Initiation Of Immune Checkpoint Inhibitors Therapy Research Articles

Treatment Patterns and Real-World Outcomes for Locally Advanced or Metastatic Urothelial Cancer in the Era of Immunotherapy

Background and objectiveThere are limited data on real-world outcomes for patients with advanced or metastatic urothelial cancer (mUC) since immune checkpoint inhibitors (ICIs) became available. Our objective was to analyze outcomes for patients with mUC since ICIs became available. MethodsWe performed a retrospective analysis of 131 patients with mUC attending the outpatient clinic of a single tertiary care center who received systemic therapy between June 2017 and July 2021 with follow-up up to December 2022. Summary and descriptive statistics were calculated for categorical and continuous variables. The Kaplan-Meier method was applied to calculate survival, and a Cox proportional-hazards model was used to explore associations between clinical variables and outcomes. Key findings and limitationsThe median patient age was 68 yr (range 35–90). The first systemic therapy administered was platinum-based in 79% of cases and ICI-based in 21%. Some 61% of the cohort received a second systemic treatment, with 75% of these an ICI. Median overall survival for the entire cohort was 24 mo (interquartile range 9–35). Patients on ICI therapy for ≥6 mo had median overall survival of 59 mo (95% confidence interval 39 mo–not reached). Metastatic sites on initiation of ICI therapy and C-reactive protein kinetics were prognostic in patients receiving ICIs. Limitations include the retrospective design and inherent selection bias. Conclusions and clinical implicationsMore than 60% of patients with mUC received second-line treatment, and 75% of these received an ICI. Patients staying on immunotherapy for more than 6 mo have substantially better outcomes in comparison to patients with less time on immunotherapy and historical cohorts. Patient summaryWe looked at the lines of therapy and outcomes for patients with advanced or metastatic cancer of the urinary tract, starting from when immunotherapy drugs called immune checkpoint inhibitors (ICIs) became available. We found that 60% of patients have received second-line therapy, which is a double the rate in comparison to historical groups of patients. Patients with long-term ICI therapy (>6 months) had significantly better outcomes, with a median survival of more than 3 years.

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

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

T-Cell Receptor Repertoire as a Predictor of Immune-Related Adverse Events in Renal Cell Carcinoma.

Immune checkpoint inhibitors (ICIs) are effective in treating renal cell carcinoma (RCC) but can also cause immune-related adverse events (irAEs). The relationship between irAEs and the T-cell receptor (TCR) repertoire in RCC patients treated with ICIs remains unclear. We analyzed the relationship between the severity and diversity of irAEs and the TCR repertoire in RCC patients who received dual checkpoint inhibitors (ipilimumab + nivolumab). The TCRβ (TRB) repertoires were characterized in peripheral blood samples from six patients with RCC before the initiation of ICI therapy. The diversity and clonality of the TCR repertoire were compared between patients with grade 2 and grade 3 irAEs. The median proportion of top 10 unique reads in the TCR repertoire was significantly higher in grade 3 compared with grade 2 irAEs in RCC patients receiving immune checkpoint inhibitors (grade 2: 0.196%; grade 3: 0.346%; p = 0.0038). We provide insight into the relationship between TCR repertoire and irAEs in RCC patients treated with ICIs. TCR repertoire clonality may be associated with the development of irAEs in RCC patients.

SAT443 Prevalence Of Immune Checkpoint Inhibitor-related Endocrinopathies In Patients With Cancers

