Immune Checkpoint Inhibitors Treatment Research Articles

Investigation of cardiotoxicity with concomitant use of anthracyclines and checkpoint inhibitors.

e24022 Background: Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment and currently are the standard of care for early stage triple negative breast cancer in combination with anthracyclines (AC). It is known that both ICI and AC carry risk of cardiotoxicity. Studies have also shown that there is increased risk of cardiotoxicity with dual ICI. However no studies have evaluated the risk with concomitant use of ICI and AC. Here we investigated if there is increased cardiotoxicity risk with this combination regimen in a retrospective study. Methods: We did a retrospective analysis of patients with stage II and stage III triple negative breast cancer treated with combined AC and ICI at University of South Alabama Mitchell Cancer Institute Mobile, AL from January 2020 until June 2023. Data included demographics, cardiovascular (CV) risk factors and treatment. CV risk factors were detailed from 2022 ASCO guidelines. Echocardiograms were used to evaluate left ventricular ejection (LVEF). Therapy related cardiovascular toxicity was defined by ESC guidelines 2022 as any new decrease in LVEF to < 40% or any decrease in LVEF < 50% and 10 percentage points decrease from baseline. Adverse events (AE) and risk analysis were calculated. Results: Of the total 49 patients, all were female with a mean age of 53 years old (30-82). 55% of patients had less than 2 CV risk factors (n = 27) and 45% had more than 2 (n = 22). 84% completed all 4 cycles of neoadjuvant AC course without dose adjustment. The median number of cycles of Pembrolizumab was 12 with a range of 7 to 17 cycles including adjuvant Pembrolizumab. All patients had a baseline echo with LVEF > 55%. Two patients (0.04%) developed cardiotoxicity. One patient had LVEF that decreased to EF 45-50% while on surveillance. Another patient developed myocarditis during treatment with EF 25-30% and died from cardiogenic shock. Both patients had 2 CV risk factors and were African American. Only 24% (n = 12) had surveillance echocardiograms completed one year post treatment. Conclusions: Our study results showed that cardiotoxicity risk was lower compared to that in the Keynote-522 trial. The outcomes are limited as a majority (76%) of the patients did not have surveillance echos completed. While the risk of cardiotoxicity with ICI and AC have been studied independently, there have been mouse models that showed that AC therapy may make heart vulnerable to toxicity from ICI therapy. To our knowledge, this is the first study to evaluate cardiotoxicity in patients who received concomitant AC and ICI treatment. Our study highlights the importance of prospective studies and long term follow up to monitor cardiotoxicity in these patients as early detection is key to prevent future morbidity. [Table: see text]

Blood based kinase activity profiling to predict response to immune checkpoint inhibitors in patients with advanced stage non-small cell lung cancer: The IOpener study.

e20576 Background: Treatment with immune checkpoint inhibitors (ICI) has become part of the standard of care for patients with advanced stage non-small cell lung cancer (NSCLC). Unfortunately, its success is limited to a subset of treated patients, while ICI treatment is associated with immune-related adverse events. The predictive value of kinase activity profiling of peripheral blood mononuclear cells (PBMCs) was previously shown in a discovery study (Hurkmans et al., JITC 2020). The aim of the current study was to perform a prospective and blinded validation of the predictive value of kinase activity profiles of PBMCs for response to ICI treatment in patients with NSCLC in a standardized setting. Preliminary results for this study were presented before (De Joode et al. 2022), here we present results for a significantly extended validation cohort with a follow-up of at least 1 year. Methods: PBMCs from patients with advanced stage NSCLC included in this observational multicenter study were collected prior to ICI treatment. Tyrosine kinase activity of PBMCs was profiled using a micro-array with 144 different peptide-substrates (Pamchip). Classification analysis was performed to discriminate between patients with or without progressive disease (RECIST v1.1) within 24 weeks after start of treatment. Only patients treated with first-line pembrolizumab ± chemotherapy were included. Results: A predictive model was first established based on kinase activity profiles, determined in a calibration cohort (N = 61) and subsequently applied to an independent validation cohort (N = 136). The predictive accuracy of the model in the validation cohort was 62% (CI95 = 53-70%). Interestingly, the accuracy improved when the model was combined with PD-L1 expression: for patients with a PD-L1 score < 50%, the accuracy for predicting progressive disease at 24 weeks was 68% (CI95 = 57-78%). Here, significant lower progression free survival (PFS) rates were observed for patients for whom progression was predicted compared to those for whom no progression was predicted (p = 0.0003, hazard ratio = 2.6, CI95 = 1.6-4.3).The 1-year PFS for patients with predicted progression was only 13% (CI95 = 5-31%) which implies a NPV of 87%. PFS rates were also lower for patients with predicted progression in the subgroups with PD-L1 score < 1% (p = 0.03, hazard ratio = 2.2, CI95 = 1.1-4.3) and PD-L1 score 1-49% (p = 0.002, hazard ratio = 5.0, CI95 = 1.8-14). The predictive kinase activity signature appears to be T-cell related, which will be further investigated to improve understanding of the underlying biology. Conclusions: In this prospective validation study the predictive value of kinase activity profiling of PBMCs for response to first-line ICI therapy of patients with advanced NSCLC was confirmed. The final aim is to apply the kinome analysis in clinical practice.

Association of baseline inflammatory biomarkers and clinical outcomes in patients with advanced renal cell carcinoma (aRCC) treated with immune checkpoint inhibitors (ICIs).

