Risk Of irAEs Research Articles

Cancer and treatment specific incidence rates of immune-related adverse events induced by immune checkpoint inhibitors: a systematic review.

Immune-related adverse events (irAE) induced by immune checkpoint inhibitors (ICI) are a treatment-limiting barrier. There are few large-scale studies that estimate irAE prevalence. This paper presents a systematic review that reports the prevalence of irAE by cancer type and ICI. A systematic review was undertaken in MEDLINE OVID, EMBASE and Web of Science databases from 2017-2021. A total of 293 studies were identified for analysis and, of these, event rate was calculated for 272 studies, which involved 58,291 patients with irAE among 305,879 total patients on ICI. Event rate was calculated by irAE and ICI type. Mean event rate for general irAE occurrence across any grade was 40.0% (37.3-42.7%) and high grade was 19.7% (15.8-23.7%). Mean event rates for six specific types of irAE are reported. Mean event rate for ICI monotherapy was 29.7% (27.7-33.2%), 45.7% (29.6-61.7%) for ICI combination therapy, and 30.3% (27.3-35.0%) for both ICI monotherapy and combination therapy. This systematic review characterises irAE prevalence across current research that examines irAE risk factors across cancers and ICI. The findings confirms that irAE occurrence is very common in the real-world setting, both high grade and irAE across any grade.

Prognostic Factors for Patients with Small-Cell Lung Cancer Treated with Chemoimmunotherapy: A Retrospective Multicenter Study

Background: This study aimed to investigate prognostic factors for predicting the survival of patients with extensive-disease-stage small-cell lung cancer treated with chemoimmunotherapy. Methods: Patients were classified according to overall survival (OS): favorable corresponded to an OS ≥ 24 months, moderate corresponded to an OS of 6–24 months, and poor corresponded to an OS < 6 months. Multivariate Cox regression analyses were used to evaluate prognostic factors. Results: Of 130 patients, the proportions of performance status decline and liver metastasis were significantly higher in the poor-prognosis group. With regard to the laboratory findings, neutrophil/lymphocyte ratios and albumin levels differed significantly among the groups. Multivariate analysis showed that the independent prognostic factors for OS were liver metastasis and decreased albumin levels (<3.5 mg/dL). After classifying the patients into three groups according to the quantities of these prognostic factors, the OS differed significantly among the groups (18.3 vs. 13.5 vs. 3.8 months; p < 0.001). The incidence of immune-related adverse events (irAEs) was higher in patients without these prognostic factors than in those with both (36% vs. 5%; p = 0.01). Conclusion: Liver metastasis and decreased albumin levels are independent unfavorable prognostic factors. Patients with both prognostic factors showed unfavorable OS; however, patients without these factors may have a favorable prognosis but be at greater risk of irAEs.

Association between statin use and immune-related adverse events in patients treated with immune checkpoint inhibitors: analysis of the FAERS database.

Understanding the risk relationship between statin use and immune-related adverse events (irAEs) in patients undergoing immune checkpoint inhibitors (ICIs) therapy is crucial for optimizing oncological management. This study aimed to investigate whether the use of statins increases the risk of irAEs in patients receiving ICI therapy. This study primarily utilized data from FAERS database. Multivariable logistic regression was the principal method of analysis, and the Benjamini-Hochberg procedure was employed to adjust for multiple hypothesis testing. In a group of 145,214 patients undergoing ICI therapy, 9,339 reported using statin medications. Multivariable analysis indicated an increased risk of irAEs among statin users (OR 1.199, 95% CI: 1.141-1.261; FDR p < 0.001) in comparison to those not using statins. Notably, increased risks were observed particularly in patients diagnosed with lung, pancreatic, and renal cancers. The link between statin usage and increased irAEs risk remained consistent across various ICIs treatments. Statin medication usage is linked to an elevated probability of experiencing irAEs in patients enrolled in ICI therapy. In cancer patients receiving immune checkpoint inhibitors, careful consideration of statin use is essential to avoid potentially increased irAEs risk. These findings provide critical guidance for clinicians in developing treatment strategies that balance therapeutic efficacy and safety in oncological management.

