG468, a Text GCN model framing drug response prediction as a text classification task. By combining natural language processing (NLP) and graph neural network techniques, TG468 effectively handles sparse and high-dimensional exome sequencing data. As a result, TG468 can distinguish survival time for patients who received ICI therapy and outperforms single gene biomarkers, TMB and some classical machine learning models. Additionally, TG468's prediction results facilitate the identification of immune status differences among specific patient types in the Cancer Genome Atlas dataset, providing a rationale for the model's predictions. Our approach represents a pioneering use of a GCN model to analyze exome data in patients undergoing ICI therapy and offers inspiration for future research using NLP technology to analyze exome sequencing data.

Association between immune checkpoint inhibitor medication and uveitis: a population-based cohort study utilizing TriNetX database.

To explore the associations between the use of immune checkpoint inhibitors (ICIs) and the risk of developing uveitis among cancer patients. Cancer patients who received ICI therapy and a comparison group of cancer patients who did not receive ICI therapy were retrospectively recruited from the TriNetX electronic heath-record registry. The outcome of interest was the development of new-onset uveitis. Propensity score matching based on a 1:1 ratio was conducted in order to reduce bias. Multi-variate cox proportional hazard models and Kaplan Meier method were also utilized to assess for the risk of uveitis among cancer patients who received ICI therapy. 71931 cancer patients (54.7% male; 76.5% white; mean age at index 63.6 ± 12.2 years) who received ICI treatment (ICI group) and 71931 cancer patients (54.7% male; 77% white; mean age at index 63.5 ± 12.4 years) who never received ICI (comparison group) were recruited. Associated Kaplan-Meier curves showed significantly increased uveitis risk among the ICI group for all follow-up years (p<0.001). The risk of uveitis was also higher among the ICI group during the 144-month follow-up period with a hazard ratio (HR) of 2.39 (95% CI: 2.07-2.75). Increased risk for specific uveitis diseases, such as iridocyclitis, chorioretinal inflammation, retinal vasculitis, unspecified purulent endophthalmitis, pan-uveitis and sympathetic uveitis were found. Subgroup analysis demonstrated an elevated hazard ratio for the development of uveitis among ICI recipients, spanning individuals below the age of 65 as well as those aged 65 and older. The elevated hazard ratio for uveitis development among ICI recipients was also observed across all genders, among those of white and Asian ethnicities, those with smoking history, and those with comorbid conditions such as hypertension and dyslipidemia, in comparison to their non-ICI counterparts. An additional subgroup analysis on monotherapy versus combinatory ICI regimens was also conducted. Individuals who received monotherapy from the class of anti-PD-1 (HR:1.98 [CI: 1.65-2.37]) and anti-CTLA-4 (HR:5.86 [CI:1.99-17.24]) exhibited elevated hazard ratios for uveitis development compared to their non-ICI comparators. Those exposed to combinatory ICI regimens, specifically a combination of anti-PD-1 and anti-CTLA4 (HR: 5.04 [CI:3.55-7.16]), showed increased hazard ratios for uveitis development compared to their non-ICI comparators. In contrast, individuals exposed to a combination of anti-PD-1 and anti-PD-L1 (HR: 2.47 [CI:0.81-7.50]) did not demonstrate an increased risk for uveitis compared to their non-ICI comparators. A significantly increased risk for uveitis diseases was found among the ICI group from the first year of follow-up. Increased awareness should be promoted on the occurrence of uveitis among cancer patients receiving ICI therapy.