Abstract Disclosure: S. Pittampalli: None. S.R. Lubin: None. R. Acharya: None. Background: Immune checkpoint inhibitors (ICIs), emerged as the primary treatment modality for a wide range of cancers improving overall survival. Nevertheless, improved overall survival is complicated by endocrine dysfunctions including thyroid dysfunction, adrenalitis, diabetes mellitus, and hypophysitis. Such adverse events offset the benefits of ICI therapy and are associated with significant morbidity and mortality. Limited data exists concerning the burden of the ICI-related endocrinopathies in cancer treatment.Objective: To identify the prevalence and timing of onset of various endocrinopathies in patients with cancers receiving ICIs. Methods: A retrospective study was conducted at SUNY Upstate Medical University, NY comprising of adult patients. The study population consisted of all patients age 18 and above seen at Upstate Medical University between 1 January 2019 and 31 December 2021. Anonymized aggregate-level data was collected using an EPIC Slicer Dicer to identify all adult patients with cancer who underwent ICI therapy and a total of 199 patients were included. Demographic, clinical, histopathological, laboratory data were examined. The study was reviewed by IRB and deemed exempt. The following ICI-related endocrinopathies were considered: Hypothyroidism, hyperthyroidism, diabetes mellitus, adrenal insuffiency, and hypophysitis. ICI treatments included: anti-PD-1 (nivolumab, pembrolizumab, cemiplimab), anti-PD-L1 (atezolizumab, avelumab, durvalumab), and combination therapy (ipilimumab and nivolumab, or any other ICI combinations). Statistical analysis including descriptive statistics, ANOVA was conducted using IBM SPSS software.Results: A total of fifty patients (25%) developed ICI-related endocrinopathy (n=28 M, 22 F) with a mean age of onset 63.69 years. Majority of the patients were being treated for lung cancers (51%) and had hypothyroidism (88%) followed by adrenal insufficiency (9%) and diabetes (2%). There were no cases of hyperthyroidism or hypophysitis observed. The average time of onset of endocrinopathies after initiation of ICI therapy was 22 weeks (anti-PD-1=122 days, anti-PD-L1=180 days and combination therapy= 252 days) with a significantly later onset with combined therapy when compared to anti-PD-1 inhibitors (252 vs 122 days, p= 0.004). Conclusion: With the increasing use of immune checkpoint inhibitors in cancer therapy, there is increased prevalence of endocrinopathies. Periodic hormonal assessment along with close monitoring of new symptoms results in early detection of endocrinopathies as the time of onset varies significantly with the type of ICI agent and the use of single vs combination therapy. Presentation: Saturday, June 17, 2023

The timing of statin initiation on survival outcomes of cancer patients treated with immune checkpoint inhibitors: A retrospective cohort study.

e14672 Background: Concomitant use of statins has been associated with improved survival outcomes in patients treated with immune checkpoint inhibitors (ICIs), but it is unclear if the timing of statin initiation plays a role in patient outcomes. We aimed to investigate the outcomes of patients who were started on a statin before and after initiation of ICI therapy. Methods: We performed a retrospective cohort study at two tertiary referral centers in Taiwan. We collected data on statin use including the timing of statin initiation, basic demographics, underlying comorbidities, and cancer information. We compared the overall survival (OS) and progression-free survival (PFS) between statin and non-statin users using Cox proportional hazard model analysis and Kaplan-Meier Survival analysis. Results: Among 734 patients who received ICIs, 76 patients received statins after ICI initiation, 52 patients received statins before ICI initiation, and 606 were non-statin users. Patients who received statins after ICI had a longer OS (median 37.6 vs. 11.3 vs. 10.3 months, p = 0.01) and PFS (median 10.5 vs. 5.6 vs. 6.3 months, p = 0.02) than patients who received statins before ICI and non-statin users. In Cox proportional hazard analyses, the use of statins after ICI was associated with a lower risk of mortality (HR, 0.65 [95% CI: 0.45-0.94], p = 0.02) or disease progression (HR, 0.71 [95% CI: 0.53-0.95], p = 0.02) compared with non-statin users. On the other hand, the use of statins before ICI was not associated with a lower risk of mortality (HR, 1.46 [95% CI: 0.96-2.22], p = 0.08) or disease progression (HR, 1.22 [95% CI: 0.86-1.73], p = 0.26) compared with non-statin users. These trends were observed in multivariate Cox proportional analyses adjusting for underlying comorbidities, cancer stage, type, and therapy. Conclusions: The use of statins after the initiation of immunotherapy is associated with improved survival outcomes. [Table: see text]

Sclerosing mesenteritis following immune checkpoint inhibitor therapy.

Sclerosing mesenteritis (SM), a fibroinflammatory process of the mesentery, can rarely occur after immune checkpoint inhibitor (ICI) therapy; however, its clinical significance and optimal management are unclear. We aimed to assess the characteristics and disease course of patients who developed SM following ICI therapy at a single tertiary cancer center. We retrospectively identified 12 eligible adult cancer patients between 05/2011 and 05/2022. Patients' clinical data were evaluated and summarized. The median patient age was 71.5years. The most common cancer types were gastrointestinal, hematologic, and skin. Eight patients (67%) received anti-PD-1/L1 monotherapy, 2 (17%) received anti-CTLA-4 monotherapy, and 2 (17%) received combination therapy. SM occurred after a median duration of 8.6months from the first ICI dose. Most patients (75%) were asymptomatic on diagnosis. Three patients (25%) reported abdominal pain, nausea, and fever and received inpatient care and corticosteroid treatment with symptom resolution. No patients experienced SM recurrence after the completion of corticosteroids. Seven patients (58%) experienced resolution of SM on imaging. Seven patients (58%) resumed ICI therapy after the diagnosis of SM. SM represents an immune-related adverse event that may occur after initiation of ICI therapy. The clinical significance and optimal management of SM following ICI therapy remains uncertain. While most cases were asymptomatic and did not require active management or ICI termination, medical intervention was needed in select symptomatic cases. Further large-scale studies are needed to clarify the association of SM with ICI therapy.