Systemic Inflammation Indexes and Risk of Immune-related Adverse Events in Patients With Metastatic Urothelial Carcinoma Treated With Immunotherapy.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic urothelial carcinoma (mUC). However, they could be associated with immune-related adverse events (irAEs), which may be clinically significant. Identifying clinical characteristics that may be associated with a higher risk of irAEs is of great importance. We retrospectively collected data from all patients who received anti-PD1 or anti-PD-L1 for metastatic UC at our Institution from January 2017 to December 2022. Patients were dichotomized according to baseline neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and platelet-to-lymphocyte ratio (PLR) values. We performed univariate and multivariate logistic regression to determine the association between baseline characteristics and the development of irAEs. A total of 119 patients were identified. At a median follow-up of 29.6 months, 96 patients progressed and 82 died. Forty-five patients developed irAEs of any grade, 8 patients developed grade 3 toxicities. In the univariate analysis PS of 0 (p<0.01), baseline NLR <3.52, baseline PLR <194 (p=0.04) and baseline SII <906 (p=0.01) were significantly associated with a higher risk of developing irAEs, whereas in the multivariate analysis only PS=0 (p<0.01) and NLR <3.52 (p=0.03) maintained their correlation. Median progression-free survival (mPFS) and overall survival (mOS) were significantly longer in patients with NLR <3 (mPFS 3.8 vs. 2.6 months, p=0.01; mOS 15.3 vs. 5.6 months, p=0.002) and PS=0 (mPFS 4.8 vs. 2.1 months, p<0.001; mOS 15.3 vs. 3.8 months, p<0.001). Low baseline NLR, PLR, and SII and good PS are associated with a higher risk of developing irAEs in patients treated with ICIs for mUC.

Sarcopenia predicts immune-related adverse events due to anti-PD-1/PD-L1 therapy in patients with advanced lung cancer.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of a number of patients with advanced cancer, and while this has resulted in increased survival times, it has also led to the emergence of novel immune-related adverse events (irAEs). In individuals with advanced cancer, sarcopenia is a significant symptom of cachexia and is linked to poor nutritional status and increased mortality. The present study aimed to evaluate sarcopenia and other risk variables that can affect the emergence of irAEs in patients with lung cancer. A single-center retrospective analysis of 129 patients with advanced lung cancer treated with programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) checkpoint inhibitors was conducted from August 2020 to August 2022. Data on baseline characteristics and adverse events of participants were collected. Computed tomography was used to determine the skeletal muscle index at the third lumbar vertebra (L3-SMI) and whether sarcopenia is present. The median age of all participants was 60 years old (range, 52-66 years), with men accounting for 68.9% of the total patient cohort. The present study showed that 44 (34%) participants presented with any degree of irAEs, and 79 (61.2%) patients presented with sarcopenia. There were no statistically significant differences in baseline characteristics, such as age and sex, between patients who presented with irAEs and those without irAEs. Using logistic regression analysis, individuals with sarcopenia were 2.635-times more likely to experience any grade of irAEs than those without sarcopenia. irAEs are prevalent side effects of PD-1/PD-L1 inhibitor therapy for patients with cancer. By diagnosing and treating sarcopenia early, it is possible to lower the potential risk of irAEs in patients with advanced cancer. Furthermore, sarcopenia can be utilized as a predictor of irAEs.

Tyrosine Protein Kinase SYK-Related Gene Signature in Baseline Immune Cells Associated with Adjuvant Immunotherapy-Induced Immune-Related Adverse Events in Melanoma.

Immune checkpoint inhibition (ICI) shows benefits in adjuvant (AT) and neoadjuvant melanoma treatments. However, ICI frequently induces severe immune-related adverse events (irAE). Unlike metastatic disease, in which irAEs are a clinical trade-off for treatment that improves survival, the toxicity burden from ICI in the AT setting is a substantial clinical problem urging for irAE-predictive biomarkers. We assessed postsurgical, pre-ICI treatment peripheral CD4+ and CD8+ T cells from clinical trial patients (CheckMate 915) treated with AT nivolumab (n = 130) or ipilimumab/nivolumab (COMBO, n = 82). Performing RNA sequencing differential gene expression analysis, we tested baseline differences associated with severe (grades 3-5) irAEs and constructed an irAE-predictive model using least absolute shrinkage and selection operator-regularized logistic regression. The analysis of predicted protein-protein interactions among differentially expressed genes in peripheral CD4+ cells revealed significant enrichment of the spleen tyrosine kinase (SYK) pathway, associated with severe irAEs in COMBO-treated patients. This gene expression signature predicted severe-irAE COMBO patients (χ2P value = 0.001) with 73% accuracy and was independent of disease recurrence (P = 0.79). The irAE-predictive model incorporating this gene expression signature demonstrated 82% accuracy (χ2P value = 8.91E-06). We identified baseline gene expression differences in key immune pathways of peripheral blood T cells from COMBO-treated patients with grades 3 to 5 irAEs and defined a SYK-related gene signature correctly identifying ∼60% of COMBO-treated patients with grades 3 to 5 irAEs. This finding aligns with our previous work linking anti-CTLA4 irAEs with a germline variant associated with high SYK expression. This gene signature may serve as a baseline biomarker of severe grade 3 to 5 irAE risk, which is especially important in AT treatment.