Colony stimulating factor-1 (CSF-1) signalling is predictive of response to immune checkpoint inhibitors in advanced non-small cell lung cancer

The identification of biomarkers related to treatment in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) represents a significant challenge. The aim of this study was to determine the predictive value of macrophage-related markers assessed in plasma and tissue samples of patients with NSCLC undergoing ICI treatment. This bicentric study included a prospective cohort of 88 patients with advanced NSCLC who received first-line therapy with ICI (either as monotherapy or in combination with chemotherapy) or chemotherapy alone (CT). Samples were collected from the patients at baseline and during follow-up. Plasma levels of CSF-1 and IL-34 were measured using ELISA, while expression levels of the macrophage receptors CD163 and CSF-1-R were evaluated using immunohistochemistry on lung biopsies. At baseline, the median plasma CSF-1 expression was higher in patients who did not respond to immunotherapy compared to those who responded (8898 pg/mL vs. 14031 pg/mL, p = 0.0005). Importantly, high CSF-1 levels at the initial assessment were associated with disease progression regardless of the treatment received. Furthermore, high CSF-1 levels were associated with shorter progression-free survival (PFS) and overall survival (OS) in patients receiving ICI therapy, but not in those treated with chemotherapy. There was no correlation between IL-34, CSF-1R, CD163 and therapeutic response. We observed in vitro that the activation of lymphocytes mediated by pembrolizumab was hindered by the treatment of PBMC with recombinant CSF-1, suggesting that CSF-1 creates a systemic immunosuppressive state that interferes with ICI treatment. In conclusion, baseline CSF-1 levels represent a potential predictive marker to ICI treatment in NSCLC.

Comprehensive molecular analysis identifies RET alterations association with response of ICIs in multi-immunotherapy cohorts

BackgroundThe RET gene, which is frequently mutated across many types of cancer, has been proven to be critically involved in tumorigenesis and tumour development; however, its prediction of the therapeutic efficacy of immune checkpoint inhibitor (ICI) therapy remains to be elucidated. The present research aims to investigate the association between RET mutations and the efficiency of ICI therapy. MethodWe analysed the role of RET mutations in predicting the prognosis of patients receiving ICIs therapy in the discovery cohort and validated it in the validation cohort. Then, multi-omics data from TCGA pan-cancer cohort was employed to propose the association between RET mutations and tumour inflamed anti-tumour immune response and tumour antigenicity. ResultsOur study revealed that among 606 cases and across five types of cancer, RET mutation was associated with better clinical outcomes for ICIs therapy, including elevated response rate, longer progression-free survival PFS, and longer overall survival OS. Multivariate analysis showed that RET mutation could independently predict the prognosis of patients treated with ICIs, after adjusting cancer types. The predictive value of RET status for the OS of patients treated with ICIs immunotherapy was further validated in the validation cohort (n = 1,409). Subgroup analysis suggested that only the monotherapy group showed significant differences in OS(P < 0.05) and PFS(P < 0.05) between RET-wildtype tumours and RET-mutant tumours. Multi-omics data analysis revealed potential anti-tumour immunity mechanisms of RET mutations, suggesting that RET-mutant tumours have enhanced immunogenicity, higher expression of immune checkpoints and chemokines, and higher immune cell infiltration than those observed in RET-wildtype tumours; thus, potentially indicating a more favourable response to immunotherapy. ConclusionsRET mutation may be a predictive biomarker of enhanced response to ICIs therapy. Extensive investigation of the underlying molecular mechanisms and prospective studies are needed in the future.

Association of antibiotic exposure with survival in patients with extensive-stage small cell lung cancer receiving immune checkpoint inhibitor therapy.