4548 Background: Multiple inflammatory biomarkers such as modified Glasgow Prognostic Score (mGPS), neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), platelet to lymphocyte ratio (PLR), and neutrophil to eosinophil ratio (NER) have been identified in RCC. We analyzed those biomarkers in patients with aRCC treated with ICIs to assess the association with treatment outcomes. Methods: A retrospective analysis was conducted on adult patients with aRCC treated with ICIs at Emory Winship Cancer Institute between 2018 and 2023. Clinical benefit (CB) is determined by stable disease, partial response, and complete response. mGPS (combining albumin and CRP), NLR, MLR, PLR, and NER data were collected from the baseline bloodwork. Multivariate and univariate analyses were conducted on PFS, OS, and CB. MVA was built by controlling the age, gender, race, BMI, smoking status, IMDC risk group, clear cell histology, prior treatment, liver metastases, ECOG performance score, and number of distant metastases, which were subject to backward elimination at the significant level of p < 0.2 Results: Our analysis included a total of 401 patients (118:283 F:M, median age: 66). On univariate analysis, high mGPS, NLR, MLR, PLR, and NER were related to inferior CB; hazard ratios (HR) (95% CI, p value) were 3.03 (1.35-6.77, p=0.005), 1.86 (1.14-3.03, p=0.013), 1.83 (1.10-3.02, p=0.019), 2.37 (1.52-3.71, p <.001), 1.93 (1.22-3.05, p=0.005) respectively. On multivariate analysis, NLR, PLR, NER had statistically significant correlation with CB, HR (95% CI) were 1.75 (1.01-3.04, p=0.047), 2.21 (1.33-3.66, p=0.002), 2.07 (1.24-3.47, p=0.006). Conclusions: The results demonstrated that high systemic inflammatory biomarkers may be related to worse clinical outcomes with ICI treatment. Prospective studies are needed for further validation. [Table: see text]

Cardiomyopathy among recipients of immune checkpoint inhibitor therapy: A prospective study.

e24025 Background: Patients treated with immune checkpoint inhibitors (ICI) may develop cardiomyopathy, but data are limited on the rate of cardiomyopathy incidence. The aim of this study was to assess the occurrence of cardiomyopathy among ICI recipients. Methods: In this prospective surveillance study, echocardiograms and EKG were performed at baseline, and quarterly during the first year of ICI therapy. New or worsening cardiomyopathy was defined as left ventricular ejection fraction (EF) decline of > 10% from baseline to < 50%. B-type natriuretic peptide (BNP) and troponin were assessed weekly during the first three weeks of ICI therapy. Subsequent troponin for myocarditis assessment was tested as needed per treating oncology team. Results: A total of 23 patients were enrolled with mean age 73±10 years, 35% female, 74% Caucasian, and body mass index 31±7 kg/m2. Cardiovascular risk factors included hypertension (86%), diabetes mellitus (29%), myocardial infarction (19%) and smoking (10%), and prior radiation treatment (30%). Malignancies included lung cancer (50%), renal cell carcinoma (14%), and Merkel cell carcinoma or urothelial carcinoma (9% each). ICI regimen included pembrolizumab (48%), nivolumab (43%), and ipilimumab or atezolizumab (4% each). There was no change in weekly troponin or BNP, or quarterly QRS duration on EKG, and no myocarditis cases were observed. Between baseline and at 1-year since ICI therapy initiation, there was no change in QRS duration on EKG, as well as no change in median LVEF (59% [IQR 46-67] vs 61% [IQR 58-65], p = 0.48), or global longitudinal strain (18% [IQR 15-20]) vs 19% [IQR 18-21], p = 0.11). New cardiomyopathy occurred in 1 (4%) patient at 3 months following ICI initiation with LVEF drop from 53% to 38% and without troponin elevation to suggest myocarditis, corresponding to an incidence rate of 43.5 cases per 1000 person-years of observation. Conclusions: In this prospective surveillance study, new cardiomyopathy was observed after ICI treatment, although the incidence was low. Larger studies are needed to confirm these findings.

Cognitive symptoms in patients with cancer receiving PD-1/PD-L1 checkpoint inhibitors: Insights from a cross-sectional pilot study.

12094 Background: Cancer-related cognitive impairment is common with traditional therapeutic modalities, affecting memory, psychomotor speed, attention, and executive function of up to 75% of adults with cancer. Over the past decade, immune checkpoint inhibitors (ICIs) have emerged as novel and efficacious treatments due to their ability to penetrate the blood-brain barrier and improve survival rates. However, they come with significant short- and long-term complications, including neurological toxicities. Despite their benefits, the impact of ICIs on cognitive function is not well understood. This study aims to examine the frequency and severity of cognitive impairment and the factors correlated among adults with cancer receiving ICIs. Methods: We collected questionnaire data on cognitive function using the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) and other concurrent symptoms, as well as saliva samples of a subset of inflammatory cytokines from patients treated with PD-1/PD-L1 checkpoint inhibitors between 2022 and 2023. Sample characteristics were described using mean, frequency, and percentage. To analyze the relationship among symptoms and demographics, we used Pearson’s correlation and the Mann-Whitney U test. Saliva cytokines were analyzed using ELISA assays. This study is IRB approved. Results: Twenty-three patients (male: n=11, female: n=12) have received ICIs for an average of eight months, with a mean age of 70.87±11.63 years. 78.3% had melanoma/skin cancer, 8.7% had head and neck cancer, and 13% had other malignancies. Pembrolizumab was administered to 47.8%, and Nivolumab to 26.1%. The mean scores of FACT-Cog for perceived cognitive impairment (PCI) and perceived cognitive abilities (PCA) were 60.87±13.06 (maximum: 72) and 22.30±6.70 (maximum: 28), respectively. 26.1% of participants (n=6) reported lower scores than the cut-off in both PCI (cut-off: ≤55.1) and PCA (cut-off: ≤19.5). Lower FACT-Cog PCI scores were significantly correlated with older age ( r=-.511, p<.05), greater fatigue ( r=-.483, p<.05) and pain ( r=-.558, p<.01). Participants with PCA and PCI scores below the cut-off showed higher mean concentrations of IL-1β (mean±SE: 188.22±133.72 vs. 80.99±14.73pg/mL), CRP (6659.47±3027.58 vs. 3910.71±1022.41pg/mL), and IL-6 (109.24±56.07 vs. 30.22±6.26pg/mL) compared to those with scores above the cut-off, although the results were not significant. This suggests that increased inflammatory cytokines may be associated with cognitive impairment. Conclusions: This preliminary study suggests that some patients may experience cognitive impairment during ICI treatment. As cancer patients are more at risk for cognitive impairment before treatment, a longitudinal study is warranted to confirm cognitive function both pre- and post-immunotherapy, along with objective measures of cognitive performance.