Pre-existing autoimmune disease as a risk factor for immune-related adverse events in cancer patients receiving immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have been widely used as standard therapies for various cancers. However, in 20-30% of cases, ICIs can lead to immune-related adverse events (irAEs), which sometimes require discontinuation of treatment. Due to the increased risk of irAEs, patients with pre-existing autoimmune diseases (AI) are often advised against receiving ICIs. However, there has not been sufficient objective risk assessment for AI. In our study, we conducted logistic regression analysis to assess the risk of irAEs by analyzing 478 cases that received anti-PD-(L)1 Ab and/or anti-CTLA4 Ab at our hospital between April 3, 2017, and May 24, 2022. Among these cases, 28 (5.9%) had pre-existing AI. We selected several independent factors for analysis: gender, age, performance status (PS), cancer type, type of ICI, type of combined anti-cancer agents, best overall response, and pre-existing AI. The adjusted odds ratio (OR) of AI for irAE occurrence was 2.52 [95% CI: 1.08-5.86] (p = 0.033), and the adjusted OR of AI for ICI discontinuation due to irAE was 3.32 [1.41-7.78] (p = 0.006). Patients with pre-existing AI experienced a significantly shorter irAE-free survival time compared to those without AI (median irAE-free survival: 5.7 months [95% CI: 3.5-7.8] vs 10.4 months [95% CI: 7.9-12.9], respectively, p = 0.035). Frequently observed irAEs in full ICI cohort, such as dermatologic issues (7.5%), pneumonitis (7.1%), hepatitis (4.6%), and hypothyroidism (4.2%), were often accompanied by pre-existing AI. Furthermore, pre-existing AI flared up in 6 cases (37.5% in AI-positive irAE-positive cases). The activity of AI was not related to the occurrence of irAEs. Grade 3 or higher irAEs were observed in 6 out of 20 (30.0%) cases in AI-accompanied patients complicated with irAEs. Although having a complicated AI increases the risk of irAEs, it may not necessarily be a contraindication for ICI treatment if closely monitored. (292<300 characters).

Plasma metabolomics of immune-related adverse events for patients with lung cancer treated with PD-1/PD-L1 inhibitors

BackgroundMetabolomics has the characteristics of terminal effects and reflects the physiological state of biological diseases more directly. Several current biomarkers of multiple omics were revealed to be associated with immune-related...

Immune-Related Adverse Events due to Concomitant Use of Immune Checkpoint Inhibitors and Chinese Herbal Medicines: A Study Based on a Japanese Adverse Event Database.

Fatigue is an immune-related adverse event (irAE) associated with immune checkpoint inhibitors (ICIs) used for cancer treatment. Chinese herbal medicines (Ho-zai) are used to treat cancer-related fatigue. However, no interactions between ICIs and Ho-zai have been reported. Herein, we investigated the risk of irAEs associated with the concomitant use of ICIs and Ho-zai. We extracted data of patients who used ICI and Ho-zai from the Japanese Adverse Event Reporting Database. The proportional reporting ratio (PRR) was calculated for patients using ICI, Ho-zai, or both. We focused on cases of interstitial lung disease (ILD) and colitis, which were among the most severe cases of irAEs among these patients. The shrinkage method used by the World Health Organization-Uppsala Monitoring Center was used to detect the interactions. Of the 799,670 patients in the database, 77,219, 2060, and 92 were using ICIs, Ho-zai, and combination treatment, respectively. The ILD and colitis groups included 39,388 and 17,522 patients, respectively. ILD signals were detected for both ICIs and Ho-zai. There were 24 cases of patients treated with concomitant ICIs and Ho-zai who developed ILD. For all combinations of all ICIs and all Ho-zai, Ω025 was negative, which suggested no ILD-related interactions. Colitis signals were detected for ICIs except for atezolizumab, avelumab, and durvalumab. There were eight patients treated with concomitant ICI and Ho-zai who developed colitis. For all combinations of all ICIs and all Ho-zai, Ω025 was negative, which suggested no colitis-related interactions. To our knowledge, this is the first study to investigate interactions between ICIs and Ho-zai. Signals were detected for ILD in both ICI and Ho-zai groups, and colitis in the ICI group. However, the combined use of these treatments did not increase the risk of irAEs.

Effects of pre-treatment on odds of immune-related adverse events.

