Toxicity Of Immune Checkpoint Inhibitors Research Articles

Managing toxicities of immune checkpoint inhibitors

Managing toxicities of immune checkpoint inhibitors

#2136 Hyponatremia as a presenting symptom of secondary adrenal insufficiency induced by immune checkpoint inhibitors

Abstract Background and Aims Endocrinopathies are common complication of treatment with immune checkpoint inhibitors (ICI). Adrenal axis may be affected through either direct adrenal toxicity leading to primary hypoadrenalism or due to pituitary dysfunction resulting in secondary adrenal insufficiency. Patients with secondary insufficiency may have variable presentation and, in some cases, initially present with hyponatremia only. This abstract reports a cohort of patients who developed hyponatremia as initial symptom of secondary adrenal insufficiency. Method After obtaining approval from the institutional review board, medical records of the nephrology service at a large cancer center were reviewed. Patient is well included in the study if they developed moderate (plasma Na <130 mEq/L) and severe (plasma Na <120 mEq/L) hyponatremia during treatment with ICI and met a biochemical criterion for adrenal insufficiency (morning serum cortisol level <3.0 mcg/dL). Results Nine patients who met the criteria were identified (Table 1). There were 5 males and four females. Mean age was 67.6 year. Median number of ICI therapy cycles was 10 but treatment number ranged from 2-84. For patient's would treat with combination of CTLA-4 and PD 1 inhibitors and 5 patients were treated with PD 1 inhibitor alone. Four patients had severe hyponatremia and five presented with moderate hyponatremia. All patients were normotensive on presentation. All patients had low morning cortisol level but only two patients had low ACTH level. All patients had low normal ACTH levels. One patient underwent ACTH stimulation test which was negative. Additionally for patient has had normal thyroid function. Eight patients underwent an MRI and 4 of them had evidence of possible pituitary inflammation. All patients were started on physiologic corticosteroid replacement with prompt resolution of hyponatremia. All patients required ongoing corticosteroid replacement therapy. Conclusion Secondary adrenal insufficiency in the setting of ICI toxicity can present with initial diagnosis of hyponatremia. Patients in this cohort were normotensive on presentation despite adrenal insufficiency and therefore required high index of suspicion for the diagnosis. Most patients in the study also had low normal ACTH levels however responded clinically to treatment with corticosteroid replacement indicating that adrenal sufficiency was the cause of hyponatremia. ACTH test may be falsely negative in these patients if adrenal insufficiency developed less than six weeks prior and adrenal atrophy did not occur yet.

Follow-up biopsies in gastrointestinal immune checkpoint inhibitor toxicity may show markedly different inflammatory patterns than initial injury

Colitis is a common manifestation of immune checkpoint inhibitor (ICI) toxicity and can present with varied histologic patterns of inflammation, some of which have been shown to be associated with specific ICI drug types. Although the histologic features of ICI colitis seen at the time of diagnosis have been described, there have been few reports following these patients over time. We evaluated initial and follow-up biopsies in 30 patients with ICI colitis and found that 37% of patients developed a different pattern of injury on follow-up biopsy compared to the initial biopsy. Patients with a different inflammatory pattern were more likely to have restarted ICI therapy before their follow-up biopsy (64%) compared to those without a change in inflammatory pattern (11%; P < 0.01). The majority of these patients had changed ICI drug types (86%). Additionally, many cases changed to an inflammatory bowel disease (IBD)-like pattern (36%), raising a question of de novo IBD. However, all of our patients with an IBD-like pattern experienced sustained resolution of symptoms without steroids or other immunosuppressive medications following discontinuation of ICI therapy, consistent with a diagnosis of ICI toxicity. Our findings suggest that follow-up biopsies in patients with ICI colitis may show a different histology and that this does not necessarily warrant a change in the histologic diagnosis to another disease.

Pediatric thyroid side effects of immune checkpoint inhibitors

Immune checkpoint inhibitors (ICIs) are associated with multiple endocrine side effects, including thyroid disfunctions. In addition, the efficacy and safety profiles of ICIs in the pediatric population need clarification. Here, we discuss the main evidence regarding the efficacy and thyroid toxicities of ICIs in children.

