Seasonal variation in immune-related adverse events in advanced cancer patients.

Immune-Related Adverse Events and Outcomes in Patients with Advanced Non–Small Cell Lung Cancer: A Predictive Marker of Efficacy?

Prognostic significance of cutaneous immune-related adverse events in patients with melanoma and other cancers on immune checkpoint inhibitors

Incidence and Predictors of CKD and Estimated GFR Decline in Patients Receiving Immune Checkpoint Inhibitors

e13156 Background: Obesity is a significant risk factor for breast cancer and is associated with a poor prognosis. Immune checkpoint inhibitors (ICIs) are the standard of care in the treatment of early-stage and metastatic triple-negative breast cancer (TNBC). ICI treatment is associated with several immune-related adverse events (irAEs); however, predictive biomarkers have not yet been identified. In this study, we hypothesized that obesity is associated with an increased risk of irAEs in patients with TNBC. Methods: A retrospective analysis of patients with TNBC treated with ICIs was conducted using the TriNetX research network using the appropriate ICD-10 code. This study incorporated PD-1/PD-L1 and CTLA-4 inhibitors. The inclusion criterion was patients receiving ICIs. The study population was further stratified into two cohorts based on the body mass index (BMI): obese with a BMI of >30 and non-obese with a BMI of 20-29.9. Descriptive statistics were used to summarize the baseline characteristics of the obese and nonobese cohorts. The p-values were derived using z-tests to compare the difference in risks of irAEs between the two cohorts. The index event was the initiation of ICI and the time window for irAEs was chosen as one year from the index event. Results: The study included 176 patients with TNBC receiving ICI treatment, with 68% being White, 18% African American, and 10% Hispanic or Latino. All patients were female, with a median age of 54.5 years. 81% of patients were obese, while 19% were non-obese. No significant difference was observed in the risk of cardiotoxicity, fatigue, mucositis, colitis, or pituitary dysfunction between the obese and non-obese groups. However, obese patients had an increased risk of developing hepatitis (0.135 vs 0, p= 0.004) and diabetes (0.179 vs 0, p= 0.002). Non-obese patients had a higher risk of developing thyroid dysfunction (0.175 vs 0, p <0.001)(Table). Conclusions: Our findings indicate that in TNBC patients treated with ICIs, higher BMI correlates with increased liver dysfunction and endocrine disorders, particularly thyroid disorders and pancreatic insufficiency. Further studies with larger sample sizes are needed to validate these findings and understand the underlying mechanisms of metabolic syndromes and immune-related adverse events for tailoring treatment options. Immune-related adverse events in obese vs non-obese TNBC patients. Adverse Effect Risk in obese group Risk in non-obese group P Value Thyroid Dysfunction 0 0.175 <0.001 Pituitary dysfunction 0.137 0.175 0.547 Mucositis 0.135 0.185 0.441 Cardiotoxicity 0.135 0.179 0.497 Colitis 0.137 0.179 0.518 Hepatitis 0.135 0 0.004 Fatigue 0.164 0.208 0.552 Diabetes 0.179 0 0.002

Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) are associated with potentially severe immune-related adverse events (irAEs). Emerging clinical practice reports have suggested higher incidence of irAEs in real-world settings than initially observed in phase III clinical trials. Objectives were to determine the incidence of irAEs associated with ICIs in a clinical population, the Veterans Health Administration, characterize their time to onset, and explore potential risk factors. This retrospective observational study included patients from eight Midwest VA medical centers who initiated an ICI between January 1, 2014, and June 30, 2022. Courses of incident prednisone therapy lasting at least seven days at a dose ≥ 20 mg/day were used to identify irAEs, within two years following ICI initiation. A multivariate Cox proportional hazards regression model was used to explore potential irAE risk factors. Of 1314 patients, the incidence of irAEs was 19.8%, with most (86.5%) occurring within one year of ICI initiation. Monthly incidence rates peaked three months following ICI initiation at 3.0% and decreased thereafter. Female gender (hazard ratio [HR] = 2.01, 95% confidence interval [CI]: 1.01-4.00) and combination therapy with ipilimumab and nivolumab (HR = 2.46, 95% CI: 1.44-4.21) were significantly associated with irAE incidence. These findings are consistent with recent studies in clinical populations that demonstrate higher irAE incidence rates than originally reported in clinical trials. Our findings may enhance prompt recognition and treatment of irAEs for VA patients.