Associations of immune checkpoint inhibitor therapy efficacy with clinical parameters and tumor‑infiltrating CD68‑positive cell counts in patients with EGFR‑mutant non‑small cell lung cancer.

Immune checkpoint inhibitor (ICI) therapy has been less effective in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations than in patients with EGFR wild-type NSCLC. This retrospective study was conducted to investigate the associations of clinical parameters with the efficacy of ICI therapy in patients with EGFR-mutant NSCLC. Clinical information was retrieved from the medical charts, and immunohistochemical analysis was performed in some cases to determine the tumor-infiltrating CD68-positive cell count. Data from 46 patients were included in the analysis. The median (95% confidence interval) progression-free survival and overall survival from the initiation of ICI therapy was 1.4 months (1.0-1.7 months) and 6.4 months (3.9-19.0 months), respectively. Analysis using a Cox proportional hazards model revealed that tumor programmed death-ligand 1 expression was associated with the overall survival of patients with EGFR-mutant NSCLC after ICI treatment. The tumor-infiltrating CD68-positive cell count was evaluated in 11 patients. Comparison using the log-rank test revealed that the progression-free survival time after ICI treatment was longer in the patients with lower tumor-infiltrating CD68-positive cell counts than those with higher tumor-infiltrating CD68-positive cell counts. The present analysis demonstrated that PD-L1 expression and the tumor-infiltrating CD68-positive cell count may be associated with the efficacy of ICI therapy in patients with NSCLC harboring EGFR mutations.

Discontinuation of Immune Checkpoint Inhibitor due to irAEs in NSCLC Patients With EGFR Mutation.

Immune checkpoint inhibitors (ICIs) have revolutionized advanced non-small cell lung cancer (NSCLC) treatment. Even patients with epidermal growth factor receptor (EGFR)-mutated NSCLC may choose an ICI after failure of EGFR-tyrosine kinase inhibitor treatment. ICI-mediated immune-related adverse events (irAEs) may prompt NSCLC patients to discontinue their treatment. This study evaluated the effect of ICI treatment discontinuation on the prognosis of patients with EGFR-mutated NSCLC. We performed a retrospective study that reviewed the clinical courses of patients with EGFR-mutated NSCLC treated with ICI therapy from February 2016 to February 2022. 'Discontinuation' was defined as failure to receive at least two treatment courses of ICI due to grade 2 irAEs (grade 1 in the lung) or higher in patients responding to ICI. During the study period, 13 of 31 patients discontinued ICI therapy due to irAEs. Survival from the initiation of ICI therapy was significantly longer in patients who discontinued ICI therapy compared with those who did not discontinue. In uni- and multivariate analyses, 'discontinuation' was a favourable factor. There was no significant difference in survival from ICI initiation between patients with grade 3 or higher irAEs and those with grade 2 or lower irAEs. In this patient cohort, discontinuation of ICI therapy due to irAEs did not adversely affect prognosis in patients with EGFR-mutant NSCLC. Our results suggest that when treating patients with EGFR-mutant NSCLC with ICIs, chest physicians should consider discontinuing ICI with close monitoring.

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

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

Abstract 11598: In Silico Identification of Immunogenic Cardiac Troponin I Epitopes and Validation in Patients Treated With Immune Checkpoint Inhibitors