Highly variable timing renders immunotherapy efficacy and toxicity impractical biomarkers of one another in clinical practice.

A useful clinical biomarker requires not only association but also a consistent temporal relationship. For instance, chemotherapy-induced neutropenia and epidermal growth-factor inhibitor-related acneiform rash both occur within weeks of treatment initiation, thereby providing information prior to efficacy assessment. Although immune checkpoint inhibitor (ICI)-associated immune-related adverse events (irAE) have been associated with therapeutic benefit, irAE may have delayed and highly variable onset. To determine whether ICI efficacy and irAE could serve as clinically useful biomarkers for predicting each other, we determined the temporal relationship between initial efficacy assessment and irAE onset in a diverse population treated with ICI. Using two-sided Fisher exact and Cochran-Armitage tests, we determined the relative timing of initial efficacy assessment and irAE occurrence in a cohort of 155 ICI-treated patients (median age 68 years, 40% women). Initial efficacy assessment was performed a median of 50 days [interquartile range (IQR) 39-59 days] after ICI initiation; median time to any irAE was 77 days (IQR 28-145 days) after ICI initiation. Median time to first irAE was 42 days (IQR 20-88 days). Overall, 58% of any irAE and 47% of first irAE occurred after initial efficacy assessment. For clinically significant (grade ≥2) irAE, 60% of any and 53% of first occurred after initial efficacy assessment. The likelihood of any future irAE did not differ according to response (45% for complete or partial response vs. 47% for other cases; P=1). In landmark analyses controlling for clinical and toxicity follow-up, patients demonstrating greater tumor shrinkage at initial efficacy assessment were more likely to develop future grade ≥2 (P=0.05) and multi-organ (P=0.02) irAE. In contrast to that seen with chemotherapy and molecularly targeted therapies, the temporal relationship between ICI efficacy and toxicity is complex and bidirectional. In practice, neither parameter can be routinely relied on as a clinical biomarker to predict the other.

Review article: Contemporary management of gastrointestinal, pancreatic and hepatic toxicities of immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) are effective oncologic agents which frequently cause immune-related adverse events (irAEs) which can impact multiple organ systems. Onco-Gastroenterology is a novel and emerging subspecialty within gastroenterology focused on cancer treatment-related complications. Gastroenterologists must be prepared to identify and manage diverse immune-mediated toxicities including enterocolitis, hepatitis, pancreatitis and other ICI-induced toxicities. To provide a narrative review of the epidemiology, diagnostic evaluation and management of checkpoint inhibitor-induced gastrointestinal and hepatic toxicities. We searched Cochrane and PubMed databases for articles published through August 2023. Gastrointestinal and hepatic irAEs include most commonly enterocolitis and hepatitis, but also pancreatitis, oesophagitis, gastritis, motility disorders (gastroparesis) and other rarer toxicities. Guidelines from the National Comprehensive Cancer Network, American Society of Clinical Oncology and European Society for Medical Oncology, in combination with emerging cohort and clinical trial data, offer strategies for management of ICI toxicities. Evaluation of irAEs severity by formal classification and clinical stability, and a thorough workup for alternative etiologies which may clinically mimic irAEs underlie initial management. Treatments include corticosteroids, biologics and other immunosuppressive agents plus supportive care; decisions on dosing, timing and choice of steroid adjuncts and potential for subsequent checkpoint inhibitor dosing are nuanced and toxicity-specific. Expanding clinical trial and cohort data have clarified the epidemiology and clinical characteristics of gastrointestinal, pancreatic and hepatic toxicities of ICIs. Guidelines, though valuable, remain based principally on retrospective cohort data. Quality prospective, controlled studies may refine algorithms for treatment and potential immunotherapy rechallenge.