CA: A Cancer Journal for Clinicians publishes information about the prevention, early detection, and treatment of cancer, as well as nutrition, palliative care, survivorship, and additional topics of interest related to cancer care.

Immune-related adverse events (irAEs) affect all organs and are associated with various symptoms. The identification of biomarkers that can predict irAEs may be particularly clinically useful. This study aimed to investigate whether the prognostic nutritional index (PNI) before the initiation of immune checkpoint inhibitor (ICI) treatment can predict the occurrence of irAEs. We conducted a survey of 111 patients with cancer who were receiving ICI fixed-dose monotherapy at Saga University Hospital from the time each ICI became available until January 2020. We compared the PNI between the patients with and without irAE expression, established a cutoff value for PNI associated with the development of irAEs, and investigated the incidence of irAEs and progression-free survival (PFS) in groups divided by the cutoff value. Patients with irAEs had significantly higher PNI than did those without, and there was a significant association between PNI and irAEs after adjusting for potential factors (odds ratio, 1.12; 95% confidence interval, 1.03-1.21). In addition, PNI ≥44.2 was associated with a significantly higher incidence of irAEs (75.0% vs. 35.2%, p = 0.0001) and significantly longer PFS than PNI <44.2 (p = 0.025). In conclusion, pretreatment PNI may be associated with the risk of developing irAEs in patients with advanced recurrent solid tumors. When the PNI is ≥44.2, patient management is important for avoiding serious AEs because while the treatment may be effective, the occurrence of irAEs is a concern.

Allopurinol, an inhibitor of xanthine oxidase (an enzyme capable of generating superoxide radicals following hypoxiaischaemia), was investigated in preterm infants to determine its ability to prevent the complications of neonatal intensive care which may be associated with oxidative injury. Four hundred infants of between 24 and 32 weeks' gestation were randomly allocated to receive enteral allopurinol (20 mg/ml) or an equivalent dose of placebo for seven daily doses. At admission, plasma hypoxanthine concentrations were significantly higher in infants who subsequently developed periventricular leucomalacia (PVL), bronchopulmonary dysplasia (BPD), or retinopathy of prematurity (ROP), but there was no difference in the primary endpoint (PVL) between the treated and control groups. The failure of allopurinol prophylaxis in this group of infants is probably related to the complex nature of the pathological processes and to the timing of treatment. If oxidant injury is an important mechanism of cellular injury in these preterm infants, an alternative biochemical modulator would be required, or a combination of agents might be effective.

Immune checkpoint inhibitor (ICI) therapy has revolutionised the treatment of various cancer types. ICIs reinstate T-cell function to elicit an anti-cancer immune response. The resulting immune response can however have off-target effects which manifest as autoimmune type serious immune-related adverse events (irAE) in ~10–55% of patients treated. It is currently challenging to predict both who will experience irAEs and to what severity. Identification of patients at high risk of serious irAE would revolutionise patient care. While the pathogenesis driving irAE development is still unclear, host genetic factors are proposed to be key determinants of these events. This review presents current evidence supporting the role of the host genome in determining risk of irAE. We summarise the spectrum and timing of irAEs following treatment with ICIs and describe currently reported germline genetic variation associated with expression of immuno-modulatory factors within the cancer immunity cycle, development of autoimmune disease and irAE occurrence. We propose that germline genetic determinants of host immune function and autoimmune diseases could also explain risk of irAE development. We also endorse genome-wide association studies of patients being treated with ICIs to identify genetic variants that can be used in polygenic risk scores to predict risk of irAE.