2540 Background: For many tumor types, there is an option to start an immune checkpoint inhibitor (ICI) at the time of diagnosis or to sequence ICI after chemotherapies or targeted therapies. The risk of immune-related adverse events (irAE) may vary by the line of therapy. Prior systemic therapies might release cancer epitopes and increase the risk of an irAE through awakened subclinical autoimmunity. Conversely, prior systemic therapies may lead to residual immunosuppression and reduce the risk of irAEs. Methods: We created an IRB-approved retrospective registry of all patients who received at least one dose of an ICI for any indication between 2/1/2011 and 4/7/2022 at a comprehensive cancer center and its outreach clinics. Study personnel reviewed the electronic medical record and defined irAEs according to Common Terminology Criteria for Adverse Events. Research specialists at Vasta Global captured most clinical outcomes. Line of therapy was defined ordinal manner, with four or more combined into a single group due to data sparsity. A multivariable logistic regression model was built to assess effect of line of therapy on any irAE while controlling for confounders identified either a priori or in univariate analysis. Given potential for heterogeneity, interaction between tumor primary and line of therapy was tested. SAS v9.4 was used for all analyses. Results: Among the final cohort of 3,101 patients, 1,169 (38%) were noted to have an irAE of any grade. ICI were used as first-line therapy in 1,432 patients and second-, third-, or at least fourth-line in 1,119, 328, and 222 patients, respectively. The most common tumor type was non-small cell lung cancer (36%), followed by melanoma (14%). At baseline, any-grade irAE were more common among first-line ICI with 618 (43.2%) than for second-line (395, 35.3%), third-line (102, 31.1%), or at least fourth-line (54, 24.3%; p&lt;0.01). After adjusting for age (over 65), sex, smoking history, and body mass index, the model revealed significant heterogeneity, indicated by a significant interaction between the ICI line and the primary tumor type (p=0.01). The impact of the ICI line on the odds ratio (OR) of irAE for each primary calculated: melanoma (OR) 0.54 (95% confidence interval [CI] 0.32-0.93), non-small cell lung cancer OR 1.14 (CI 0.96-1.35), head-neck cancer OR 0.82 (CI 0.58-1.14), and renal cell carcinoma OR 0.78 (CI 0.57-1.06). Conclusions: The effect of pre-treatment with prior systemic therapy was significantly associated with the odds of developing an irAE, though this effect was significantly heterogeneous between tumor primaries. Melanoma was significantly less likely to develop irAE when heavily pre-treated. In contrast, NSCLC suggested a trend of increased odds of irAE with more pre-treatment however it was not statistically significant. Further study is indicated to clarify the types of prior systemic therapy that may modulate the risk of irAE and better clarify the optimal sequencing of ICI.

Germline variation and risk of immune-related adverse events (irAEs): A real-world BioVU study.

10582 Background: IrAEs are prevalent in patients treated with immune checkpoint inhibitors (ICI) and mimic classical autoimmune diseases. IrAE risk prediction could improve clinical decision making and patient safety for ICI-treated patients. Classical autoimmune diseases show strong associations with germline polymorphisms and with Human Leukocyte Antigen (HLA) variants, though it is unclear if these same genetic risk factors predispose to irAEs. To identify both tolerant and irAE patients, we mined Vanderbilt University Medical Center (VUMC) BioVU, a biorepository of &gt;300K DNA samples linked to de-identified medical records and evaluated genome-wide and imputed HLA class I and II associations with irAE risk. Methods: We identified 1,472 ICI-treated BioVU subjects: 428 with ≥ 1 irAE, and 1044 with no irAEs ≤ 6 months from last ICI treatment. Genotyping was performed by Illumina MEGAEX array. Records were screened for use of irAE therapies ( e.g. systemic corticosteroids, infliximab, levothyroxine) after ICI treatment, with chart adjudication. Association tests were performed using Firth’s logistic regression adjusting for age, sex, ICI regimen, and 3 principal components to assess 1) HLA Class I and II alleles; 2) HLA evolutionary divergence; and 3) GWAS to evaluate total irAEs, organ-specific irAEs, or other specific irAEs (sample size permitting). Endocrine irAEs were excluded to be presented in a separate focused study. Results: In GWAS analyses, 53 SNPs and 23 SNPs were identified significantly (nominal p ≤ 5e-8) associated with GI and neuro-toxicity, respectively. We did not identify any significant HLA class I or II associations with irAE or organ-grouped irAEs, including most evolutionary divergence association tests. We noted marginal association (FDR=0.12, OR=6.85) of rheumatic irAEs with HLA-DRB1*10:01, an HLA class II allele with RA-specific epitope motif. Patients experiencing lung irAEs were more likely to have a high HLA class I and II evolutionary divergence sum (p = 0.013 and p=0.046, respectively). Assessment of associations with specific irAEs, validation of known associations with irAEs or autoimmune disorders, including polygenic risk scores, are underway. Conclusions: We had several SNP-irAE associations, though appropriate classification schemas to maximize power and detect genetic variation remain challenging. We will soon expand with 1,800 additional ICI-treated patients (n=~3,300 in toto), creating a robust resource for irAE genetic associations. [Table: see text]

Serum multiplex analysis of checkpoint proteins in association with immune-related adverse events in patients with melanoma receiving adjuvant anti-PD-1 therapy.