Treatment patterns and survival outcomes of patients admitted to the intensive care unit due to immune-related adverse events of immune checkpoint inhibitors.

Severe immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICIs) can lead to admission to the intensive care unit (ICU). In this retrospective study, we determined the incidence, treatment patterns and survival outcomes of this patient population at a comprehensive cancer center. All patients admitted to the ICU due to irAEs from ICI treatment between January 2015 and July 2022 were included. Descriptive statistics were reported on patient characteristics and treatment patterns during hospital admission. Overall survival (OS) from the time of ICU discharge to death was estimated using the Kaplan-Meier method. Over the study period, 5561 patients received at least one ICI administration, of which 32 patients (0.6%) were admitted to the ICU due to irAEs. Twenty patients were treated with anti-PD-1 plus anti-CTLA-4 treatment, whereas 12 patients were treated with ICI monotherapy. The type of irAEs were de novo diabetes-related ketoacidosis (n = 8), immune-related gastrointestinal toxicity (n = 8), myocarditis or myositis (n = 10), nephritis (n = 3), pneumonitis (n = 2), and myelitis (n = 1). The median duration of ICU admission was 3 days (interquartile range: 2-6 days). Three patients died during ICU admission. The median OS of the patients who were discharged from the ICU was 18 months (95% confidence interval, 5.0-NA). The incidence of irAEs leading to ICU admission in patients treated with ICI was low in this study. ICU mortality due to irAEs was low and a subset of this patient population even had long-term survival.

Immune-related adverse event prediction and influential factor identification.

e14650 Background: Immune checkpoint inhibitors (ICIs), have demonstrated efficacy in treating patients with non-small cell lung cancer (NSCLC) and advanced melanoma. However, ICIs can lead to immune-related adverse events (irAE), which will cause discontinuance of the ICI treatment. The objective of this study is to identify factors that predict which patients with NSCLC or melanoma will develop irAE(s) from ICIs. Methods: We curated the patient cohort from the Immune-Oncology data repository developed at the Georgetown-Lombardi Comprehensive Cancer Center. This cohort encompassed 466 patients (245 individuals with NSCLC and 221 with advanced melanoma) who received single-agent anti-PD-(L)1 or combination of anti-PD-1 and anti-CTLA4 therapy. Parameters selected for prediction comprises baseline demographics, laboratory results, treatment information, and cancer-related mutations. The classification of irAE were identified by CTCAE V4.03 guidelines. Overall, 219 patients experienced one or more irAE, while the remaining 247 patients were irAE-free. We employed machine learning models for prediction, which were trained using 80% of the dataset with a five-fold cross-validation, and their performance was evaluated using the area under the receiver-operating curve (AUROC) and F1 score. Furthermore, we identified the key factors that significantly impacted the model by SHAP values. Results: Nine machine learning models were deployed, including logistic regression, support vector machine, gradient boosting (GB), etc. The GB model demonstrated the highest performance, achieving an AUROC score of 75% and an F1 score of 77%. According to the SHAP value obtained from the GB model, NSCLC patients exhibited a higher propensity for irAE development compared to melanoma patients. The top three features associated with a heightened likelihood of irAE development are the treatment of the combination of anti PD-1 and anti CTLA-4, a higher albumin/globulin ratio, and a pre-treatment ECOG Performance Status score of 0. The top three features associated with a lower likelihood of irAE development are an elevated red cell distribution width, the treatment with single agent anti-PD-1, and a higher globulin level. Conclusions: Our research harnesses a comprehensive set of variables to forecast the development of irAEs in NSCLC and melanoma patients undergoing ICI treatment. The results underscore the predictive capabilities of ML models. Investigating the connections between pivotal biomarkers, such as globulin and red cell distribution width, has the potential to offer insights that enable patients to mitigate irAE. These findings emphasize the promising potential of ML techniques not only in predicting the likelihood of irAE but also in the grade of irAE. To mitigate the limitation of a relatively small sample size, we are actively working to expand the data registry by collaborating with additional institutions.

Effect of immune checkpoint inhibitor administration timing on survival outcomes in advanced biliary tract cancers: A single-center propensity score matching analysis.

e16186 Background: Circadian rhythms in the immune system and anti-tumor immune responses have not received adequate attention in terms of their impact on cancer immunotherapy. Recent advances in immune checkpoint inhibitors (ICIs) have marked a significant breakthrough in the treatment of advanced biliary tract cancer (BTC), but not all patients benefit from this therapy. Our study aimed to investigate whether the timing of ICI administration affects the treatment outcomes in BTC patients. Methods: We included patients with advanced BTC patients at West China Hospital of Sichuan University who received at least two ICI treatments from October 2019 to May 2023, with follow-up until December 2023. The primary outcome was overall survival (OS), with secondary outcomes including progression-free survival (PFS), objective response rate (ORR), and adverse event incidence. Propensity score matching (1:2 ratio, nearest-neighbor caliper width of 0.1) and COX regression were used to analyze the relationship between the proportion of ICI administrations after 16:30 and both OS and PFS, while the Chi-square test was used to compare the ORR and adverse event rates between groups. Results: A total of 207 patients were eligible for analysis. Before matching, 37 patients had more than 20% of their ICI administrations after 16:30, and 170 had less than 20%. After matching, 34 patients receiving more than 20% of ICIs after 16:30 were compared with 65 who did not. The former group showed significantly shorter OS (median 10 months [95%CI: 8-14 months] vs. 17 months [95%CI: 12-20 months], HR = 2.067 [95%CI: 1.226-3.485, P = 0.00645]) and PFS (median 5 months [95%CI: 4-7 months] vs. 9 months [95%CI: 8-12 months], HR = 2.093 [95%CI: 1.315-3.331, P = 0.00183]), with these results remaining robust after multivariate Cox regression analysis. No significant difference in ORR (χ^2 = 2.287, p = 0.131) was observed. Safety analysis showed no difference in the incidence of adverse events, including Grade 3/4 adverse events, immune-related adverse events, and medication discontinuation due to adverse events (all p > 0.050). Sensitivity analyses in patients receiving at least three ICI treatments revealed similar results. Conclusions: The timing of ICI administration influences the efficacy of immunotherapy in advanced biliary cancer, with administrations before 16:30 associated with better survival outcomes. Further research with larger sample sizes and prospective studies is needed to validate these findings.