Introduction: Immune checkpoint inhibitors (ICIs) have contributed to the recent decline in death due to cancers like melanoma. However, serious cardiotoxic side effects (like fatal myocarditis) have been reported. Autoimmunity against cardiac proteins has been suspected but the underlying mechanism is not known. Hypothesis: ICI treatment induces the formation of autoantibodies against immunogenic sequences of cardiac troponin I (cTn I). Methods: We identified antigenic sequences in cardiac myosin and troponin I by bioinformatic analyses, including T- and B-cell epitope prediction methods. The sequences with the highest antigenicity scores were coated on plates for enzyme-linked immunosorbent assays (ELISAs). Sera from ICI-treated mouse models and patients were used as primary antibodies to detect self-reactivity against these peptides. Mice were treated every 3 days with a total of 17 doses of PD-1, CTLA-4, a combination of both, or isotype IgG control antibodies (Abs). For clinical samples, sera was taken from 26 ICI-treated patients with melanoma, including pre-treatment samples from 20 patients. Results: From the in silico analysis, we identified 5 cTn I and 2 myosin sequences as antigenic. Using ICI-treated mouse serum, we screened these peptides and found cross-reactivity with cTn I peptide T5, which reflects a flexible linker and portion of a helix in cTn I. After completing ICI treatment in mice, there was significant reactivity to T5 in combination treatment versus control (Absorbance: IgG 0.135±0.037, CTLA-4+PD-1 Abs 0.247±0.060, IgG vs. CTLA-4+PD-1 Abs p=0.02, n=5-9). There were also increased autoantibodies in combination treatment compared to CTLA-4 Abs (CTLA-4 Abs 0.123±0.040, CTLA-4 vs. CTLA-4+PD-1 Abs p=0.001, n=9-10). In our clinical studies, there was positive reactivity against peptide T5 of 6-7 fold change in 4 subjects (15% of patients) with late stage melanoma after the initiation of ICI therapy, as compared to the average pre-treatment value. Conclusions: Our study showed that ICI-therapy induced immune-reactive antibodies directed against antigenic targets of cTn I in both animal models and patients. These data suggest a novel mechanism of ICI-induced cardiotoxicity, which warrants further investigation.

S65 Distinct Imaging Patterns of Immune Checkpoint Inhibitor-Induced Acute Pancreatitis

Introduction: The presentation of immune checkpoint inhibitor (ICI)-induced pancreatic injury ranges from asymptomatic hyperlipasemia to acute pancreatitis. Imaging features of ICI-induced acute pancreatitis (ICI-AP) remain poorly described. We evaluated radiographic patterns of pancreatic inflammation in patients with ICI-AP. Methods: We assessed a retrospective cohort of patients diagnosed with ICI-AP after initiation of ICI therapy between 2011 and 2019. Abdominal imaging findings with computed tomography (CT), magnetic resonance imaging (MRI), and 18-Fluorine-flurodeoxyglucose positron emission tomography (18F-FDG PET/CT) were reviewed by an independent radiologist. We performed univariate analyses to evaluate associations between clinical characteristics and radiographic patterns of ICI-AP. Results: Among 6,450 cancer patients treated with ICI, 27 (0.4%) developed ICI-AP. All three Atlanta criteria for AP (typical symptoms, imaging, and lipase ≥3 upper limit of normal) were satisfied in 13 (48%). Abdominal pain was present in 23 (85%), and 4 (15%) presented asymptomatically with hyperlipasemia and pancreatic inflammation on imaging. Diagnostic abdominal imaging was performed in 26/27 patients (mean age 62.4 ± 11.3 years, 46% female, 92% White) via CT in 22 (85%), MRI in 3 (12%), and 18F-FDG PET/CT in 1 (4%). The most frequent radiologic appearance was a diffuse interstitial pattern with diffuse edematous pancreas and peripancreatic stranding, present in 10 (38%) patients, followed by a focal interstitial pattern with focal pancreatic edema and peripancreatic stranding in 7 (26%), and pancreatic enlargement without peripancreatic inflammation in 3 (12%). Six patients (23%) had normal imaging. Individuals with diffuse interstitial inflammation and normal imaging were more likely to be female (p=0.02). Those with diffuse inflammation or pancreatic enlargement without inflammation were older than those with focal inflammation and normal pancreatic imaging (p=0.046). Conclusion: We propose three distinct radiologic patterns of ICI-AP. The notable subset of patients who were asymptomatic but had imaging evidence of ICI-AP supports the role of abdominal imaging in patients on ICIs with hyperlipasemia. The presence of pancreatic enlargement without peripancreatic inflammation in a small but notable proportion of patients highlights the importance of comparing baseline pancreatic imaging when interpreting imaging for ICI-AP. (Table) Table 1. - Title: Imaging Characteristics in Patients with Immune Checkpoint Inhibitor-Induced Acute Pancreatitis Characteristics Overall (N = 26) Diffuse interstitial pattern (N = 10) Focal interstitial pattern (N = 7) Pancreatic enlargement alone (N = 3) Normal (N = 6) P-value Age (years), mean (SD) 62.4 (11.3) 65.6 (11.9) 57.4 (14.6) 70.0 (3.6) 59.2 (4.0) 0.046 Female, n (%) 12 (46.2%) 6 (60.0%) 1 (14.3%) - 5 (83.3%) 0.02 Race (White) n (%) 24 (92.3%) 9 (90.0%) 7 (100%) 2 (66.7%) 6 (100%) 0.27 Cancer type, n (%) 0.40 Melanoma 11 (42.3%) 3 (30.0%) 2 (28.6%) 2 (66.7%) 4 (66.7%) Non-melanoma 15 (57.8%) 7 (70.0%) 5 (71.4%) 1 (33.3%) 2 (33.3%) ICI class, n (%) 0.77 CTLA4 2 (7.7%) - 1 (14.3%) - 1 (16.7%) PD1/PDL1 18 (69.2%) 8 (80.0%) 5 (71.4%) 2 (66.7%) 3 (50.0%) CTLA4 + PD1/PDL1 6 (23.1%) 2 (20.0%) 1 (14.3%) 1 (33.3%) 2 (33.3%) Pancreatitis severity by revised Atlanta criteria, n (%) 0.38 Mild 23 (88.5%) 9 (90.0%) 7 (100%) 3 (100%) 4 (66.7%) Moderately severe 3 (11.5%) 1 (10.0%) - - 2 (33.3%) Lipase severity by CTCAE v.5 0.99 3 4 (15.4%) 2 (20.0%) 1 (14.3%) - 1 (16.7%) 4 22 (84.6%) 8 (80.0%) 6 (85.7%) 3 (100%) 5 (83.3%) Days from ICI initiation to pancreatitis, mean (SD) 161.8 (242.5) 134.0 (148.7) 156.1 (158.8) 451.0 (633.4) 70.2 (40.7) 0.52 Duration of lipase elevation (days), mean (SD) 65.4 (81.1) 54.2 (62.3) 41.0 (37.0) 32.3 (43.4) 129.0 (130.0) 0.66 Managed with steroids, n (%) 21 (80.1%) 8 (80.0%) 5 (71.4%) 2 (66.7%) 6 (100%) 0.53 ICI discontinued due to ICI-induced pancreatic injury, n (%) 19 (73.1%) 7 (70.0%) 5 (71.4%) 1 (33.3%) 6 (100%) 0.23 Response to steroids, n (%) 10 (38.5%) 3 (30.0%) 4 (57.1%) 1 (33.3%) 2 (33.3%) 0.76 Abbreviations: Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v.5); cytotoxic T-lymphocyte-antigen protein-4 (CTLA-4); Immune checkpoint inhibitor (ICI); programmed cell death-1 (PD-1) / PD-1 ligand (PD-L1).

