Practice patterns and outcomes in cancer patients developing immune checkpoint inhibitors-related AKI.

Background The use of immune checkpoint inhibitors (ICI) has been associated with a 3-fold higher risk for cardiovascular events as compared to cancer patients who did not receive ICI. Therapies targeting vascular endothelial growth factor (VEGF) have also been associated with a wide range of cardiovascular events. The combination use of ICIs and VEGF inhibitors is currently approved as a treatment for patients with renal-cell carcinoma, hepatocellular carcinoma, non-small cell lung cancer, and endometrial cancer. Data are lacking whether the combination of ICIs and VEGF-targeted therapy is associated with an additional increase in cardiovascular events. Purpose To evaluate whether the combination use of ICI and VEGF targeted therapies are associated with a higher risk of cardiovascular events as compared to ICI therapy alone, we performed a retrospective matched case-control study. Methods Cases received both ICI and VEGF-targeted therapy (n=157), and control patients (n=157) only received ICI therapy. The primary outcome was a composite of cardiovascular events (myocardial infarction, coronary revascularization, ischemic stroke, deep venous thrombosis, and pulmonary embolism). Patients were censored at time of first event or at last date of follow up. Cox proportional hazard regression analysis was performed to calculate hazard ratio (HR) with 95% confidence interval (CI), counting only the first cardiovascular event. Results Baseline characteristics for the cases and controls are shown in Table 1. Overall cases (combination ICI and VEGF inhibitor) and controls (ICI alone) were not different with respect to age, type of cancer, and a prior history of any cardiovascular event. Cases received more ICI cycles as compared to controls (median of 7 [4–17] cycles vs. 4 [2–10] cycles, P<0.001). Cases also had a longer follow-up time (334 [127–663] days vs. 201 [60–564] days, P=0.008) as compared to the control group. As compared to ICI alone, a similar risk for a composite cardiovascular event was observed in those who received both ICI and VEGF-targeted therapy (HR, 0.70 [95% CI, 0.39–1.25]; P=0.23, Table 1). In total, 21/157 patients had a composite cardiovascular event among the cases, who received the combination of ICI and VEGF inhibitor (9 DVT, one MI, 9 PE, two ischemic strokes) as compared to 25/157 among the controls, who received ICI alone (14 DVT, 3 MI, 7 PE, one ischemic stroke). The median time to event was not different between the two groups (126 [98–260] days vs. 145 [28–205] days, P=0.47). Conclusion We found that among 157 patients who received a combination of ICI and VEGF-targeted therapy and 157 matched control patients who only received ICI therapy, the risk for cardiovascular events was not different between the two groups. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding.

Introduction: Awareness of cardiac toxicity with immune checkpoint inhibitor (ICI) therapy is increasing with emerging data on the manifestations and diagnosis of cardiotoxicity. However, risk stratification of these patients remains undefined. Hypothesis: We examined associations of traditional cardiovascular risk factors with ICI cardiotoxicity and patterns of cardiac evaluation prior to and during ICI therapy within a quaternary integrated health network. Methods: We reviewed patients on ICIs for atherosclerotic cardiovascular disease (ASCVD) risk factors, cardiology office visits, patterns of screening for cardiac disease (ECG, echocardiogram, cardiac biomarkers), and correlated with the incident of cardiac adverse events. Results: We studied 344 patients receiving ICIs for lung cancer (50%), melanoma (15%), and other malignancies (34%). Smoking (75%), hypertension (71%), and hyperlipidemia (49%) were the most common ASCVD risk factors. Pre-ICI initiation cardiac evaluation included ECG in 60%, TTE in 37%, and 63% of patients had at least one ECG or TTE while on ICIs. Less than 20% were seen by Cardiology before ICI therapy, despite 81% having ≥2 ASCVD risk factors. Cardiac toxicity with ICIs was observed in 12% of patients and was significantly more common in those with more ASCVD risk factors (4.6% vs 9.7% vs 16.4% with 0-1 vs 2-3 vs ≥4 ASCVD risk factors, respectively; P= 0.03) and in patients with atrial fibrillation (AFib) before ICI initiation (26.5% vs 8.5% without AFib; P=0.0008). ICIs were discontinued in 87 patients, of which 15% were due to cardiac toxicity. Conclusions: The incidence of cardiac toxicity is high, especially in patients with multiple ASCVD risk factors or AFib, and is often the reason for ICI discontinuation, warranting close surveillance prior to and during therapy. Cardiac evaluation and monitoring for cardiotoxicity were infrequent in patients receiving ICI therapy, despite the high prevalence of ASCVD in this population.