Effect of longitudinal changes of cachexia on the efficacy and toxicity of immune checkpoint inhibitors in esophageal squamous cell cancer (ESCC) patients

PurposeImmune checkpoint inhibitors (ICIs) have enhanced survival in advanced esophageal squamous cell cancer (ESCC) patients, but their efficacy varies. Cachexia, characterized by muscle loss and significant weight loss, might influence ICI response. This study examines the relationship between cachexia's longitudinal changes and ICI outcomes in ESCC patients. MethodsESCC patients undergoing at least two ICI cycles from 2017 to 2021 were studied. Cachexia's baseline and evolving patterns during ICI treatment were observed. Kaplan-Meier and Cox regression analyses were used to assess cachexia's effect on ICI efficacy. Chi-square tests were used to determine cachexia's link to immune-related adverse effects (irAEs). ResultsTwo hundred seventy-eight ICI-treated patients had a median progression-free survival (PFS) of 5.78 months and overall survival (OS) of 8.3 months. Pretreatment cachexia led to worse outcomes: PFS 7.87 versus 5.3 months, time to progression (TTP) 10.9 versus 6.1 months, and OS 14.3 versus 9.2 months. Irreversible cachexia showed the poorest results. Cachexia's changes weren't associated with irAEs. ConclusionBaseline and evolving cachexia significantly impact ICI efficacy in ESCC patients. Continuous cachexia monitoring during ICI therapy is crucial for optimal ESCC management.

Prediction of Effectiveness and Toxicities of Immune Checkpoint Inhibitors Using Real-World Patient Data.

Although immune checkpoint inhibitors (ICIs) have improved outcomes in certain patients with cancer, they can also cause life-threatening immunotoxicities. Predicting immunotoxicity risks alongside response could provide a personalized risk-benefit profile, inform therapeutic decision making, and improve clinical trial cohort selection. We aimed to build a machine learning (ML) framework using routine electronic health record (EHR) data to predict hepatitis, colitis, pneumonitis, and 1-year overall survival. Real-world EHR data of more than 2,200 patients treated with ICI through December 31, 2018, were used to develop predictive models. Using a prediction time point of ICI initiation, a 1-year prediction time window was applied to create binary labels for the four outcomes for each patient. Feature engineering involved aggregating laboratory measurements over appropriate time windows (60-365 days). Patients were randomly partitioned into training (80%) and test (20%) sets. Random forest classifiers were developed using a rigorous model development framework. The patient cohort had a median age of 63 years and was 61.8% male. Patients predominantly had melanoma (37.8%), lung cancer (27.3%), or genitourinary cancer (16.4%). They were treated with PD-1 (60.4%), PD-L1 (9.0%), and CTLA-4 (19.7%) ICIs. Our models demonstrate reasonably strong performance, with AUCs of 0.739, 0.729, 0.755, and 0.752 for the pneumonitis, hepatitis, colitis, and 1-year overall survival models, respectively. Each model relies on an outcome-specific feature set, though some features are shared among models. To our knowledge, this is the first ML solution that assesses individual ICI risk-benefit profiles based predominantly on routine structured EHR data. As such, use of our ML solution will not require additional data collection or documentation in the clinic.

Immune checkpoint inhibitor-related colitis in patients on immunotherapy for cancer.

Immune checkpoint inhibitors, a revolutionary class of cancer immunotherapy drugs, have transformed cancer treatment by bolstering antitumor immunity for various advanced-stage solid cancers. The US Food and Drug Administration has approved 7 immune checkpoint inhibitors that target 3 major immune checkpoint proteins: cytotoxic T-lymphocyte-associated protein 4, programmed cell death 1 protein, and programmed cell death 1 ligand 1. In addition to their remarkable efficacy, however, these inhibitors have been observed causing immune-related adverse events, particularly immune checkpoint inhibitor-related colitis, which often results in severe or life-threatening clinical issues. The diagnosis of immune checkpoint inhibitor-related colitis relies on incorporation of clinical evaluation as well as endoscopic and histopathologic examination, with exclusion of other potential etiologies. The common histopathologic manifestations of immune checkpoint inhibitor-related colitis are acute active colitis, chronic active colitis, microscopic colitis (collagenous or lymphocytic), and ischemic colitis, with patterns overlapping. Notably, enterocyte apoptosis is a unique feature of immune checkpoint inhibitor toxicity. The proposed mechanisms for the pathogenesis of immune checkpoint inhibitor-related colitis are primarily associated with autoimmune-type dysregulation and gut microbiome alteration. This review summarizes the clinical and pathologic characteristics of immune checkpoint inhibitor-related colitis and elucidates its underlying pathogenic mechanisms. Future successful management of this form of colitis relies on our comprehension of the intricate interplay between tumoral and systemic immune responses to immune checkpoint inhibitors and innovative approaches to modify these responses, along with specific immune cell populations, to preclude immune-related adverse events while achieving antitumor therapeutic outcomes.