Immune checkpoint inhibitors (ICIs) have dramatically shifted the therapeutic paradigm of extensive-stage small cell lung cancer (ES-SCLC). Antibiotic (ATB) exposure before or during ICI therapy can harm the integrity of the gut microbiome and lead to intestinal dysbiosis, which has a profoundly negative impact on the treatment response for various malignancies. Whether this is applicable to ES-SCLC remains unclear. We retrospectively reviewed the electronic medical records of all patients diagnosed with ES-SCLC who were treated with ICI-based immunotherapies from July 2019 to December 2020 at Shandong Cancer Hospital and Institute, China. Outcomes with the use of ATBs before or after the first infusion of ICI, including progression-free survival (PFS) and overall survival (OS), were investigated using the Kaplan-Meier method. Multivariate analyses were also conducted using a Cox proportional hazards model. A total of 214 patients were included, among whom 41 (19.2%) received ATBs within 2 months before or after the first initiation of ICI therapy and were assigned to the ATB group. The ATB group showed a shorter median PFS (4.3 vs. 6.3 months; HR = 1.43, 95% CI: 0.97-2.11; p = 0.043) and a significantly shorter median OS (6.9 vs. 13 months; HR = 1.47, 95% CI: 0.98-2.20; p = 0.033) than the non-ATB group. In the multivariate analysis, ATB exposure was markedly associated with worse PFS (HR = 1.47, 95% CI: 1.03-2.09, p = 0.035) and OS (HR = 1.46, 95% CI: 1.01-2.11, p = 0.043). Our results demonstrate that ATB exposure was significantly associated with worse survival in ES-SCLC patients who received ICI therapy.

The association between aspirin use and immune-related adverse events in specific cancer patients receiving ICIs therapy: analysis of the FAERS database.

Background: The promise of immune checkpoint inhibitors (ICIs) therapy in cancer treatment is tempered by the occurrence of immune-related adverse events (irAEs). Many patients undergoing ICIs also take aspirin, but the association between aspirin and irAEs is not well understood. Methods: This study analyzed adverse reaction data associated with the use of ICIs in the US Food and Drug Administration (FDA) Adverse Event Reporting System FDA Adverse Event Reporting System database, from the approval date of each drug until 1 October 2022. Multivariate logistic regression was employed to assess the association of aspirin use with irAEs in patients receiving ICIs. Results: The results indicated that aspirin use was associated with an increased risk of irAEs in a pan-cancer analysis, with a more pronounced association in specific cancer types such as lung cancer, mesothelioma, and pancreatic cancer. However, in lymphoma, aspirin use was associated with a reduced risk of irAEs. Furthermore, aspirin use was associated with an increased risk of certain irAEs, such as anemia, colitis, myocarditis, myositis, pancreatitis, pericarditis, and pneumonia, while it was associated with a reduced risk of rash, Stevens-Johnson syndrome, and thyroiditis. Conclusion: This study has unveiled an association between aspirin use and irAEs in cancer patients receiving ICIs therapy, emphasizing the need for individualized consideration of patients' medication history when devising cancer treatment plans to enhance efficacy and reduce risks.

Arterial inflammation induced by immune checkpoint inhibitors assessed on 18F-FDG PET-CT scans in stage III/IV melanoma patients

Abstract Background In recent years, immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, as they lead to a substantial improvement in the prognosis of cancer patients. In high-grade melanoma patients, ICIs have doubled the three-year survival rate. However, ICIs may not only increase the immune response to tumor cells, but also to non-tumor cells, potentially inducing pro-atherogenic effects that can result in increased vascular inflammation and subsequent cardiovascular events. Purpose The objective of this study is to assess differences in vascular inflammation in the large arteries, as detected by 18F-FDG PET-CT scans, between stage III/IV melanoma patients receiving ICI therapy compared to stage III/IV melanoma patients not treated with ICIs. Methods The study population consisted of a cohort stage III/IV melanoma patients who underwent PET-CT scans at baseline, defined as &amp;lt; 1 year after diagnosis of stage III/IV melanoma and at T1 and T2, 6 months and 18 months after the baseline scan respectively. Patients with a history of cardiovascular events, treated with statins or corticosteroids (prednisolone &amp;gt; 10 mg per day) were excluded. Vascular inflammation was evaluated in the following eight arterial segments: the left and right carotid artery, ascending aorta, aortic arch, thoracic descending aorta, abdominal aorta and the left and right iliac artery. For each segment, the maximum standardized uptake value (SUV) for 18F-FDG uptake was derived and target-to-background ratio (TBR) was calculated from the ratio of the maximum SUV of the segment and the mean SUV of the superior and inferior vena cava. Vascular inflammation was defined as the total TBR per patient, calculated by sum of the TBR values of the eight arterial segments. The study endpoint was the difference in the increase in total TBR between patients treated with ICIs (exposure group) and patients without ICI treatment (control group). Results A total of 70 stage III/IV melanoma patients of whom 46 received ICIs and 24 did not receive ICI therapy were analyzed in this study. The median age at diagnosis was 61 years [IQR: 49-69] and 37 patients (52.9%) were female. The exposure group had a median ICI treatment of 9 [6-13] cycles. The results showed a significant difference in the TBR between the baseline PET-CT scan and T1 between the two groups. The control group showed a decrease in TBR by -0.33 [95% CI: -0.66 – 0.01], whereas the exposure group showed an increase in TBR by 0.17 [-0.14 – 0.49] (p = 0.045). No differences in TBR were found between T1 and T2. Conclusion The present study demonstrated that in stage III/IV melanoma patients treated with ICIs, there was a significant increase in vascular inflammation assessed by PET-CT in the large arteries during the first six months after treatment initiation, as compared to a control group without ICI treatment.∆TBR on PET-CT between baseline and T1∆TBR on PET-CT between T1 and T2