Early evaluation of subclinical cardiotoxicity in patients with lung cancer receiving immune checkpoint inhibitors by cardiovascular magnetic resonance: a prospective observational study.

BackgroundFew studies have focused on the subclinical cardiotoxicity of immune checkpoint inhibitors (ICIs) in cancer patients. This study aimed to evaluate the manifestations of subclinical cardiotoxicity of ICI therapy using cardiovascular magnetic resonance (CMR) and to explore whether CMR parameters can help predict cardiotoxicity at the early stage of ICI therapy.MethodsA prospective, longitudinal study was conducted among patients with lung cancer. The patients were planned to undergo serial CMRs before (baseline), 3 weeks after (1st follow-up), and 3 months after (2nd follow-up) the initiation of ICI therapy, respectively. Patients with 3 CMRs were included in the analysis. Serial quantitative measurements based on CMR were compared using one-way repeated measures analysis of variance (RM-ANOVA). On the basis of cancer therapy-related cardiac dysfunction (CTRCD) observed at the second follow-up, patients were categorized into a CTRCD group and a non-CTRCD group. Baseline clinical and CMR parameters and the relative reduction of left ventricular global strain at the second follow-up was compared between the CTRCD group and the non-CTRCD group. Receiver operating characteristic (ROC) analysis was used to identify CTRCD that developed 3 months after ICI therapy.ResultsA total of 36 patients with 3 CMRs (60.7±9.2 years old, 77.8% male) were included in the analysis. Left ventricular-global radial strain (LV-GRS) decreased significantly at the second follow-up (37.9%±8.5% vs. 33.1%±1.0%; P=0.014), but left ventricular ejection fraction (LVEF) did not change significantly (51.5%±6.0% vs. 49.2%±6.5%; P>0.05). A total of 7 patients (19.4%) had developed CTRCD by the second follow-up. Baseline clinical and CMR parameters did not differ between the CTRCD group and the non-CTRCD group (P>0.05 for all). In the CTRCD group, the left ventricular-global circumferential strains (LV-GCSs) showed significant reductions at both the first and second follow-up (P=0.008 and 0.035, respectively), but the LVEF only showed a significant reduction at the second follow-up (P<0.001). The relative reduction of LV-GRS at the second follow-up was significantly higher in the CTRCD group than in the non-CTRCD group (29.8%±25.8% vs. 6.8%±20.4%; P=0.036) and was used to predict CTRCD developed at the 3-month timepoint after ICI therapy [area under the curve (AUC) =0.759; P=0.036].ConclusionsIn the early stage of ICI therapy, assessment of myocardial strain can be used to detect subclinical left ventricular systolic dysfunction in patients with lung cancer earlier than LVEF. The relative reduction of LV-GRS can be used to predict CTRCD 3 months after ICI therapy.