9588 Background: Immune checkpoint inhibitors have significantly improved melanoma (MEL) patient (PT) outcomes. Immune-related adverse events (irAEs) may cause significant morbidity, rarely including death. Soluble immune checkpoints have been identified as biomarkers of autoimmune activity and potential off-target pathology. Understanding their relationship to pathologic outcomes may assist in the identification of PTs at highest risk of irAEs. Methods: PTs with resectable stage IIB-IV MEL who received adjuvant anti-programmed-death-1 (PD-1) therapy were identified from the University of Pittsburgh’s MEL Center biospecimen repository (N=273). MILLIPLEX Human Immuno-Oncology Checkpoint Protein Panel 2 was used to study serum levels of immunomodulatory proteins. Mean pretreatment serum levels in PTs with and without irAEs were compared using a two-sample t-test after performing Box-Cox transformation for non-normally distributed data. Results: Sera from 43 PTs were analyzed. The cohort included 28 (65.1%) male, mean age at diagnosis (62), including MEL stage IIIA = 7 (16.3%), IIIB = 16(37.2%) and IIIC = 20(46.5%). The most common irAEs (n=24, 55.8%) were thyroiditis (n=9, 20.9%), dermatitis (n=8, 18.6%), and adrenal insufficiency (n=9, 21.0%). Multiple irAEs were observed amongst 22 (51.2%) PTs with ≥3 irAEs and 6 (13.9%) with 5 irAEs. Visceral irAEs included Hepatitis (n=3, 7.0%), pneumonitis (n=2, 4.7%), and colitis (n=5, 11.6%). Seven of 8 patients with visceral irAEs required corticosteroids. Siglec-7 (mean 23.4 vs 3.51 pg/mL, p=0.018) and siglec-9 (mean 77.0 vs 33.1 pg/mL, p=0.049) were significantly elevated in the PTs who developed any irAE. After stratifying for each individual irAE, PTs with thyroiditis had elevated Nectin-4 (mean 2785.5 vs 494.7 pg/mL, p&lt;0.001) and serum arginase (mean 2437.5 vs 1383.1 pg/mL, p= 0.046) was elevated in PTs who developed colitis. PTs with hepatitis demonstrated increased galectin-3 (mean 10103.9 vs 9915.3 pg/mL, p=0.045) and decreased levels of CD40L (mean 2869.2 vs 9496.9 pg/mL, p=0.033). In PTs with dermatitis B7-H3 (mean 2503.3 vs 732.4 pg/mL, p=0.009) and MHC class I polypeptide-related sequence B (mean 1598.0 vs 259.1 pg/mL, p=0.048) were elevated. Conclusions: We have demonstrated unique serum checkpoint protein profiles related to specific irAEs in melanoma patients receiving adjuvant anti-PD1. Further studies are warranted to confirm and validate the utility of these irAE predictors during adjuvant anti-PD-1.

Retrospective analysis on association of body mass index and immune checkpoint inhibitor response.

e14536 Background: The relationship between Body Mass Index (BMI) and cancer is a complex. We aim to study the impact of BMI on the response to immunotherapy in cancer patients. Methods: We did a retrospective observational study to investigate the influence of different BMI groups on patients receiving Immune Checkpoint Inhibitors (ICIs) at the University of Vermont Cancer Centre. We examined the medical records of people who received ICIs between January 2017 and June 2022 and collected demographic data, including age, sex, ethnicity, cancer stage, BMI, type and metastasis. We looked at Hazard Ratio (HR) in BMI subcategories compared to normal. The occurrence of immune-related adverse events (irAEs), metastasis and receipt of chemotherapy in different BMI subgroups was evaluated with relative risks (RRs). Results: A total of 288 cases were identified, out of which 269 had documented BMI, including 58% males, 94.8% whites with 64.17 years mean age. Lung cancer was most common at 41.3%, 46.5% were and 63.2% were stage 4. Total 71.4% of people received Pembrolizumab and 42.8% had concomitant chemotherapy. The median ECOG was 1 and the Charlson comorbidity index was 6. irAEs observed in 33% of cases, whereas mortality in 36%. The BMI distribution had 36.1% normal, 27.1% overweight, 16.5% obese, 14.5% extremely obese and 5.6% underweight. The HR in underweight subgroup was significant at 5.223 (p &lt;0.001; 95CI: 2.2 to 12.4) compared to normal. The HR of overweight, obese and extremely obese decreased with HR of 1.15, 0.77 and 0.18 respectively but wasn’t significant as seen in Table 1. Table also shows that relative risk of irAEs, cancer stage, metastasis and concomitant chemotherapy were not significant. Conclusions: Clinically significant association was found between being underweight and mortality in cancer patients receiving immunotherapy. [Table: see text]

The impact of COVID-19 mRNA vaccines on immune-related adverse events in patients with cancer receiving immune checkpoint inhibitors.