Risk of cardiovascular toxicity with combination of immune-checkpoint inhibitors and angiogenesis inhibitors: a meta-analysis.

Combinations of immune checkpoint inhibitors (ICIs) and angiogenesis inhibitors (AIs) have been investigated for the treatment of several tumor types. Both ICIs and AIs may lead to cardiovascular adverse events, and their combination may potentially increase the risk for cardiovascular toxicity. In the present meta-analysis, we aim to assess the cardiovascular toxicity of ICIs plus AIs vs. AIs alone. Secondary objectives are non-cardiovascular adverse events and efficacy. Systematic review was performed according to PRISMA statement. Phase II and III randomized clinical trials were identified by searching the MEDLINE/PubMed, Cochrane Library and ASCO Meeting abstracts, from inception to June 2022. The pooled risks for overall response rate (ORR), 1-year progression-free survival (PFS), adverse events (AEs), immune-related AEs, (irAEs), hypertension, and vascular events defined as stroke, myocardial infarction and pulmonary embolisms, were calculated. In terms of cardiovascular toxicity, we found higher risk for severe hypertension among patients treated with ICIs plus AIs as compared with those receiving AIs (OR 1.24, 95% CI: 1.01-1.53), but no significant difference was found for any-grade hypertension, and for vascular events. There was also no difference in terms of overall AEs, whereas the incidence of irAEs was increased in the ICIs plus AIs arm, as expected. In terms of efficacy, ICIs plus AIs achieved better ORR (OR 2.25, 95% CI: 1.70-2.97) and PFS (HR 0.49, 95% CI: 0.39-0.63) as compared to AIs alone. The addition of ICIs to AIs significantly increased the risk of high-grade hypertension, but not that of acute vascular events.

Will it be possible to find predictive genetic markers of immune checkpoint inhibitor toxicity that are not also predictive of survival?

Will it be possible to find predictive genetic markers of immune checkpoint inhibitor toxicity that are not also predictive of survival?

Class II HLA-DRB4 is a predictive biomarker for survival following immunotherapy in metastatic non-small cell lung cancer

Immune checkpoint inhibitors (ICI) are important treatment options for metastatic non-small cell lung cancer (mNSCLC). However, not all patients benefit from ICIs and can experience immune-related adverse events (irAEs). Limited understanding exists for germline determinants of ICI efficacy and toxicity, but Human Leukocyte Antigen (HLA) genes have emerged as a potential predictive biomarker. We performed HLA typing on 85 patients with mNSCLC, on ICI therapy and analyzed the impact of HLA Class II genotype on progression free survival (PFS), overall survival (OS), and irAEs. Most patients received pembrolizumab (83.5%). HLA-DRB4 genotype was seen in 34/85 (40%) and its presence correlated with improved OS in both univariate (p = 0.022; 26.3 months vs 10.2 months) and multivariate analysis (p = 0.011, HR 0.49, 95% CI [0.29, 0.85]). PFS did not reach significance (univariate, p = 0.12, 8.2 months vs 5.1 months). Eleven patients developed endocrine irAEs. HLA-DRB4 was the predominant genotype among these patients (9/11, 81.8%). Cumulative incidence of endocrine irAEs was higher in patients with HLA-DRB4 (p = 0.0139). Our study is the first to suggest that patients with metastatic NSCLC patients on ICI therapy with HLA-DRB4 genotype experience improved survival outcomes. Patients with HLA-DRB4 had the longest median OS (26.3 months). Additionally, we found a correlation between HLA-DRB4 and the occurrence of endocrine irAEs.