EP08.01-045 The Impact of Current Smoking Status at Initiation of Immune Checkpoint Inhibitor Therapy on Tumor Mutation Burden and Survival

Smoking associates with better immune checkpoint inhibitor (ICI) therapy response in patients with advanced non-small cell lung cancer (NSCLC). This may be because smoking correlates with increased tumor mutation burden (TMB), a known ICI response predictor. However, it is unknown whether benefits from smoking are static (i.e., ICI response benefit continues after smoking cessation) or ongoing (i.e., smoking cessation mitigates ICI response benefit). We assess the relationship between TMB and smoking status at initiation of ICI therapy and evaluate how treatment response may vary by TMB and ongoing smoking versus cessation.

Abstract 017: Dual Immune Checkpoint Inhibitor Therapy Is Associated With Increased Blood Pressure In Melanoma Patients

Background: Immune checkpoint inhibitor (ICI) therapy has revolutionized cancer therapy through activating immune cells to overcome tumor immune evasion. Increasing evidence suggests that adaptive immune cells play an important role in blood pressure elevations in the pathogenesis of hypertension. Whether ICI therapy enhances blood pressure remains unclear. Methods: We performed a retrospective cohort study of patients with advanced melanoma treated with ICIs in a single academic center. Baseline and 2-year blood pressure readings after initiation of ICI therapy were compared. To determine the relationship between the demographic and treatment variables and the change in blood pressure at two years, a multivariable linear regression model was used. Results: A total of 259 individuals were identified with 2-year follow-up. Of the entire cohort, 31% were treated with nivolumab, 47% with pembrolizumab, and 23% with ipilimumab and nivolumab combination therapy. In the total cohort, ICIs were not associated with significant changes in systolic (SBP) or diastolic (DBP) blood pressure at 2 years compared to baseline (132.2 mmHg vs . 133.2 mmHg, p=0.17, and 78.6 vs . 78.1 mmHg, p=0.50, respectively). There were also no statistically significant changes in SBP or DBP in patients treated with nivolumab or pembrolizumab alone. However, in those treated with ipilimumab and nivolumab as combination therapy, SBP increased by 5.5 mmHg (128.2 vs. 133.7 mmHg, p=0.005). After adjusting for age, sex, weight, ICI type and duration, steroid and tyrosine kinase inhibitor use, and antihypertensive medication use at baseline and 2-years, combination therapy with ipilimumab and nivolumab remained a significant predictor of SBP change at two years. Holding the baseline SBP constant, the predicted SBP was 6.2 mmHg (95% CI 0.08 - 12.0 mmHg, p=0.047) higher for combined therapy than nivolumab alone. Conclusions: Patients who received combination ICI therapy had a higher SBP compared to those treated with single agent therapy. These findings suggest immune cell activation with ICI therapy contributes to blood pressure elevations and that close follow-up of blood pressure is needed in cancer survivors, particularly those previously treated with combination ICI therapy.

Cancer immunotherapy associated hypophysitis: Pathophysiology and management

Immune checkpoints are small molecules produced by immune cells that play crucial role in maintaining homeostasis of immune system. Targeting the immune checkpoint molecule, specifically, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD1) with inhibitory monoclonal antibodies has been reported to have antitumor activity. The US Food and Drug Administration (FDA) has been recognized several immune checkpoint inhibitors (ICIs) for the treatment of several types of cancer, mainly two types of ICIs that target CTLA-4 and PD1, have been approved as immunotherapeutic agent for cancer treatment. Autoimmune side effects results from immune checkpoint blockade, termed as immune related adverse events (irAEs) are frequent and usually mild, can include multiple endocrinopathies. The unique characteristic of irAEs is their non-reversibility, with incidence and prevalence expected to be increased in the upcoming years. Immune-related hypophysitis (IRH) is one of the most frequently reported irAEs after thyroid dysfunction. Hypophysitis, specifically associated with anti-CTLA-4 therapy, primary adrenal insufficiency (PAI) and diabetes mellitus are rare irAEs but can be fatal if not diagnosed and treated in early stage. Combinatorial therapy using anti- CTLA-4 and anti-PD1 drug is associated with increasing prevalence of IRH. The exact mechanism behind the development of irAEs remain to be elucidated. Most ICI associated endocrinopathies are manifested within 8-12 weeks after the initiation of ICI therapy. Management of ICI associated hypophysitis requires withdrawal of the ICI therapy, initiation of steroids and finally initiation of hormone replacement therapy and usually includes long-term management and care for controlling the irreversible side effects. In this review, we try to summarize the current scenario regarding the epidemiology, mechanism pathophysiology and management procedure for IRH in cancer patients receiving immunotherapy.