2648 Background: Cancer patients are a vulnerable population to COVID-19. COVID-19 mRNA vaccines have shown to decrease hospitalization and death risk from COVID-19 in cancer patients. Concurrent COVID-19 vaccination and immune checkpoint inhibitors (ICIs) use may impact immune-related adverse events (irAEs) synergistically. Limited data exist on how COVID-19 mRNA vaccines affect irAEs in ICI-treated cancer patients, especially those with breakthrough infections. Methods: We retrospectively analyzed adult patients with malignant solid tumors receiving ICIs at a single cancer institute (January 2020 to July 2021). Fully vaccinated status is defined as two consecutive doses of mRNA vaccines (BNT162b2 and mRNA-1273). Patients who were partially vaccinated, fully vaccinated post COVID-19 infection, vaccinated with non-mRNA COVID-19 vaccines, or last visit within 30 days post vaccination were excluded. All COVID-19 infections were confirmed by PCR. In the vaccinated group, only post-vaccination irAEs were considered as events. Results: 443 patients were included in our study, with 251 (56.7%) vaccinated and 192 (43.3%) unvaccinated. The baseline characteristics were similar between the two groups, except for age (vaccinated median 68 years, unvaccinated median 62 years, p=0.004). With a median follow-up of 12 months, incidences of all-grade irAEs (19.1% vs. 20.3%, p=0.72) and severe irAEs (5.6% vs. 4.2%, p=0.66) were comparable between vaccinated and unvaccinated groups. 34 breakthrough COVID-19 infections occurred. In the vaccinated group, a non-significant trend of higher all-grade irAEs incidence was noted in the COVID-19 infected subgroup compared to uninfected subgroup (29.4% vs. 17.5%, p = 0.11). Univariate analysis linked COVID-19 vaccination (OR 1.54, 95% CI 1.01-2.35, p=0.04) and ipilimumab + nivolumab use (OR 5.57, 95% CI 1.79-17.35, p=0.003) to a higher risk of all-grade irAEs in the entire cohort. After multivariate adjustment, ipilimumab + nivolumab use remained the only variable associated with all-grade irAEs (OR 4.95, 95% CI 1.57-15.64, p=0.006). Conclusions: Our study suggests that COVID-19 mRNA vaccines do not increase irAE risk in cancer patients on ICIs. Fully vaccinated patients with breakthrough COVID-19 infections may safely continue ICI treatment without an increased irAE risk. [Table: see text]

HLA associations with immunotherapy related endocrine toxicity.

2516 Background: Endocrine immune related adverse events (irAEs), including thyroid dysfunction (ICI-T), diabetes mellitus (ICI-DM) and hypophysitis (ICI-HP), caused by treatment with immune checkpoint inhibitors (ICIs) are largely irreversible and pose a burden to cancer patients. Variation in HLA predisposes to many autoimmune conditions, but data associating endocrine irAEs to HLA types is limited. Methods: We included 6300 patients from multiple centers across the United States, Canada, Europe and Australia who were treated with ICIs for multiple cancer types. The most common endocrine irAE in these patients was ICI-T (806 cases), followed by ICI-HP (163 cases) and ICI-DM (75 cases). Cases of ICI induced adrenal insufficiency were considered to be ICI-HP unless the patient had an elevated ACTH. Patients without the specific irAE were considered controls. Genotyping and HLA imputation were completed at each institution independently. Associations between HLA types and ICI-T, ICI-DM, and ICI-HP were tested in patients of European ancestry after adjustment for type of immunotherapy (PD-1/PD-L1 monotherapy, anti-CTLA-4 monotherapy, and combination), cancer type, sex, age and 5 principal components, at each center. The results were then meta-analyzed using fixed-effects inverse-variance weighted approach. False discovery rate (FDR) adjusted p-value of 0.05 was considered significant whereas those between 0.05 and 0.1 were considered nominally significant. Results: In the ICI-DM group, we identified 1 significant association with HLA DRB1*04:01 (OR=2.45, FDR=0.002) which is known to increase risk for type 1 DM (T1DM) in European ancestry. There were 5 additional nominal associations including DRB1*0301 (OR=2.16, FDR=0.07), a known HLA for T1DM in European ancestry. For ICI-HP, there were 7 significantly associated HLA types. Of particular interest are DRB1*14:01 (OR=3.98, FDR=0.02), DRB1*07:01 (OR=1.86, FDR=0.02) and C*07:02 haplotype (OR=1.79, FDR=0.02). While DR7 and DR14 are novel associations, C*07:02 is in linkage disequilibrium with DR15 and DQB1*06:02, both of which have previously been associated with ICI-HP. For ICI-T, there were no associated HLA types. Conclusions: In our study, we report HLA types associated with endocrine irAEs. In particular, we see HLA associations for ICI-DM that are known to be associated with T1DM. This suggests a potential shared mechanism between these forms of autoimmune DM. Additionally we found novel HLA associations with ICI-HP. These findings may have an impact on the clinical care of patients treated with ICI. However, further work is warranted to determine if HLA typing prior to ICI initiation should be considered for irAE risk prediction, irAE surveillance, irAE prevention, and possibly cancer treatment decisions.