Endocrine toxicity of immune checkpoint inhibitors: a network meta-analysis of the current evidence

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but pose a challenge of immune-related adverse events (irAEs), particularly endocrine toxicity, that can severely compromise patient well-being. Existing research has often been limited in scope and has not provided comprehensive safety profiles across the diverse range of ICI therapies. We addressed this gap by performing a network meta-analysis on 55 randomized controlled trials involving 32,522 patients. Using STATA to calculate the surface under the cumulative ranking curve, we ranked the safety of various ICI monotherapies and combination therapies. ICIs were found to increase the risk of endocrine toxicities, such as hypothyroidism, hyperthyroidism, hypophysitis, thyroiditis, and adrenal insufficiency; this risk was greater with dual ICI regimens. Specifically, cytotoxic T lymphocyte associated antigen-4 (CTLA-4) inhibitors, such as ipilimumab, are closely associated with hypophysitis, whereas programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors, notably pembrolizumab and nivolumab, predispose patients to thyroid-related dysfunction, such as hyperthyroidism, hypothyroidism, and thyroiditis. Interestingly, nivolumab showed no elevated risk of adrenal dysfunction, in contrast to the elevated risk observed with other ICI treatments. This study provides critical evidence-based insights for optimizing the risk-benefit balance of ICI therapies in clinical practice.

An issue that should be considered is the potential toxicity of ICIs to the cardiovascular system

An important consideration is the potential cardiovascular toxicity of immune checkpoint inhibitors (ICIs) in cancer therapy, given their increasing popularity and revolutionizing effects on certain treatment regimens. However, ICIs also exhibit unavoidable side effects such as immune-related adverse events (irAEs), which are particularly significant due to their interaction with underlying diseases. This review aims to explore the reported cardiovascular toxicity in patients treated with ICIs, providing insights into potential mechanisms, monitoring methods, and management strategies for the rational use of these drugs. The awareness of ICIs' use is crucial for clinicians as these adverse immune events can interact with the patient's underlying disease. This review focuses on cardiovascular toxicity reported in patients after ICI usage, aiming to elaborate potential mechanisms, monitoring methods, and management strategies that may inspire rational clinical use of ICIs.

Hematological Toxicity of Immune Checkpoint Inhibitors: Real-World Retrospective Outcomes from a Cohort Study in Qatar