Background: There have been discrepant results between development of irAE, and their effect on overall survival (OS) in several cancer types treated with ICI. Some studies have shown a positive correlation between incidence of irAE and OS. While these effects are being explored in breast cancer, there is a paucity of data regarding patients (pts) with metastatic breast cancer (mBC) treated with ICI. Methods: This multicenter retrospective study, involving four academic institutions, evaluates the incidence of irAE in pts with mBC who received ICI between 2014 and 2024. The presence and grading of irAE were determined by physician documentation. Pts demographic data and characteristics were summarized using descriptive statistics. OS was calculated from the date of treatment initiation to death from any cause. Pts who were still alive were censored at the last clinic encounter. Survival probabilities were estimated with Kaplan–Meier curves and log-rank tests. All other co-covariables were analyzed using multivariate logistic regression and cox proportional hazards model. Results: There were a total of 252 evaluable cases, with median age at the start of ICI of 54. The study population consisted of 66% white, 9% black and 25% others. Median body mass index (BMI) was 26.4. Among the pts, 64% were triple negative breast cancer (TNBC), 30% hormone receptor positive (HR+), 5% human epidermal growth factor receptor 2 positive (HER2+) and 1% both HR/HER2+. Combination therapy was received by 78% of the patients, while 22% received ICI alone. Amongst pts who received ICI, 45% pts were enrolled in clinical trials. Pts were on ICI for an average of 138.38 days before their first irAE. irAE were noted in 47% pts, with 35% experiencing at least 1 irAE, 11% had 2 irAE and 1% with 3-4 irAE. Grade 1-2 irAE were noted in 34%, and grade 3-4 in 13.5%. The median OS was 17 months amongst all pts. Pts with irAE had a longer median OS compared to those without irAE (23 vs 13 months; HR, 0.50; 95% CI 0.36-0.69; p &amp;lt; 0.00001). Pts with TNBC had improved overall survival (OS) with ICI in comparison to HR+ and HER2+ pts (OS 17 months; 95% CI 13-28; p = 0.0074). In addition, those with higher grade irAE had improved OS compared to those with low grade irAE (HR 0.41, 95% CI 0.15-1.16; p=0.03). Higher number of treatment cycles and higher baseline BMI were associated with a significantly lower risk of mortality (p=0.006 and p=0.018, respectively). Clinical factors such as age, smoking and other comorbidities, while potentially influential, did not reach statistical significance in this multivariable analysis. Conclusion: Our analysis shows that almost half of the pts in the study (47%) had irAE with median OS of 17 months. Pts with irAE had a longer OS (23 months) compared to those without irAE (13 months). The median OS for TNBC was higher than HR+ and HER2+ breast cancer. The total number of ICI cycles and baseline BMI were shown to have a significant impact on the survival of mBC pts. The combined irAE grades show a trend towards a decreased risk of mortality, but the findings are not statistically significant. Overall, while there are indications that specific side effects and treatment factors may influence patient outcomes, including increased OS among patients with irAE, further research with larger datasets is needed to confirm these results. This study provides a foundation for understanding how various factors contribute to the survival of breast cancer patients undergoing ICI therapy. Citation Format: Madhuri Chengappa, Thejaswi K Poonacha, Nikitha Vobugari, Go Nishikawa, Saya Jacob, Samantha Fisch, Carolyn Face, Alexis LeVee, Nikita V. Baclig, Andrew Soliman, Laura Huppert, Laura Quintal, Michelle Melisko, Melanie Majure, Jo Chien, Joanne Mortimer, Kelly McCann, Hope S. Rugo, Dame Idossa, Anne Blaes. Correlation between Immune-Related Adverse Events (irAE) and Survival Outcomes in Metastatic Breast Cancer Patients Treated with Immune Checkpoint Inhibitors (ICI): a multi-institutional study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-12-04.