Immune-related adverse events in patients treated with immunotherapy according to corticosteroid exposure.

e14709 Background: Patients with cancer require treatment with corticosteroids for multiple reasons, including prevention of chemotherapy-related side effects. Although corticosteroid use has been associated with lower efficacy of immune checkpoint inhibitors (ICI) in some studies, whether corticosteroid exposure affects the presence and severity of immune-related adverse events (irAEs) remains unclear. Methods: Retrospective single-center study of patients diagnosed with solid tumors treated with ICI. Eligible patients were those who received at least one cycle of ICI and had at least 1 month of follow-up post-ICI initiation. Patient data were extracted from electronic medical records. Comparisons between groups were made based on steroid exposure (defined as the administration of >10 mg of prednisone or its equivalent for >10 days within a 30-day period or at any point during ICI treatment, excluding steroid treatment for irAEs). Associations between variables were assessed using independent samples T-test, Chi-square, and Fisher’s exact tests. Results: We included 135 patients (mean age 61 years, SD 13); 72 (54%) were male. Forty-two (31%) had been exposed to steroids (mean prednisone equivalent of 427 mg, SD 298). Most patients received ICI as palliative treatment for advanced disease (105/135; 78%), primarily as first-line therapy (79/105; 75%). Patients exposed to corticosteroids were more likely to have received ICI with chemotherapy (76% vs 1%, p<0.001), were younger (56 vs. 63 years, p=0.009), more likely to be female (62% vs. 39, p=0.014), and had lower median Charlson Comorbidity Index scores (2 vs. 3, p=0.026). Steroid-exposed patients were more likely to have employed ICI in the neoadjuvant or adjuvant settings (36 vs. 16%, p=0.024) or as third or subsequent line therapy (26 vs. 8%, p=0.044). There were no statistically significant differences in the frequency of irAEs of any grade based on steroid exposure (31% vs 41%, p=0.252). However, patients who were exposed to steroids were significantly less likely to delay or suspend ICI (10% vs. 32%, p=0.005). No other parameters were associated with the rate or severity of irAEs. Conclusions: Our findings suggest that corticosteroid exposure does not increase the frequency of irAEs in patients treated with ICI, but it is associated with a reduced likelihood of discontinuing ICI due to irAEs. These observations suggest that corticosteroids may play a beneficial role in managing patients undergoing immunotherapy, particularly in sustaining treatment continuity despite irAEs. This study underscores the need for further investigation into optimal steroid use strategies to enhance patient outcomes with immunotherapy, especially in situations when they are commonly prescribed, such as premedication for chemotherapy.

Delayed immune-related adverse events in patients with advanced melanoma treated with immune checkpoint inhibitors.

12047 Background: Immune checkpoint inhibitors (ICIs) have changed the treatment landscape of melanoma but can have serious or life-altering immune-related adverse events (irAEs). Most toxicities associated with ICIs occur within the first few months (mo) of treatment initiation, but delayed irAEs occurring 12 mo after ICI start are not well characterized. Further, clinical trials often have limited follow-up of AEs and thus, real world data is valuable. Methods: Patients (pts) ≥18 years with advanced melanoma who received ≥1 cycle of an ICI at BC Cancer from 2012-2019 with ≥12 mo of follow-up from time of ICI initiation were identified using the BC Cancer Registry and Pharmacy databases. Data on baseline clinicopathologic factors prior to the first cycle of ICI, and delayed irAE history and management were extracted. Delayed irAEs were graded using CTCAEv5. Results: In total, 530 pts treated with ≥1 cycle of an ICI were identified of which 309 pts had ≥12 mo of follow-up. Median follow-up for alive pts was 65.3 mo (13.0-143.5 mo). 96 (31%), 147 (48%), 19 (6%), and 47 (15%) pts received combination ICI (nivolumab/ipilimumab ± nivolumab maintenance), PD-1 inhibitor monotherapy (nivolumab or pembrolizumab), CTLA-4 inhibitor monotherapy (ipilimumab), and sequential CTLA-4 and PD-1 inhibitors, respectively. A total of 142 delayed irAEs were recorded in 94 (30%) pts. Median time to onset of delayed irAEs was 20.0 mo (12.2-80.6 mo). The most common delayed irAEs were dermatologic (27%), gastrointestinal (23%), and rheumatologic (20%). Most delayed irAEs were grade ≤2 (84%), but some were grade ≥3 (16%). Of individual delayed irAEs, 75 (51%) occurred on ICI treatment at time of onset, 39 (26%) after ≤3 mo of the last ICI cycle, and 34 (23%) after >3 mo of the last ICI cycle. 79 (56%) and 20 (14%) delayed irAEs were treated with systemic steroids and immunomodulators, respectively. Further, 12 (8%) delayed irAEs led to hospitalization, and 64 (45%) required subspecialty consultation. Pts with a history of autoimmune disease were more likely to have a delayed irAE (p=0.02), as were pts who achieved a partial or complete response (p=0.02). There was a trend towards a greater frequency of delayed irAEs in pts treated with PD-1 (37%) compared with combination (28%), CTLA-4 (11%), or sequential CTLA-4 and PD-1 (28%) (p=0.068). Conclusions: Delayed irAEs occurred in almost a third of pts with advanced melanoma treated with ICIs and followed for at least 1 year. Extended follow-up to monitor for delayed irAEs should be considered as many events required immunosuppressive therapy and rarely, may be life threatening. [Table: see text]