Development of a novel risk stratification model for immune-related adverse events for patients with advanced melanoma and non-small cell lung cancer treated with immune checkpoint inhibitors.

2649 Background: Immune checkpoint inhibitors (ICI) transformed treatment paradigm across cancers. There remain few reliable, clinically accessible predictors of ICI-induced immune related adverse events (irAEs). We derive a novel risk stratification model for irAEs using baseline patient, tumor and treatment variables in a large cohort of patients with advanced melanoma (AM) or non-small cell lung cancer (NSCLC) treated with ICI. Methods: We conducted a multi-centre retrospective observational cohort study of consecutive patients with AM or NSCLC receiving ≥ 1 cycle of single-agent or combination ICI, in any line, 2015 - 2023, in Alberta, Canada. Clinically significant irAEs, defined as those requiring treatment delay or systemic steroids/steroid sparing agents, were identified as outcome of interest. The association between irAEs, overall survival (OS), and time to next treatment (TTNT) was assessed with Cox Proportional Hazards regression. Stepwise logistic regression was used to select and weight baseline variables associated with development of irAEs to derive a predictive risk score. Model validation was carried out on 500 iterations of bootstrapped samples. Harrel’s C-index was calculated and internally validated to ascertain the model’s discriminatory performance. Results: 1,292 total patients were included, 519 (218/489 [44.6%] AM and 301/803 [37.5%] NSCLC) developing a clinically significant irAE. Using a subset of 801 patients with available baseline characteristics, the following variables were identified and weighted for creation of risk model (risk score attributed): tumor type (NSCLC) (+1), age &gt;60 (+1), ECOG ≥1 (-1), BMI ≥ 25 (+1), ICI after first line (-1), combination ICI (+4), &gt;10 cycles of ICI (+2), albumin level &lt; LLN (+2), adrenal metastasis (+1), multiple sites of metastasis (-1). Patients were stratified into 3 irAE risk groups based on combined score: low (n = 230, risk score ≤ 0), intermediate (n = 412, risk score 1-2), high (n = 159, risk score ≥3). The risk model performed well with an optimism-corrected c-index of 0.707 in internal validation, and strong association with odds of irAE occurrence (Table). The development of irAE was associated with an improvement in OS (HR 0.48, 95% CI 0.41-0.44, p&lt;0.001), with a median OS of 34.3 (95% CI 28.8-39.6) months compared to 12.0 (95% CI 10.6-14.3) months for those who did not develop an irAE. Similar robust stratification was also seen with TTNT. Conclusions: We presented and internally validated, a simple risk stratification tool that utilizes readily available baseline patient, tumor, and treatment characteristics to robustly stratify risk of irAE development. [Table: see text]

Diabetes Mellitus Induced by Nivolumab plus Regorafenib in a Patient with Esophageal Cancer

Abstract Nivolumab is now preferred as first-line and second-line treatment for advanced esophageal cancer, while regorafenib improves survival in refractory gastroesophageal cancer. The combined use of nivolumab and regorafenib has shown promising results. Nivolumab-induced thyroid dysfunction is a common immune-related adverse event (irAE), while type 1 diabetes mellitus induced by immune checkpoint inhibitors is rare and usually permanent. It is unclear whether the combination of regorafenib and nivolumab increases the risk of irAEs. We report a patient with recurrent esophageal squamous cell carcinoma who was treated with nivolumab plus regorafenib and developed thyroiditis and diabetic ketoacidosis. The rechallenge was successful, and the patient achieved a good treatment response.

Association of Baseline Tumor-Specific Neoantigens and CD8+ T-Cell Infiltration With Immune-Related Adverse Events Secondary to Immune Checkpoint Inhibitors.

Recent evidence has shown that higher tumor mutational burden strongly correlates with an increased risk of immune-related adverse events (irAEs). By using an integrated multiomics approach, we further studied the association between relevant tumor immune microenvironment (TIME) features and irAEs. Leveraging the US Food and Drug Administration Adverse Event Reporting System, we extracted cases of suspected irAEs to calculate the reporting odds ratios (RORs) of irAEs for cancers treated with immune checkpoint inhibitors (ICIs). TIME features for 32 cancer types were calculated on the basis of the cancer genomic atlas cohorts and indirectly correlated with each cancer's ROR for irAEs. A separate ICI-treated cohort of non-small-cell lung cancer (NSCLC) was used to evaluate the correlation between tissue-based immune markers (CD8+, PD-1/L1+, FOXP3+, tumor-infiltrating lymphocytes [TILs]) and irAE occurrence. The analysis of 32 cancers and 33 TIME features demonstrated a significant association between irAE RORs and the median number of base insertions and deletions (INDEL), neoantigens (r = 0.72), single-nucleotide variant neoantigens (r = 0.67), and CD8+ T-cell fraction (r = 0.51). A bivariate model using the median number of INDEL neoantigens and CD8 T-cell fraction had the highest accuracy in predicting RORs (adjusted r2 = 0.52, P = .002). Immunoprofile assessment of 156 patients with NSCLC revealed a strong trend for higher baseline median CD8+ T cells within patients' tumors who experienced any grade irAEs. Using machine learning, an expanded ICI-treated NSCLC cohort (n = 378) further showed a treatment duration-independent association of an increased proportion of high TIL (>median) in patients with irAEs (59.7% v 44%, P = .005). This was confirmed by using the Fine-Gray competing risk approach, demonstrating higher baseline TIL density (>median) associated with a higher cumulative incidence of irAEs (P = .028). Our findings highlight a potential role for TIME features, specifically INDEL neoantigens and baseline-immune infiltration, in enabling optimal irAE risk stratification of patients.