Dupilumab has been added to National Cancer Comprehensive Network (NCCN) guidelines as a therapeutic strategy for managing certain cutaneous immune-related adverse events (cirAEs) from immune checkpoint inhibitor (ICI) therapy. However, little is known about the implications of dupilumab for cancer outcomes in this population. In this multi-institutional study, we evaluate the impact of dupilumab treatment on survival among ICI recipients. We conducted a muti-institutional retrospective cohort study of ICI recipients from the Mass General Brigham Healthcare System and Dana-Farber Cancer Institute. The dupilumab group was compared to two control groups who did not receive dupilumab: with and without cirAEs (control groups 1 and 2, respectively) that were 1:2 matched on sex, race, age at ICI initiation, Charlson Comorbidity Score, year of ICI initiation, and ICI type. Manual chart review was performed to obtain cirAE characteristics, systemic glucocorticoid use, dupilumab treatment, vital status, and last contact date. Time-varying multivariable Cox proportional hazards regressions were used to evaluate the impact of dupilumab on overall survival, adjusted for sex, race, age at ICI initiation, ICI type, Charlson Comorbidity Index score, cancer type, cancer stage at ICI initiation, and systemic glucocorticoid use. A total of 53 cirAE patients treated with dupilumab were compared to two control groups of 106 patients each. Most patients receiving dupilumab demonstrated either complete or partial resolution of their cirAE (88.7%). In multivariable modeling, the overall survival of the dupilumab group was not significantly different from control group 1 (HR=0.74, 95% CI:0.35-1.60, p=0.5) or control group 2 (HR=0.70, 95% CI:0.32-1.51, p=0.4). However, the use of systemic glucocorticoids within two years after ICI initiation was associated with poorer overall survival when comparing the dupilumab group to control group 1 (HR=2.03, 95% CI:1.04-3.96, p=0.039) and control group 2 (HR=2.21, 95% CI:1.25-3.91, p=0.006). This study suggests that dupilumab is an effective therapeutic option for recalcitrant cirAEs and does not adversely impact mortality. Due to the observed detrimental effects of systemic glucocorticoid therapy, this study supports the need to shift away from systemic glucocorticoid immunosuppression and towards targeted immune modulators for irAE management that are less detrimental to ICI response. Current guidelines recommend the use of dupilumab in the treatment of certain moderate to severe cutaneous immune related adverse events (cirAE) and systemic glucocorticoids for others. Previous studies have shown dupilumab to be effective for steroid refractory cirAEs; 1 however, the impact dupilumab on survival outcomes among recipients of immune checkpoint inhibitor therapy (ICI) remains under studied. This study concludes that dupilumab is an effective modality to treat cirAEs, with 88.7% of patients responding to treatment. Additionally, this study demonstrates a 206-day average delay from cirAE onset to dupilumab treatment suggesting the need for more timely consideration of this therapeutic option. Finally, our results demonstrated that dupilumab does not increase mortality among ICI recipients. The results of this study suggest that use of dupilumab in the treatment of cirAEs is effective and does not adversely impact mortality in the cancer population. Based on these findings, clinicians should consider dupilumab treatment for cirAEs in the appropriate clinical setting. Moreover, this study provides further evidence for the use of targeted immune modulators as preferred over more commonly utilized broad-based glucocorticoid immunosuppression for the management of immune related adverse events in the setting of ICI therapy.

9079 Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but are associated with unique IRAEs, including pneumonitis (PNS). Thoracic radiotherapy (TRT) is also associated with PNS but it is unknown whether TRT+ICI increases the risk of PNS or other IRAEs. Furthermore, low serum LDH levels are associated with better response/survival to ICI but its potential role as a biomarker for IRAEs is unexplored. Methods: We retrospectively reviewed 164 pts with metastatic lung cancer (95% NSCLC, 5% SCLC) consecutively treated at our institution from 2013-2016 with PD-1/PD-L1 inhibitors and a minimum of one month follow-up, except in cases of rapid death from an IRAE ( n =4). Pts were grouped according to TRT received (+ vs -). IRAE grades were assigned using NCI CTCAE v4.0. Outcomes were compared using Fisher’s exact test and two-sided Student’s t-test. Results: Baseline characteristics such as age, gender, smoking status, supplemental oxygen requirement, median number of chemotherapy lines prior to ICI (1 vs 1), median ICI cycles (5 vs 3), and median follow-up after ICI initiation (8 vs 7 months) were similar in the +TRT ( n = 73) and -TRT ( n =91) groups. Rates of grade ≥ 2 IRAEs (18.1 vs 14.4%, p = 0.67), all-grade PNS (8.2 vs 5.5%, p= 0.54), and grade ≥ 2 PNS (4.1 vs 3.3%, p = 1) were not significantly different between the +TRT and -TRT cohorts. Mean TRT dose was similar between those pts who developed PNS and those who did not (55.8 vs 55.9 Gy). In the +TRT group, 85% received TRT a median of 8.6 months before ICI. Among 7 pts (10%) who had concurrent TRT+ICI, none developed symptomatic PNS. Patients who developed grade ≥ 2 IRAEs ( n= 26) had significantly higher mean serum LDH before initiation of ICI than patients who did not (283 vs 214, ref 98-192 IU/L, p= 0.03). Conclusions: TRT in lung cancer pts receiving ICI was not associated with increased risk of PNS in this series. LDH may be a negative predictive biomarker as pts who suffered grade ≥ 2 IRAEs had significantly higher baseline LDH than those who did not. Larger cohorts and prospective studies would be helpful to validate these findings.