Immune-related gastritis: An orphan immune-related adverse event.

e24138 Background: Immune checkpoint inhibitors (ICI) have revolutionized the field of oncology with a significant impact on patients' survival. However, they are not without shortcomings, with 70-90% of patients experiencing immune-related adverse events (irAEs(. Immune-related gastritis is a relatively uncommon irAE, literature publications are scarce and limited to case reports. We aimed to investigate this rare irAE to enhance understanding and improve patient care for oncologists and gastroenterologists. Methods: We performed a retrospective review of medical records of all cancer patients treated with ICI who completed upper gastrointestinal endoscopy during ICI treatment, at a single tertiary center between 2017 and 2023. Results: Of 2553 patients receiving immunotherapy at our medical center, 64 completed upper gastrointestinal endoscopy, and 18 (0.7%) had either endoscopic or microscopic gastritis or both. Overall, 17 (94%) patients with gastritis were symptomatic compared to only 31 of 46 patients (67%) without gastritis (p = 0.025). Epigastric pain was the most common symptom and was experienced by seven (39%) patients with gastritis, and eight (17%) patients without gastritis (P = 0.068). Other symptoms in patients with gastritis were gastrointestinal bleeding (28%), nausea (17%) and vomiting (11%). However, gastrointestinal bleeding (17%), nausea (9%), and vomiting (11%) were also experienced by patients without gastritis at similar rates (P > 0.05 for all comparisons). Two patients had grade 4 and two patients had grade 3 immune-related gastritis. Symptoms resolved in all patients, though most patients continued ICI (77%). Ten patients were treated with high-dose proton pump inhibitors (PPIs), and only four were treated with corticosteroids. Overall survival in patients experiencing gastritis was 40 months and did not differ from that of patients without gastritis (p = 0.929). Conclusions: Immune-related gastritis is an infrequent and non-lethal adverse event. Diagnosis is challenging due to non-specific symptoms, that are common among cancer patients undergoing antineoplastic therapies. Nonetheless, upon diagnosis, treatment with high doses PPIs with or without corticosteroids leads to prompt resolution.

Unraveling the role of CTLA-4 variants in acute kidney injury after ICI treatments.

e14682 Background: Immune checkpoint inhibitors (ICIs) often result in various immune-related adverse events (irAEs), which limit their therapeutic application and pose challenges to clinical decision-making. Among these irAEs, the incidence rate of ICI-related acute kidney injury (ICI-AKI) is on the rise. Understanding the genetic predisposition to ICI-AKI can inform personalized treatment plans, thereby minimizing risks and optimizing outcomes. This study aims to interrogate risk loci for AKI patients to gain insights into ICI-related AKI in cancer patients and to support the design of more personalized cancer therapies. Methods: This study comprehensively integrates meta-analysis, replication genome-wide association study (GWAS), fine-mapping, and mendelian randomization (MR) to explore potential genetic variants related with ICI-AKI. We first conducted a meta-analysis of 6 ICI pharmacogenomics studies, aggregating effect sizes from these studies using both fixed-effect and random-effects models to address heterogeneity and identified 186 significant genotypes. Subsequently, a GWAS was carried out over the 186 candidate genotypes in an independent cohort from the NIH All of Us program (N = 230,013) using logistic regression, identifying14,773 patients who developed AKI. To identify causal variants, we implemented fine-mapping techniques to further refine our genotype selection. Results: Our study identified genetic variants associated with an increased risk of AKI. Among these, the variant with the strongest association was located at the cytotoxic T lymphocyte antigen 4 (CTLA-4) gene locus, rs3087243 (chr2: 203874196, G>A,T). This genotype exhibited a significant inverse relationship with AKI risk (beta = -8.19e-2, P = 2e-11), suggesting that reduced activity of the CTLA-4 gene may be linked to an elevated risk of developing AKI. Our findings indicate that cancer patients with this genotype may have a lower risk of ICI-related AKI after immunotherapy. In our future study, we will continue investigating significant SNPs including rs3087243 in cancer patients for their ICI-AKI risk. Conclusions: We identified an AKI-tolerant genotype, rs3087243. Patients with this genotype may be safter from developing ICI-related AKI after immunotherapy treatment. This work also highlights the research potential of All of Us clinicogenomics data.

Stereotactic body radiation therapy combined with atezolizumab and bevacizumab for hepatocellular carcinoma with extrahepatic metastasis: Preliminary result of a single-arm study.