Introduction: The integration of immune checkpoint inhibitors (ICPIs) into cancer management has brought a paradigm shift in the outcome of cancer care. The incidence of hematological immune-related adverse events (Hem-irAEs) associated with ICIs is uncommon or exceedingly rare, particularly in comparison to chemotherapy (Johar, 2020). In this study, we provide an analysis of real-world experience with Hem-irAEs from the National Center of Cancer Care and Research (NCCCR) in Qatar. Methods: Patient electronic medical records (EMR) were retrospectively analyzed for all patients who received ICPIs between 2015 and 2020. Collected data included patient demographics, Hem-irAEs-related incidence, characterization, management, and outcomes of Hem-irAEs. Results Over the five-year review period, a total of 165 irAEs were experienced among the 256 patients who received ICPIs in Qatar. The incidence of Hem-irAEs was 15 events (9.1% of all irAEs) among 14 patients (5.5% of all patients). Baseline characteristics of patients experiencing Hem-irAEs are described in Table 1. Majority of patients were diagnosed with solid malignancies (n=11; 78.6%) and were pre-treated with either chemotherapy or targeted therapies (n=12; 86%). Baseline hematological functions were also acceptable in most patients as shown in Table 1. Nivolumab was the most used ICPI (n=8, 57%), followed by pembrolizumab (n=4, 29%), durvalumab (n=1, 7%) and avelumab (n=1, 7%). The most common Hem-irAE was thrombocytopenia (5/15); however, four of those events were worsening of baseline thrombocytopenia (Table 2). During this review period, two bleeding events have occurred; one was grade 1 gingival bleeding that spontaneously resolved, while the other event was grade 4 leading to severe anemia (hemoglobin 5.7 g/dL) requiring transfusion and ICPI discontinuation. Two grade 4 pancytopenia events were identified; one resolved with supportive transfusions and ICPI discontinuation, while the other resulted in fatal limbic encephalitis despite the use of intravenous immunoglobulins. There were no other fatal irAEs, but one more patient discontinued ICPI due to grade 3 anemia. Co-occurrence of non-HEM-irAEs were manifested in half of this population (n=7); majority of which were dermatitis (33.3%) and hepatitis (33.3%), followed by hypothyroidism (22.2%) and cardiac toxicity (11.2%). Conclusion Compared to the current literature describing Hem-irAEs, our center experience shows similar distribution of adverse events with thrombocytopenia and anemia. Thrombocytopenia was the most Hem-irAEs experienced followed by neutropenia and eosinophilia (1). On the other hand, our population is slightly different with the majority of cases described here being non-melanoma solid malignancies. Considering the rate of Hem-irAEs in the investigated population at NCCCR, there is a need for an integrated pathway for the diagnosis and management of these events.

Comparative severe dermatologic toxicities of immune checkpoint inhibitors in malignant melanoma: A systematic review and network meta-analysis.

Immune checkpoint inhibitors (ICIs) have advanced the therapeutic landscape for malignant melanoma patients. However, they can cause permanent and irreversible dermatologic immune-related adverse events (irAEs) that may lead to interruption of ICI treatment or become life-threatening. To assess the risk of severe dermatologic irAEs (grade 3 or higher) among ICIs for advanced melanoma, we conducted a network meta-analysis (NMA). Phase II/III randomized controlled clinical trials (RCTs) involving ICIs were retrieved from various databases, including PubMed, Embase, Cochrane Library, and Web of Science. These trials were published from the inception of databases to October 15, 2022. In addition, the risk of severe dermatologic irAEs associated with ICI types and doses was evaluated and compared by NMA. This study included 20 Phase II/III RCTs with a total of 10 575 patients. The results indicated that ICIs carry a higher risk of severe dermatologic irAEs compared to chemotherapy. Additionally, the combinational therapy of Nivolumab + Ipilimumab was associated with a higher risk than ICI monotherapy. Comparatively, the latest treatment option involving dual ICI therapy with Relatlimab + Nivolumab showed a lower toxicity risk, but higher than Ipilimumab alone. Lastly, Nivolumab, at a dose of 3 mg/kg every 2 weeks, was observed as the lowest-risk dosing regimen for severe dermatologic irAEs in patients with advanced melanoma. The findings suggest that Nivolumab (1 mg/kg) + Ipilimumab (3 mg/kg) administered every 3 weeks should be used cautiously in patients with advanced melanoma at high risk for dermatologic irAEs. While we recommend the preferred regimen of Nivolumab (dose = 3 mg/kg, every 2 weeks).

Gut microbial structural variation associates with immune checkpoint inhibitor response

The gut microbiota may have an effect on the therapeutic resistance and toxicity of immune checkpoint inhibitors (ICIs). However, the associations between the highly variable genomes of gut bacteria and the effectiveness of ICIs remain unclear, despite the fact that merely a few gene mutations between similar bacterial strains may cause significant phenotypic variations. Here, using datasets from the gut microbiome of 996 patients from seven clinical trials, we systematically identify microbial genomic structural variants (SVs) using SGV-Finder. The associations between SVs and response, progression-free survival, overall survival, and immune-related adverse events are systematically explored by metagenome-wide association analysis and replicated in different cohorts. Associated SVs are located in multiple species, including Akkermansia muciniphila, Dorea formicigenerans, and Bacteroides caccae. We find genes that encode enzymes that participate in glucose metabolism be harbored in these associated regions. This work uncovers a nascent layer of gut microbiome heterogeneity that is correlated with hosts’ prognosis following ICI treatment and represents an advance in our knowledge of the intricate relationships between microbiota and tumor immunotherapy.