Exploration of Germline Correlates and Risk of Immune-Related Adverse Events in Advanced Cancer Patients Treated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of many tumor types, and durable responses can be observed in select populations. However, patients may exhibit significant immune-related adverse events (irAEs) that may lead to morbidity. There is limited information on whether the presence of specific germline mutations may highlight those at elevated risk of irAEs. We evaluated 117 patients with metastatic solid tumors or hematologic malignancies who underwent genomic analysis through the ongoing Personalized OncoGenomics (POG) program at BC Cancer and received an ICI during their treatment history. Charts were reviewed for irAEs. Whole genome sequencing of a fresh biopsy and matched normal specimens (blood) was performed at the time of POG enrollment. Notably, we found that MHC class I alleles in the HLA-B27 family, which have been previously associated with autoimmune conditions, were associated with grade 3 hepatitis and pneumonitis (q = 0.007) in patients treated with combination PD-1/PD-L1 and CTLA-4 inhibitors, and PD-1 inhibitors in combination with IDO-1 inhibitors. These data highlight that some patients may have a genetic predisposition to developing irAEs.

Abstract 2533: In-depth multi-omic profiling of immune cells in cancer patients developing immune-related adverse events

Abstract Background: The clinical efficacy of immune-checkpoint inhibitors is complicated by the risk for immune-related adverse events (irAEs) that can involve any organ systems. To date, (1) we cannot predict irAE risk reliably at patient level and (2) irAEs remain a diagnosis of exclusion as there are no specific clinical or biological markers. The goal of this study was to elucidate intricate transcriptomic and proteomic signatures of immune cells in patients evolving irAEs. Methods: This pilot trial was conducted as part of a prospective multicenter cohort study (NCT04631731). The study cohort consisted of n=71 patients who were treated with ICIs across Blacktown and Westmead Hospitals, NSW, Australia. Peripheral blood mononuclear cells (PBMCs) were collected from both pre-treatment and after 6-8 weeks post-ICI commencement. Samples were further utilized for RNA sequencing, flow cytometry and Chromium 3’ gene expression analysis (10x Genomics). Results: The median age was 67 years old with the 78% (n=56) of Caucasian origin. The predominant number of patients were treated with dual ICIs. N=21 patients experienced irAEs. Firstly, a differential analysis established a set of genes which were significantly (FDR&amp;lt;0.01) dysregulated between patients with (group A) and without irAEs (group B) and were mostly related to cell cycle and regulation. Notably, phospholipase D signaling pathway was exclusively upregulated in group A and is known to be linked to B cell expansion. Secondly, a cell enrichment analysis within the group A revealed a significant increase of CD4+ and CD8+ T central memory (Tcm) cells upon the toxicity onset as compared to baseline stage. Thirdly, the flow cytometry data established that group A had (1) higher expression of CD27 on CD4+ T cells, a member of Traf-linked tumor necrosis factor receptor family essential for T cells’ maturation and (2) lower expression of inhibitory receptor LAG3 (CD223) which is crucial for maintaining homeostasis of immune system through suppression of T cell proliferation. Finally, we sequenced CD45+ cells from n=4 patients from group A and n=4 from group B at both pre- and post-treatment stages. The unsupervised clustering established 17 different clusters in our single cell dataset with cluster 11 was unique only to patients from group A. The differential analysis established that a set of n=62 genes was significantly upregulated (p&amp;lt;0.05) in cluster 11. Functional annotation established that B cell activation and proliferation pathways were enriched by those genes further stressing B cells’ role in irAEs development. Conclusions: Our real-world cohort study established significant molecular and cellular differences between patients with and without irAEs. Further research in larger cohorts is imperative to validate the established findings and to elucidate the precise mechanisms contributing to the development of irAEs. Citation Format: Dmitrii Shek, Bo Gao, Joey Lai, Brian Gloss, Adnan Nagrial, Ines Pires da Silva, Matteo S. Carlino, Scott A. Read, Golo Ahlenstiel. In-depth multi-omic profiling of immune cells in cancer patients developing immune-related adverse events [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 2533.