e16205 Background: IMbrave150 study confirmed the clinical benefit of atezolizumab and bevacizumab in patients with advanced hepatocellular carcinoma (HCC). However, patients with extrahepatic metastasis (EHS) had a poorer prognosis. Studies suggested “abscopal effect” of synchronous radiotherapy and immunotherapy may improve antitumor activity. This study aimed to evaluate efficacy and safety of stereotactic body radiation therapy (SBRT) combined with atezolizumab and bevacizumab in HCC patients with EHS. Methods: This single-arm study included HCC patients with EHS from January 2022 to November 2023 in Fudan University Shanghai Cancer Center. Prior tyrosine kinase inhibitor and/or immune checkpoint inhibitor treatment were eligible. After first dose atezolizumab and bevacizumab, SBRT was performed with a total dose of 25-50 Gy. The primary endpoint was objective response rate (ORR). The secondary endpoints included overall survival (OS), disease control rate (DCR), progression-free survival (PFS), time to progression (TTP), and duration of response (DOR). Results: Thirty-nine patients were included. Fourteen patients were treated as first-line therapy and 25 patients were treated as later-line therapy. The mean age was 56.69±11.21 years and 89.7% were male. Of these patients, 66.7% had hepatitis viral infection and 25.6% had vascular invasion. 53.8% of patients had ≥2 extrahepatic spread lesions. In addition, 33.3% of patients had received prior immunotherapy and 23.1% of patients had received tyrosine kinase inhibitor therapy. The median follow-up was 6.50 (range: 1.43-22.17) months. The ORR and DCR were 43.6% and 92.3%, respectively. The ORR was 57.1% and 36.0% in first-line subgroup and later-line subgroup, respectively. The 12-month OS rates was 54.7%. The median PFS, median TTP and median DOR were 6.73 months, 8.67 months, and 7.17 months, respectively. The incidence of all grade TRAE and grade ≥3 TRAE were 38.5% and 12.8%, respectively. The most common grade ≥3 TRAEs were decreased platelet count (7.7%), decreased white blood cell count (2.6%), pruritus (2.6%) and rectal bleeding (2.6%). No serious adverse events occurred. Conclusions: SBRT combined with systemic atezolizumab and bevacizumab showed encouraging efficacy with manageable safety profile for HCC patients with EHS regardless of prior treatment. Further studies are warranted. Clinical trial information: NCT05396937 . [Table: see text]

Breaking the Mold: Trailblazing Melanoma Therapy Beyond Checkpoint Through Innovative Approaches.

Melanoma has long been a difficult malignancy to treat with low response rates to standard chemotherapies. In recent years, the use of immune checkpoint inhibitors have demonstrated promising results, paving the way for the use of the rapidly developing novel immune targeting therapies. In this review, we look beyond immune checkpoint inhibitor treatments and summarize several emerging treatment strategies for melanoma, including neoantigen vaccines, conventional antibody drug-conjugates, and bispecific T-cell engager therapies.

Clinical features and prognostic analysis of 247 patients with ovarian clear cell carcinoma (OCCC) and an exploration of the treatment of recurrent OCCC: A single-center study in China.

e17548 Background: Ovarian clear cell carcinoma (OCCC) is relatively resistant to chemotherapy and has a worse prognosis than other ovary cancer. In this study, we reviewed the case files of OCCC in a single center to find its clinical characteristics and explore the treatment of recurrent cases, and the efficacy of immunotherapy. Methods: From August 2007 to August 2023 247 patients with OCCC were retrospectively involved. Univariate and multivariate Cox regression analyses were used to identify independent clinicopathological factors. The relapse OCCC were divided into four groups based on the different treatment who underwent chemotherapy or chemotherapy combined with surgery, bevacizumab, immune checkpoint inhibitors treatment. Kaplan–Meier curves were utilized to compare OS and DFS/PFS between the groups. Results: (1) 247 patients with OCCC were included, CA125 abnormality (> 35 U/ml) 65.2%, ascites cytology positive 10.1%, and the overall satisfactory reduction of tumor was 92.7%, CR and PR were 93.1 and 6.9%, respectively. 16.2% patients received more than 6 cycles of postoperative chemotherapy.(2)Univariate Cox regression analysis identified ascites (HR=4.012, 95% CI: 1.846 - 8.720, P<0.001), initial treatment effect (HR=2.714, 95% CI: 1.132 - 6.506, P=0.025), and chemotherapy cycles (HR=2.564, 95% CI: 1.402 - 4.689, P=0.002) were identified as independent prognostic factors for OS.(3)The patients who received chemotherapy cycles exceeding 6 cycles had worse prognosis(HR=3.01, 95%CI: 1.70-5.33, P<0.001), the result is the first proposal in our study.(4) Kaplan-Meier survival analysis showed that the OS of the chemotherapy combined with surgery relapse OCCC group was significantly better than the other three groups (HR=0.2732, 95%CI: 10.133-0.559, P=0.001). Subgroup analysis showed that relapse patients with satisfactory tumor reduction had more significant survival benefits(HR=3.86, 95%CI: 0.79-18.93, P=0.096).(5)The PFS of the chemotherapy combined with surgery group was also better than the other three groups (median PFS 25 months vs 8.5 months in chemotherapy vs12 months in chemotherapy combined immunotherapy vs 12 months in chemotherapy combined with bevacizumab). (6)4 patients who tested positive for PD-L1 received immune maintenance therapy after chemotherapy for 6-24months. There has been no recurrence since follow-up. Conclusions: Ascites, initial treatment effect and chemotherapy cycles were identified as independent prognostic factors for OCCC OS, chemotherapy combined with surgery for recurrent OCCC was significantly improving patient prognosis. For patients who achieve CR after initial treatment, if PD-L1 expression is positive, maintenance immunotherapy can be considered, but further studies with large samples are needed.

Immune checkpoint inhibitor treatment in PD-L1-negative gastroesophageal cancer tumors.