Norway has one of the highest rates of cutaneous melanoma (CM) incidence and mortality globally. Immune checkpoint inhibitor (ICI) therapy for CM was introduced between 2014 and 2017 to improve treatment and patient prognosis, but knowledge about its clinical usage is limited. This study investigates patient's characteristics and treatment patterns in real-world practice compared to clinical trial results. All adult (≥18) CM patients treated with ICI therapy in Norway from 2014 to 2021 were included, utilizing high-coverage data from multiple national registries to describe patients' health, socioeconomic factors, and treatment management, stratified by first ICI therapy. We compared patient and tumour characteristics with findings from five randomized controlled trials (RCTs). Among 2,083 patients receiving ICI therapy, 975 (47%) received nivolumab as their first treatment in the metastatic setting. Patients on combination therapy were younger and had higher education and income levels compared to those on monotherapy. Overall, real-world patients were older and had a higher incidence of brain metastases than those in RCTs. Approximately, 1 in 5 patients would have been excluded from RCTs due to pre-existing autoimmune diseases. Targeted therapy was the most common secondary systemic treatment after first-line PD-1 inhibitors. This study details ICI therapy in Norway, highlighting differences between real-world ICI users and clinical trial participants, raising questions about the effectiveness of this treatment for patients not eligible for trials.

As indications for immune checkpoint inhibitor (ICI) therapy have increased in recent years, so has the proportion of patients eligible for this type of therapy. However, a lack of data exists about the risks and benefits of ICI therapy in hospitalized patients, who tend to be frailer and sicker than patients enrolled in clinical trials. We conducted a retrospective cohort study among hospitalized patients with metastatic solid tumors who received ICI therapy at a large academic cancer center over the course of 4 years. We analyzed the characteristics and outcomes of these patients and identified demographic and clinical factors that could be used to predict mortality. During the 4-year study period, 106 patients were treated with ICI therapy while admitted to the hospital; 70 (66%) had Eastern Cooperative Oncology Group Performance Status ≥2, which would have prevented them from enrolling in most clinical trials of ICIs. Fifty-two patients (49%) died either during admission or within 30 days of discharge; median overall survival was 1.0 month from discharge, and 16 patients (15%) were alive 6 months after discharge. Independent predictors of death following receipt of inpatient ICI included a diagnosis of non-small cell lung cancer relative to melanoma and prior treatment with two or more lines of therapy. The poor overall outcomes observed in this study may give clinicians pause when considering ICI therapy for hospitalized patients, particularly those with characteristics that are associated with a greater risk of mortality. Immunotherapy strategies for patients with cancer are rapidly evolving and their use is expanding, but not all patients will develop a response, and secondary toxicity can be significant and challenging. This is especially evident in hospitalized patients, where the economic cost derived from inpatient immune checkpoint inhibitor (ICI) administration is important and the clinical benefit is sometimes unclear. The poor overall outcomes evidenced in the ICI inpatient population in this study highlight the need to better identify the patients that will respond to these therapies, which will also help to decrease the financial burden imposed by these highly priced therapies.