Abstract 17199: A Case of Ventricular Fibrillation Arrest After Immune Checkpoint Inhibitor Therapy

Description of Case: Our patient is a 65-year-old male who suffered sudden cardiac arrest due to ventricular fibrillation while receiving his second cycle of therapy for non-small cell lung cancer, which consisted of carboplatin, pemetrexed, nivolumab, and ipilimumab. Initial symptoms included sudden onset chest pain and dyspnea during infusion, which then rapidly progressed to ventricular fibrillation, and he was successfully defibrillated with ROSC. Subsequent coronary angiogram revealed patent coronary arteries, and cardiac MRI (CMR) was consistent with acute myopericarditis. Our patient was treated with high dose steroids and colchicine. Discussion: Immune checkpoint inhibitors (ICI) are a novel drug class with an emerging role in treatment of various tumors, including lung cancer. ICIs prevent the interaction between host checkpoint proteins and tumor partner proteins, allowing the immune system to appropriately attack tumor cells. Two such ICI include nivolumab and ipilimumab, which are frequently administered together. ICI therapy is linked with very rare but potentially life-threatening cardiac side effects including malignant arrhythmias, such as ventricular fibrillation and polymorphic ventricular tachycardia, along with risk of myocarditis and pericarditis. The risk is highest in the first 30 days; patients who received nivolumab and ipilimumab in combination and those treated for non-small cell lung cancer were found to have a higher risk of cardiac side effects. The timeline of events in our patient with subsequent CMR findings make the diagnosis of sudden cardiac arrest secondary to ICI therapy the most likely cause. Patients receiving ICI therapy should be monitored appropriately with algorithms in place for prompt detection and triaging of such patients who develop these side effects.

Management of autoimmune and viral hepatitis in immunotherapy: a narrative review.

Cancer immunotherapy has firmly established itself as a pillar of cancer care due to its advantages over traditional anti-tumor therapy but also carries limitations due to potential for severe adverse reactions. This review highlights the current understanding and management of patients with autoimmune and viral hepatitis immune in the setting of immune checkpoint inhibitor (ICI) therapy. A literature search was conducted on PubMed, Scopus, Google Scholar SEER*Stat databases (from inception to December 2022) using search terms: "immune checkpoint inhibitor", "autoimmune hepatitis", "viral hepatitis", "HBV pathogenesis", "HCV pathogenesis", "HBV reactivation", "HCV reactivation", "cancer immunotherapy", "immune related adverse events", "immune related hepatitis". Pre-existing autoimmune disease (AD), whether active or inactive, can predispose patients receiving ICI therapy to develop autoimmune disease flares or immune-related adverse events (irAEs). Thus, patients with AD have routinely been excluded from clinical trials and data on safety of ICI therapy are limited. Hepatic irAE can be seen in ICI therapy and is a distinct entity from autoimmune hepatitis (AIH). ICI therapy alters the immune environment in patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Patients who had prior exposure to HBV are at risk for viral reactivation. However, the prevalence of viral hepatitis in patients receiving immunotherapy is underrecognized and can lead to increases in liver biochemical tests as well as deterioration of liver function ultimately limiting treatment. The high morbidity and mortality associated with immune-related hepatitis emphasizes the need for screening of underlying diseases, including autoimmune and viral hepatitis, prior to initiation of ICI. Presence of AIH or chronic viral hepatitis is the most important risk factor for hepatic adverse events in ICI therapy. Screening for AIH, HBV and HCV is paramount in patients who will undergo ICI therapy.