e16062 Background: We aimed to investigate whether there is a subgroup of patients with gastroesophageal cancers who, despite having IHC-PD-L1 negative tumors, might still benefit from ICI treatment. Furthermore, the impact of ICI treatment on patients with tumors that are PD-L1 negative by IHC but exhibit high CD274 (PD-L1) expression remains undefined. Methods: 1,416 esophageal adenocarcinomas (EA), 486 esophageal squamous carcinomas (ES), 859 esophagogastric junction adenocarcinomas (EJA), and 1,613 gastric adenocarcinoma (GA) samples were analyzed using NGS of DNA (NextSeq, 592 genes and NovaSeq, WES) and RNA (NovaSeq, WTS) (Caris Life Sciences, Phx, AZ). PD-L1 IHC positivity was defined as > 1% CPS (Agilent's 22c3). Correlation between PD-L1 CPS and CD274 expression (transcripts per million – TPM) were assessed by Spearman’s coefficient. Tumors were divided into CD274-H (high expression) and CD274-L (low expression) cohorts, representing the top 25% and bottom 25% of expression levels, respectively. Real-world overall survival (OS) data were obtained from insurance claims records and analyzed using Cox proportional hazards with hazard ratios (HR) and log-rank tests. Results: Weak correlations were observed between PD-L1 CPS and CD274 expression in adenocarcinoma histology tumors (EA: 0.374, EJA: 0.358, GA: 0.387), while a stronger correlation was found in squamous tumors (ES: 0.537). Median CD274 expression was significantly higher in PD-L1+ compared to PD-L1- ES tumors (2.65-fold) and in EA (1.68-fold), EJA (1.92-fold), and GA (1.96-fold) tumors (p < 0.001). In PD-L1 IHC-negative ES, there was no association between CD274-H expression and OS (H 12.4 vs L 10.6 mo; HR 0.90, p = 0.48). However, in adenocarcinomas, CD274-H showed a slightly improved OS (12.8 vs 11.3 mo; HR 0.79, p < 0.05). CD274-H trended towards worse post-Carboplatin/paclitaxel (CP) OS (ES: 13.8 vs 18.2 mo; HR 1.60; p = 0.22; Adenocarcinoma: 18.2 vs 27.4 mo; HR 1.50, p = 0.19). Interestingly, CD274-H was associated with improved post-CP/nivolumab survival in ES (96.5 vs 28 mo; HR 0.32; p = 0.047), with a similar but not statistically significant pattern in Adenocarcinoma EGC (Not Reached vs 30.2 mo; HR 0.39, p = 0.23). Furthermore, in CD274-L GEC, there was no difference in post-treatment survival with the addition of Nivolumab to CP (Squamous: 30 vs 18.2 mo; HR 0.91, p = 0.83; Adenocarcinoma: 30.2 vs 27.4 mo; HR 1.14; p = 0.76). In contrast, CD274-H showed improved survival with the addition of Nivolumab (Squamous: 96.5 mo vs 13.8 mo; HR 0.15; p = 0.01; Adenocarcinoma: NR vs 18.2 mo; HR 0.30; p = 0.08). Conclusions: High CD274 expression was associated with improved survival when Nivolumab was added to chemotherapy in patients with PD-L1-negative tumors. Further investigation is needed to confirm the potential benefits of Nivolumab treatment in gastroesophageal cancer patients with tumors that are PD-L1-negative by IHC but exhibit high mRNA expression.

Prognostic and predictive value of ultrasensitive ctDNA monitoring in a metastatic pan-cancer cohort treated with immune checkpoint inhibitors in the context of phase 1 clinical trials.

2510 Background: Determining which patients will achieve clinical benefit from immune checkpoint inhibition (ICI) therapy remains an open question. Liquid biopsy tests to assess baseline and early dynamics of circulating tumor DNA (ctDNA) may allow clinicians to track response more granularly and predict ICI response or resistance prior to imaging. However, lack of sensitivity may hinder accurate detection of low ctDNA levels in tumors with low shedding rates or during substantial drops and clearance in response. Methods: This study represents a cohort of 175 patients with refractory metastatic tumors from 18 different cancer types, who received 1-3 successive lines of ICI treatment in the context of phase-1 clinical trials. Thus far, 609 plasma samples from 90 stage-IV cancer patients receiving immune checkpoint inhibitor (ICI) treatment have been processed. ctDNA was profiled using the NeXT Personal assay, a liquid biopsy platform that leverages whole-genome sequencing of tumor and normal samples to create custom, patient-specific panels that include up to 1,800 somatic variants. This enables the detection of molecular residual disease (MRD) down to a detection threshold of 1 part per million (PPM) of ctDNA. Results: NeXT Personal assay detected positive levels of ctDNA in 99% (81/82) of plasma baseline samples, with a wide dynamic range, extending from 4.2 PPM (~0.00042% TF) to ~640,000 PPM (~64% TF) (median limit of detection = 2 PPM, 0.0002% TF). Lower ctDNA values at baseline were correlated with increased duration of PFS (log-rank p=0.017, HR=0.57, 95% CI 0.36-0.91) and extended OS (log-rank p=0.002, HR=0.46, 95% CI 0.28-0.75). Early reduction in ctDNA level from baseline to treatment cycle 3 was associated with significant increases in PFS (log-rank p=0.001, HR=0.36, 95% CI 0.19-0.67) and OS (log-rank p=0.015, HR=0.44, 95% CI 0.22-0.87), representing a >3-fold increase in both median PFS and OS. ctDNA clearance resulted in significant improvement in both PFS and OS (PFS: log-rank p=0.002, HR=0.24, 95% CI 0.09-0.62; OS: log-rank p=0.01, HR=0.29, 95% CI 0.1-0.8). All plasma timepoints from periods of durable complete response (CR) assessed via RECIST 1.1 were ctDNA-negative, with a molecular clearance lead time of 277 days over radiographically confirmed CR. Conclusions: We demonstrate that early ctDNA dynamics are predictive of long-term ICI response in the advanced, pan-cancer ECT setting. Even in this refractory advanced cancer cohort, an ultra-sensitive assay was required for accurate MRD status determination, with low ctDNA detections down to 4.2 PPM that might otherwise have been missed. Taken together, these findings suggest a high sensitivity ctDNA assay is crucial for accurate monitoring of ICI response, providing information for more accurate patient management.

Retrospective analysis of change in frequency of STK11 mutation in lung adenocarcinomas over a 10-year period.