Immune Checkpoint Inhibitor (ICI) therapy is the most exciting development in cancer treatments in recent years. As of the end of 2021, more than a hundred of clinical trials have been carried out by several major drug makers and research hospitals all over the world just to explore the use of ICI antibodies in almost every type of cancer and under various clinical settings. These clinical trials have resulted waves of good news in every year’s major academic conferences and FDA approvals, and now ICI therapy is in the move to take over traditional therapy to become the major player in clinical management of cancer. On the other hand, most of these clinical trials have failed to show clear benefits in most cancer patients, and only few have been reported in public. In real-world clinical setting, ICI antibodies are being massively and sometimes abusively prescribed for almost every desperate situation with clear clinical benefit in only a few (<10%). Yet, the enthusiasm behind ICI therapy is not dampened by the massive clinical failure but has been growing. The reason for the consistent enthusiasm among clinicians and patients is the miracle-like clinical responses seen in some of the responders that even including late-stage hopeless cases. Every clinician wants to repeat this miracle in the next seemingly identical patient, and every patient and their family members want to believe that they are in line for that miracle. But the reality is disheartening in that clinicians do not see the predictable repeat of miracle-like responses in seemingly identical patients and most patients selecting ICI therapy as the last straw in life did not benefit from it, if not hurt by it. What then are the reasons that ICI therapy is so impressive when working and so unpredictable in responses? This review attempts to draw some mechanistic aspects based on our own experiences in ICI therapy and to come up with a different explanation for the unexplained clinical observations. The goal of this review is to alert the clinical field about the danger and irreversible damages that wrongly used ICI antibodies may cause, and at the same time to introduce some preliminary criteria to select proper patient for the benefits and to avoid the harms of ICI therapy.

IntroductionImmune checkpoint inhibitors (ICIs) are used across many solid tumor malignancies. The mechanism varies depending on the agent but ultimately leads to immune system activation by targeting key regulators of immune tolerance. Toxicities occur due to persistent activation of the immune system that can manifest in nearly all organs, including endocrinopathies. Although recognition has improved, the incidence of endocrinopathies should be evaluated in the real-world setting. The primary objective was to evaluate the incidence of select endocrine toxicities secondary to curative-intent ICI therapy in patients with solid tumor malignancies.MethodsThis was an observational, retrospective, single-center, cohort study of patients with solid tumor malignancies who received ICIs for curative intent at our institution. Patients had to be ≥ 18 years old and received ICI therapy between May 1, 2022 and March 30, 2023.ResultsFive hundred ten patients were included. Majority of patients received pembrolizumab or nivolumab, and the most common malignancies were breast (28%), melanoma (24%), and non-small cell lung cancer (16%). Twenty-five patients (4.9%) developed an endocrine toxicity with a median onset of 103 days. Hypothyroidism was the most common endocrine toxicity (52%). Nearly all endocrine toxicities were of Grade 2 severity (92%) with no Grade ≥ 4 events.ConclusionWe observed an incidence of endocrine toxicities of 4.9% with a median onset of 103 days in patients with solid tumor malignancies receiving curative intent ICI therapy. Generalizability of these results may be impacted by the exclusion of documented stage IV disease and palliative intent treatment.

4559 Background: Glucagon-like peptide-1 (GLP-1) receptor agonists have played a pivotal role in the management of type 2 diabetes (T2DM). At the same time, immune checkpoint inhibitor (ICI) therapy remains one of the mainstay treatments for metastatic renal cell carcinoma (mRCC). There has been a scarcity of research on the effect of GLP-1 receptor agonists on ICI efficacy in cancer patients. This study presents the first real-world analysis of the effect of GLP-1 receptor agonists on outcomes in mRCC patients receiving ICI therapy. Methods: Data was retrospectively collected from TriNetX, a national electronic health record database with 120 million US patients from over 70 healthcare organizations, from 2012-2024. We included patients ≥ 18 years old with T2DM and mRCC who underwent ICI therapy. Patients were then stratified into two cohorts: on GLP-1 receptor agonists prior to ICI therapy and not on GLP-1 receptor agonists. Patients in each cohort were then 1:1 propensity score matched (PSM) based on age, sex, race, type of ICI therapy used, comorbidities, other diabetic medications and staging. 1 year outcomes for mortality, major adverse cardiovascular events (MACE) and various immune‐related adverse events (irAEs) were reported. Results: A total of 2378 patients were identified who met the inclusion criteria. 535 (22%) were in the GLP-1 receptor agonist cohort compared to 2378 (68%) in the non GLP-1 receptor agonist cohort. After 1:1 PSM, 497 patients were in each group. Among both cohorts, 66% were male, 77% white and the average age was about 65 years old. After conducting Cox proportional hazard analyses, GLP-1 receptor agonist use was associated with lower mortality (HR, 0.49 [95% CI: 0.37-0.64]). Moreover, GLP-1 receptor agonist use had lower rates of irAEs, including pneumonitis (HR, 0.61 [95% CI: 0.43-0.85]), hematological complications (HR, 0.78 [95% CI: 0.64-0.95]) and renal complications (HR, 0.67 [95% CI: 0.54-0.84]). There was no significant difference in MACE or other irAEs between the two cohorts. Conclusions: Analysis of one of the largest US based databases showed that the use of GLP-1 receptor agonist in T2DM patients with mRCC undergoing ICI therapy, is associated with better overall survival and lower irAES such as pneumonitis, hematological and renal complications. There was no significant difference in MACE. To our knowledge, this is the first study to identify the impact of GLP-1 receptor agonists on the outcomes of mRCC patients undergoing ICI therapy. Further prospective studies are needed to validate these findings and to identify the underlying mechanisms.