Survival Among Veterans Receiving Steroids for Immune-Related Adverse Events After Immune Checkpoint Inhibitor Therapy

Systemic steroids are commonly used to manage immune-related adverse events (irAEs), but it remains unclear whether they may undermine immune checkpoint inhibitor (ICI) therapy outcomes. Few studies have assessed the impact of steroid timing and its association with continuation or cessation of ICI therapy. To characterize how systemic steroids and steroid timing for irAEs are associated with survival in patients receiving ICI therapy. This multicenter retrospective cohort study encompassed veterans receiving ICI for cancer between January 1, 2010, and December 31, 2021. Data analysis was conducted September 8, 2023. Identifiable primary diagnosis of cancer. Patients were categorized into 3 cohorts: those receiving no steroids, systemic steroids for irAEs, and steroids for non-irAE-associated reasons. All eligible patients received 1 or more doses of an ICI (atezolizumab, avelumab, cemiplimab, durvalumab, ipilimumab, nivolumab, or pembrolizumab). Eligible patients in the steroid group received at least 1 dose (intravenous, intramuscular, or oral) of dexamethasone, hydrocortisone, methylprednisolone, prednisone, or prednisolone. Steroid use at baseline for palliation or infusion prophylaxis or delivered as a single dose was deemed to be non-irAE associated. All other patterns of steroid use were assumed to be for irAEs. The primary outcome was overall survival, with a 5-year follow-up after ICI initiation. Kaplan-Meier survival analyses were performed with pairwise log-rank tests to determine significance. Risk was modeled with Cox proportional hazard regression. The cohort consisted of 20 163 veterans receiving ICI therapy including 12 221 patients (mean [SD] age, 69.5 [8.0] years; 11 830 male patients [96.8%]; 9394 White patients [76.9%]) who received systemic steroids during ICI treatment and 7942 patients (mean [SD] age, 70.3 [8.5] years; 7747 male patients [97.5%]; 6085 White patients [76.6%]) who did not. Patients with an irAE diagnosis had significantly improved overall survival (OS) compared with those without (median [IQR] OS, 17.4 [6.6 to 48.5] months vs 10.5 [3.5 to 36.8] months; adjusted hazard ratio, 0.84; 95% CI, 0.81-0.84; P < .001). For patients with irAEs, systemic steroids for irAEs were associated with significantly improved survival compared with those who received steroids for non-irAE-related reasons or no steroid treatment (median [IQR] OS, 21.3 [9.3 to 58.2] months vs 13.6 [5.5 to 33.7] months vs 15.8 [4.9 to not reached] months; P <.001). However, among those who received steroids for irAEs, early steroid use (<2 months after ICI initiation) was associated with reduced relative survival benefit vs later steroid use, regardless of ICI continuation or cessation following steroid initiation (median [IQR] OS after ICI cessation 4.4 [1.9 to 19.5] months vs 16.0 [8.0 to 42.2] months; median [IQR] OS after ICI continuation, 16.0 [7.1 to not reached] months vs 29.2 [16.5 to 53.5] months; P <.001). This study suggests that steroids for irAE management may not abrogate irAE-associated survival benefits. However, early steroid administration within 2 months of ICI initiation is associated with shorter survival despite continuation of ICI therapy.