Immunotherapy-induced Colitis: A Comprehensive Review of Epidemiology, Clinical Presentation, Diagnostic Workup, and Management Plan.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of a variety of malignancies including advanced melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancers among others. Since their introduction, there has been significant improvement in survival and prognosis in patients with advanced malignancies. Unfortunately, improved outcomes have come at a price of significant immune-related adverse events, with those of the gastrointestinal tract being the most common. Gastrointestinal immune-related adverse events frequently present as diarrhea and colitis, the severity of which can range from mild diarrhea to fulminant colitis with intestinal perforation. Currently, management of ICI-induced colitis is primarily guided by retrospective studies and expert opinion. A significant number of ICI-induced colitis responds to high-dose corticosteroids; however, some patients require further therapy with biologics. There is limited information on the factors which may predispose patients to ICI-induced colitis. Future research elucidating these risk factors along with development of a scoring system could allow for risk-stratification of patients before initiation of ICI therapy. Such a system may help clinicians and patients keep a high index of suspicion regarding ICI-induced colitis and could hopefully reduce the incidence of severe cases. Similarly, future studies should investigate protective factors against ICI-induced colitis, which could potentially allow more patients to safely benefit from ICI therapy.

Clinical Course and Impact of Immune Checkpoint Inhibitor Colitis Resembling Microscopic Colitis.

Microscopic colitis (MC) is suspected to result from increased immune activity in gut mucosa. Immune checkpoint inhibitors (ICIs) treat cancer by activating the immune system, and further investigation is needed regarding their role in the development of MC. A retrospective case series investigated cases of endoscopically and histologically confirmed MC developing after administration of ICIs. Clinical notes and medication administration records were reviewed for demographics, symptom duration, and treatment response. Nineteen cases of de novo MC were identified, with 95% of cases requiring steroid treatment, 53% presenting with hospitalization, and colitis-related mortality in 1 individual. Symptom onset occurred a median of 160 days after initiation of ICI therapy and 53 days after their most recent dose of therapy. Patients had a median of 125 days of symptoms, and ICI therapy was held in 70% of individuals due for treatment. MC can develop after ICI administration, and presents with severe symptoms, often requiring hospitalization and steroid treatment. In certain individuals this can require a prolonged treatment course of steroid therapy or immunomodulators. Individuals developing diarrhea after ICI therapy warrant thorough workup including endoscopy and rapid treatment initiation given the disease severity observed in this series.

The Association of Antibiotic (ATB) exposure prior to immune checkpoint inhibitor (ICI) treatment on early emergency room and hospitalization utilization: A population-based study.

304 Background: ICIs are becoming a common therapeutic option for many solid tumors. Prior studies have shown that ATB exposure can negatively impact ICI outcomes through gut microbiome changes leading to poorer overall survival; however, less is known about the potential impact of ATB exposure on toxicities from ICI. We undertook a population-based retrospective cohort study in patients receiving ICIs to evaluate the impact of ATB exposure on early acute care use, defined as emergency department visit or hospitalization, within 30 days of initiation of ICI therapy. Methods: Administrative data was utilized to identify a cohort of cancer patients &gt; 65 years of age receiving ICIs from June 2012 to October 2018 in Ontario, Canada. We linked databases deterministically to obtain socio-demographic and clinical co-variates, ATB prescription claims and acute care utilization. Patients were censored if they died within 30 days of initiating ICI therapy. The impact of ATB exposure within 60 days prior to starting ICI on early acute care use was evaluated using multi-variable logistic regression models, adjusted for age, gender, rurality, recent hospitalization within 60 days prior to starting ICI and comorbidity score. Results: Among 2737 patients (median age 73 years), 43% received Nivolumab, 41% Pembrolizumab and 13% Ipilimumab, most commonly for lung cancer (53%) or melanoma (34%). Of these patients, 19% had ATB within 60 days prior to ICI with a median ATB treatment duration of 9 days (SD = 13). 647 (25%) patients had an acute care episode within 30 days of starting ICIs; 182 (7%) patients passed away within 30 days without acute care use and were censored from further analyses. Any ATB exposure within 60 days prior to ICI was associated with greater likelihood of acute care use (aOR = 1.34 95% CI [1.07-1.67] p = 0.01). A dose effect was seen based on weeks of ATB exposure within 60 days prior to ICI (aOR = 1.12 per week [1.04-1.21] p = 0.004) and early acute care use. ATB class analysis identified that exposure to penicillins (aOR = 1.54 [1.11-2.15] p = 0.01) and fluoroquinolones (aOR = 1.55 [1.11-2.17] p = 0.01) within 60 days of starting ICIs were associated with a greater likelihood of acute care use, while there was no significant association between cephalosporin exposure and early acute care use (p &gt; 0.05). Conclusions: Exposure to ATBs, specifically fluoroquinolones and penicillins, prior to ICI therapy is associated with greater likelihood of hospitalization or emergency room visits within 30 days after initiation of ICIs, even after adjustment for relevant co-variates including age, comorbidity score and recent hospitalization prior to ICI initiation. Further studies are required to better understand the mechanisms of recent ATB exposure on early acute care use among patients receiving ICIs.