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

BackgroundFew treatment options are available for brain metastases (BMs) in EGFR-mutant non-small cell lung cancer (NSCLC) that progress with prior EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. This study aimed to evaluate the efficacy of immune checkpoint inhibitor (ICI) therapy in these patients.MethodsNSCLC patients with confirmed sensitive EGFR mutations and BMs were retrospectively reviewed. All patients experienced failure of EGFR-TKI therapy and were divided into two cohorts based on subsequent treatment. Cohort 1 included patients who received ICI therapy, while cohort 2 included patients treated with chemotherapy. Overall and intracranial objective response rates (ORRs) were used to evaluate the treatment response. Overall and intacranial progression-free survival (PFS) were calculated by Kaplan−Meier analysis and compared with the log-rank test. Univariate and multivariate Cox analyses were used to identify prognostic factors.ResultsA total of 53 patients treated with ICI therapy and 40 patients treated with chemotherapy were included in cohorts 1 and 2, respectively. In cohort 1, the overall ORR was 20.8%, with a median overall PFS of 4.2 months. The median intracranial PFS was 5.1 months. Of the 38 patients with measurable intracranial lesions, the intracranial ORR was 21.0%. Patients who received ICI combined with chemotherapy had the highest intracranial ORR of 37.5%. Compared to patients treated with chemotherapy in cohort 2, patients receiving ICI combined with chemotherapy had both longer intracranial PFS (6.4 vs. 5.1 months, p = 0.110) and overall PFS (6.2 vs. 4.6 months, p = 0.054), and these differences approached statistical significance. Univariate and multivariate Cox analyses demonstrated that high disease burden (p = 0.019), prior third-generation EGFR-TKI therapy (p = 0.019), and a poor lung immune prognostic index (LIPI) (p = 0.012) were independent negative predicators of overall PFS and that multiple BMs were negatively correlated with intracranial PFS among patients treated with ICI therapy.ConclusionsOur results suggested that ICI combined with chemotherapy had potent intracranial efficacy and may be a promising treatment candidate in EGFR-mutant NSCLC patients with BMs for whom prior EGFR-TKI therapy failed.

Immune-Related Hematologic Adverse Events in the Context of Checkpoint Inhibitors

This study investigates the predictive potential of circulating cytokines for response and survival outcomes in patients with advanced non-small cell lung cancer (NSCLC) undergoing immune checkpoint inhibitor (ICI) therapy. A cohort of 64 patients with advanced NSCLC receiving ICI therapy were included. Baseline serum samples were collected prior to ICI initiation and profiled using a multiplex cytokine panel. Logistic regression, Cox regression, and Kaplan-Meier survival analysis were employed to assess associations between cytokine levels, therapeutic response, progression-free survival (PFS), and overall survival (OS). Gene expression levels of key cytokines were validated in peripheral blood mononuclear cells (PBMCs) of 17 patients (Responders = 7, Non-Responders = 10) and 3 Healthy Controls using quantitative real-time PCR. Elevated baseline levels of IL-2, IL-23, and sPD-L1 were significantly associated with clinical response to ICI therapy. Among these, sPD-L1 emerged as an independent predictor of response (AUC = 0.87). Multivariate Cox regression showed IL-2 (HR = 0.67), sPD-L1 (HR = 0.15), and IL-23 (HR = 1.18) were significantly associated with PFS and also predictive of OS. Notably, combined profiling of IL-2 and sPD-L1 enhanced predictive power (AUC = 0.95 for both PFS and OS). RT-PCR analysis of PBMCs corroborated these findings, confirming upregulation of IL-2 in responders and elevated IL-23 expression in non-responders. Baseline cytokine profiling particularly of IL-2, sPD-L1, and IL-23 provides important prognostic and predictive information in advanced NSCLC patients undergoing ICI therapy. These biomarkers may facilitate more personalized approaches to immunotherapy and guide clinical decision-making.