8032 Background: Previous studies have linked the presence of inactivating mutations in the tumor suppressor gene STK11 with reduced efficacy of immune checkpoint inhibitor (ICI) treatments in lung adenocarcinoma (LA). We queried whether there has been a change in the STK11 mutation frequency over the last 10-year period that could potentially reflect the emergence of additional acquired resistance mutations. Methods: Over a 10-year period from 2013 through 2022, 109,763 clinically advanced LA underwent hybrid capture based comprehensive genomic profiling (CGP) to assess all classes of genomic alterations (GA) at a single reference laboratory (Foundation Medicine). MSI-high status and tumor mutational burden (TMB) were determined from the sequencing data. PD-L1 status was measured by immunohistochemistry (IHC) using the Dako 22C3 kit with TPS scoring. Statistical comparisons utilized the 2-tailed Chi Square method with the Yates’ correction. Results: The frequency of STK11 inactivating GA in all cases of LA significantly increased during the study period from 2013 to 2022 (16.1% vs 20.1%; p=0.0005). This increase appeared to be predominantly in KRAS wild type LA (10.1% vs 15.5%; p<0.0001). The STK11 GA frequency slightly declined in the KRAS mutated LA over the 10-year period (29.9% vs o 27.0%, P=0.25). During the same time period, the KEAP1 GA frequency increased from 12.6% to 14.9% (p= 0.076) and the frequency of combined STK11 and KEAP1 GA increased from 4.8% to 8.0% (p=.0006). The frequencies of MSI-high status, TMB and PD-L1 expression did not significantly change over the observation period. Conclusions: The continuously increasing approved indications for ICI-based treatments for both early stage and clinically advanced LA appears to be accompanied by a significant increase in the frequency of inactivating STK11 GA predominantly in the KRAS mutation negative LA population. This inactivation is associated with an attenuated response rate and progression-free survival in this population. Given the development of novel therapies focused on potential restoration of STK11 function by HDAC/CoREST inhibition, further study of the STK11 GA distribution in LA appears warranted. [Table: see text]

Phenotyping Hepatic Immune-Related Adverse Events in the Setting of Immune Checkpoint Inhibitor Therapy.

We present and validate a rule-based algorithm for the detection of moderate to severe liver-related immune-related adverse events (irAEs) in a real-world patient cohort. The algorithm can be applied to studies of irAEs in large data sets. We developed a set of criteria to define hepatic irAEs. The criteria include: the temporality of elevated laboratory measurements in the first 2-14 weeks of immune checkpoint inhibitor (ICI) treatment, steroid intervention within 2 weeks of the onset of elevated laboratory measurements, and intervention with a duration of at least 2 weeks. These criteria are based on the kinetics of patients who experienced moderate to severe hepatotoxicity (Common Terminology Criteria for Adverse Events grades 2-4). We applied these criteria to a retrospective cohort of 682 patients diagnosed with hepatocellular carcinoma and treated with ICI. All patients were required to have baseline laboratory measurements before and after the initiation of ICI. A set of 63 equally sampled patients were reviewed by two blinded, clinical adjudicators. Disagreements were reviewed and consensus was taken to be the ground truth. Of these, 25 patients with irAEs were identified, 16 were determined to be hepatic irAEs, 36 patients were nonadverse events, and two patients were of indeterminant status. Reviewers agreed in 44 of 63 patients, including 19 patients with irAEs (0.70 concordance, Fleiss' kappa: 0.43). By comparison, the algorithm achieved a sensitivity and specificity of identifying hepatic irAEs of 0.63 and 0.81, respectively, with a test efficiency (percent correctly classified) of 0.78 and outcome-weighted F1 score of 0.74. The algorithm achieves greater concordance with the ground truth than either individual clinical adjudicator for the detection of irAEs.

Enfortumab vedotin plus pembrolizumab in the treatment of locally advanced or metastatic bladder cancer of variant histology: A phase II study.

TPS4615 Background: Bladder cancers of variant histology (BCVH) account for up to 25% of bladder cancer incidence and affected patients (pts) usually have poor outcomes. The treatment options are limited due to the underrepresentation or exclusion of BCVH pts from trials for locally advanced or metastatic urothelial cancer (mUC). Enfortumab vedotin (EV) is an antibody-drug conjugate specific for Nectin-4. In the EV 302 Phase III trial, EV+pembrolizumab (pembro) significantly prolonged overall survival (OS) compared to platinum-based chemotherapy in mUC (HR 0.47, 95% CI 0.38-0.58) and was recently FDA-approved as standard of care in 1L mUC. Translational studies from our center show Nectin-4 expression in many BCVH pts and data support immune-checkpoint inhibitor (ICI) activity in subsets of these pts. We hypothesize the presence of clinical activity of this combination in BCVH. Therefore, we designed this trial to assess the efficacy and safety of EV+pembro in locally advanced or metastatic BCVH (mBCVH). Methods: This is a Phase II, open-label, single-center trial at the Winship Cancer Institute of Emory University (NCT05756569) for pts with mBCVH. Pts will receive pembro 200mg IV on Day 1 and EV 1.25mg/Kg IV on Days 1 and 8 of a 21-day cycle for up to two years. The eligibility criteria include histologically confirmed variant histology or non-urothelial bladder cancer of epithelial origin including squamous cell carcinoma and adenocarcinoma (according to the WHO 2016 Classification), ECOG 0-1, and any line of therapy. Pts with neuroendocrine bladder cancer, non-epithelial cancers (e.g. sarcoma, lymphoma), prior ICI and/or EV treatment are excluded. Overall response rate (ORR) per RECIST 1.1 is the primary outcome and will be tested using Simon's two-stage design (n=25). The first interim analysis is planned after 15 patients. The desirable target is ORR≥30% relative to a null hypothesis of ORR ≤10%. This statistical design yields a type I error rate of 0.05 and a power of 80% for a true ORR≥30%. Key secondary outcomes include OS, progression-free survival, duration of response, and incidence of adverse events per CTCAE v5.0. Correlative biomarker analyses using blood- and tissue-based assays will be conducted during screening and at disease progression. The trial is currently open for enrollment. Clinical trial information: NCT05756569 .