Long-term survival outcomes with immune checkpoint inhibitors (ICI) in metastatic uveal melanoma (MUM).

e21585 Background: The treatment of MUM remains highly unsatisfactory. Single agent ICI produce low response rates. Two recent phase II trials of combination Ipilimumab and Nivolumab yielded response rates of 12% and 18%. We report the long-term survival results of MUM patients (pts) treated with ICI in our institution. Methods: We conducted a retrospective analysis of all pts with a diagnosis of MUM in St Vincent’s University Hospital. Overall survival (OS) was calculated from time of first systemic relapse to death or latest follow-up. One-way ANOVA is used with p &lt; 0.05 considered statistically significant. Results: Out of 244 pts with UM registered in our clinics between April 2008 to October 2020, 52 developed MUM. Median age at initial diagnosis 63 years. 26(50%) are females. Median duration of follow-up of the MUM pts is 35.1 months [2.71-123.2]. Median duration of follow-up from initiation of ICI therapy is 9.1 months [1.6-84.2]. First sites of metastases: liver only 71%, liver plus extrahepatic 17%, and extrahepatic only 12%. Fifteen pts (29%) underwent radical metastasectomy as initial treatment. Thirty-seven (71%) had non-resectable MUM and received systemic treatment (23 total: ICI = 18, chemotherapy = 4, BRAF inhibitors = 1), non-surgical locoregional therapies (5 total: chemosaturation = 3, radiofrequency ablation = 2) or supportive/palliative care (9) as first-line. An additional 22 pts received ICI as second or subsequent treatment, for a total of 40 treated with ICI. Of these, 17 received single agents ICI (Ipilimumab = 11, Pembrolizumab = 6), 13 received sequential Ipilimumab and anti-PD1, and 10 received combination Ipilimumab /Nivolumab. At the time of analysis on 31st October 2020, 9 out of 52 pts (17%) are alive at 2.6, 5.0,5.4,8.9,17.3, 54.7, 77.5, 83.1 and 121.7 months (the 6 longest all had ICI). The median OS is 14.3 months [0.6-121.7]. Pts treated with ICI demonstrated longer OS than pts who did not receive ICI [15.0 months, 5.0-121.7 vs 7.2 months, 0.6-34.6; p = 0.089]. The median OS is 24.9 months (sequential Ipilimumab and anti-PD1) vs 15.0 months (combination Ipilimumab/Nivolumab) vs 13.4 months (single agents). Of the three pts remain alive &gt; 5 years, one is currently disease-free. Conclusions: Prolonged survival beyond five years is achieved by a minority of pts with MUM who receive ICI during their treatment history, although durable initial ICI-induced remission is very rare. Our data suggest that pts who receive two ICI drugs during their illness may have longer survival compared to those who receive only a single ICI.

Reconsidering Dexamethasone for Antiemesis when Combining Chemotherapy and Immunotherapy.

Whether the immune suppressive action of glucocorticoid steroids, such as dexamethasone, might reduce the benefits of cancer immunotherapy has long been a concern. Observations that established tumor regressions in response to immune checkpoint inhibitors (ICIs) often persist, despite the use of steroids to mitigate ICI-related autoimmune breakthrough, are not sufficiently reassuring, because these observations do not address the potential blunting of immune priming at the initiation of ICI therapy. With increasing indications for ICI in combination with chemotherapy, this issue merits reconsideration. Professional society guidance advises that dexamethasone should be used as first-line prophylaxis for nausea and vomiting in patients receiving ICI and highly emetogenic chemotherapy combination regimens. Here, we review the availability of data on this subject and propose an alternative approach focused on the adoption of steroid minimization or sparing for prophylaxis of nausea until the underlying immune biology is better understood.