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

BackgroundThe use of probiotic supplementation by cancer patients is increasing, including amongst those undergoing immune checkpoint inhibitor (ICI) therapy. While probiotic supplementation has been identified as an important factor influencing...

In the United States, there are disparities in access to care for patients with non-small cell lung cancer (NSCLC) on the basis of socioeconomic and racial/ethnic factors. This study investigates the association between race/ethnicity and the utilization of immune checkpoint inhibitor (ICI) therapy among older patients with advanced NSCLC (aNSCLC). This retrospective study used data from the SEER-Medicare-linked database. The cohort included patients (age 66 years or older) diagnosed with aNSCLC (stage III/IV) between March 2015 and December 2017, and they were followed through December 2019. Race/ethnicity was categorized as non-Hispanic (NH)-White, NH-Black, Hispanic, and Other. ICI therapy utilization was determined by identifying any usage of ICI agents (nivolumab, pembrolizumab, atezolizumab, durvalumab, ipilimumab, and cemiplimab-rwlc) from the Medicare database. Multivariable logistic regression models assessed the association between race/ethnicity and ICI therapy utilization (yes, no). Effect measure modification analyses were conducted by sex, socioeconomic status, and comorbidity. The final sample included 26,836 patients; 76.2% were NH-White, 10.1% NH-Black, 5.7% Hispanic, and 8.0% Other. The overall ICI therapy utilization proportion was 17.8%, varying across ethnicities: NH-Black 14.1%, Hispanic 16.3%, NH-White 18.4%, and Other 18.5%. In comparison with NH-White patients, NH-Black patients were 15% less likely to receive ICI therapy (adjusted odds ratio, 0.85 [95% CI, 0.75 to 0.96]). Furthermore, the association between race/ethnicity and utilization of ICI therapy was modified by comorbidity status, sex, and socioeconomic status. NH-Black patients with aNSCLC were less likely to receive ICI therapy than their NH-White counterparts. Our findings indicate the racial/ethnic disparities in ICI therapy utilization and call for further interventions to optimize access to care.

While acute kidney injury (AKI) is commonly reported following hematopoietic stem cell transplant (HCT), the incidence and impact of AKI on mortality among patients undergoing HCT are not well described. We conducted this systematic review to assess the incidence and impact of AKI on mortality risk among patients undergoing HCT. Ovid MEDLINE, EMBASE and the Cochrane Databases were searched from database inceptions through August 2019 to identify studies assessing the incidence of AKI and mortality risk among adult patients who developed AKI following HCT. Random-effects and generic inverse variance method of DerSimonian-Laird were used to combine the effect estimates obtained from individual studies. We included 36 cohort studies with a total of 5144 patients undergoing HCT. Overall, the pooled estimated incidence of AKI and severe AKI (AKI Stage III) were 55.1% (95% confidence interval (CI) 46.6-63.3%) and 8.3% (95% CI 6.0-11.4%), respectively. The pooled estimated incidence of AKI using contemporary AKI definitions (RIFLE, AKIN and KDIGO criteria) was 49.8% (95% CI 41.6-58.1%). There was no significant correlation between study year and the incidence of AKI (P = 0.12) or severe AKI (P = 0.97). The pooled odds ratios of 3-month mortality and 3-year mortality among patients undergoing HCT with AKI were 3.05 (95% CI 2.07-4.49) and 2.23 (95% CI 1.06-4.73), respectively. The incidence of AKI among patients who undergo HCT remains high, and it has not changed over the years despite advances in medicine. AKI after HCT is associated with increased short- and long-term mortality.