2545 Background: While Immune checkpoint inhibitors (ICI) have revolutionized the field of oncology, the benefits have come at the cost of serious side effects known as immune-related adverse events (irAEs). Approaches that can predict patients’ susceptibility to irAEs are key to their early detection and management. In the present study, we investigate the association between irAEs reported during ICI therapy across multiple cancer types and markers of tumor immune response. Our primary objective is to explore potential biomarkers for assessing patients’ risk of irAEs. Methods: 472 patients were evaluated who had tumor immune profiling performed paraffin embedded formalin fixed archival tumor biopsy samples using Omniseq Immune Report Card (IRC) and subsequently underwent ICI therapy. The IRC consisted of enumeration of tumor infiltrating lymphocytes (TILs) by immunohistochemistry (IHC) and TIL-associated genes by RNA-Seq, PD-L1 expression by IHC, and tumor mutational burden (TMB) by DNA-Seq. irAE type and grade were determined based on retrospective chart review. Fisher’s exact test was used to determined statistically significant associations between immune markers and irAE development. Results: Patients with lung (55%), ovarian (9%), and melanoma (5%) cancers constituted the majority of the cases. The median age of patients was 61, with 56% being female and 44% male. Most patients underwent treatment with (94%). irAEs developed in 36% of patients, with 2% of patients developing high-grade irAEs (Grade 3 or 4). Skin (11%), thyroid (10%), and GI (9%), were the most commonly affected organ systems. Increased TILs were associated with increased risk for any irAE (p = 0.04). A stronger association was noted in patients who underwent anti-PD-1/L1 monotherapy (p = 0.01) and/or in cases of lung cancer (p = 0.01). Interestingly, subanalyses by gender showed a statistically significant correlation between increased TILs and risk for any irAE in males (p = 0.006) but not in females (p = 0.63). High PD-L1 (defined as &gt; 70% by IHC) was also significantly associated with increased risk for any irAE (p = 0.03). Subanalyses by gender and age again showed a similar association in females (p = 0.0002) and/or patients &lt; 65 years (p = 0.04). high TMB and any irAE in female patients (p = 0.01) and in breast cancer cases (p = 0.03). On multivariate analysis, TILs by IHC appeared to be the strongest predictor of irAEs (p = 0.03). Conclusions: The tumor immune microenvironment (TME) has been shown to influence response to ICI, yet its association with irAEs has not been well studied. Our analysis sheds light on potential TME predictors for irAE in patients receiving ICI therapy. Further studies are needed to deepen our understanding of immune toxicity and to develop tools for identifying patients who are at risk.

T cell activation can lead to osteoporosis and while there are several case reports of fractures occurring after immune checkpoint inhibitor (ICI) use, to date, there are no population level studies looking at fracture risk related to ICI use. Using Alberta Cancer Registry data, we identified all individuals treated with ICI for cancer between September 29, 2010, and March 31, 2019. Linked records from Alberta's healthcare administrative databases were assessed for the presence of fracture diagnostic codes in the year prior to and up to two years after ICI initiation. Fracture rate was stratified based on the time-period before and after ICI initiation. Fracture rates after ICI were compared to baseline. The study cohort consisted of 1600 ICI users (mean age 65.7years, 60% male). Most patients were treated with an anti-PD-1 agent (73.9%). ICIs were initiated on average 707.8days after cancer diagnosis. 76 (4.8%) individuals had a remote history of a major fracture, and 141 (8.8%) had been treated with an osteoporosis medication prior to ICI treatment. The fracture rate in the year prior to ICI initiation was 11.3 per 1000 patient-years. The fracture rate in the year after ICI initiation was significantly higher at 27.3 per 1000 patient-years. The fracture rate dropped to 17.6 per 1000 patient-years in the second year after ICI initiation. The incidence rate ratio of sustaining a major fracture in the year after compared to the year prior to ICI initiation was 2.43 (95% CI 1.34-4.27). Fracture risk may be increased in cancer patients early after initiation of ICI, and this may represent a novel immune-related adverse event.