Abstract 15756: To Close or Not to Close: A Case of Multisystem Immune Checkpoint Inhibitor Toxicity and PFO

Introduction: Recent emergence of immune checkpoint inhibitors (ICIs) in oncologic treatments has led to increasing research on their side effect profile. Myocarditis occurs in roughly 0.04-1.14% of patients treated with ICIs and is associated with up to 50% mortality. We present a case of multisystem ICI toxicity requiring comprehensive evaluation to ultimately reveal a PFO shunt as the cause of persistent hypoxemia. Case: A 67-year-old male with Stage IIIC cutaneous melanoma presented with non-radiating pleuritic chest pain, diplopia, dyspnea and syncope. ECG showed high grade AV block and right bundle branch block. Labs showed elevated troponin, creatinine kinase and inflammatory markers. An echocardiogram showed edematous myocardium, a small pericardial effusion, and akinetic apical/inferior septal segments. Despite diuresis, 5g of methylprednisolone, IV immunoglobulin plus mycophenolate and resolution of AV block, the patient had hypoxemia on 100% FiO2. He underwent a CTA (which ruled out PE and ICI-induced pneumonitis) and fluoroscopic sniff test (revealing bilateral moderate diaphragm paresis). A recent cardiac catheterization on prior admission showed no obstructive coronary disease. Arterial blood gas showed pO2 120 mmHg without hypercapnia on 100% FiO2. We suspected a shunt as the underlying cause and obtained a bubble study disclosing a large (&gt; 25 bubble) PFO with right-to-left shunt. Results: Given the timing of symptoms, it was determined that pembrolizumab administration caused myocarditis and myositis with diaphragmatic paresis. In patients with pulmonary disease or diaphragmatic paresis, elevated intrathoracic and pulmonary artery pressures have been a proposed mechanism of acute worsening of right-to-left shunt resulting in hypoxemia. The patient underwent right heart catheterization and PFO closure using Gore Cardioform septal occluder with resolution of hypoxemia. A repeat echocardiogram obtained 1 month later was normal. Conclusion: All concerning clinical symptoms in the setting of ICI use require a thorough evaluation. In this case, persistent hypoxemia despite treatment for ICI toxicity unmasked a large PFO requiring closure. A multisystem approach should be used to assess suspected ICI myocarditis.

Abstract 16450: Increased Monocyte Count and Neutrophil-to-Lymphocyte Ratio With ICI Myocarditis

Introduction: Diagnosing immune checkpoint inhibitor (ICI) myocarditis remains complex in practice, often requiring advanced imaging or invasive endomyocardial biopsy. We constructed an institutional cohort of patients who received at least 1 dose of ICI and developed probable or definite ICI myocarditis. Hypothesis: We hypothesized that routine serum biomarkers, including troponin I, neutrophil-to-lymphocyte ratio (NLR), monocytes, and AST/ALT, would be elevated and peak at diagnosis. Methods: This retrospective cohort study used EHR data from patients on ICI at a single academic institution who developed probable or definite myocarditis from 7/2015 - 1/2023. Inclusion criteria and diagnosis date were defined using Bonaca criteria and/or documented clinical consensus, e.g. initiation of steroids for presumed myocarditis. Primary outcomes were levels of troponin I/high sensitivity troponin I, monocytes, NLR, and AST/ALT. LOESS regression with default smoothing parameter α = 0.75 was used to evaluate biomarker patterns 7 days pre- and post- diagnosis. Results: We included 16 cases of myocarditis. At diagnosis, most patients had at least 1 significant elevation in troponin I (100%), AST (81%), ALT (63%), or monocytes (69%) while on ICI (Figure 1). After diagnosis, absolute monocyte and lymphocyte count initially decreased before rebounding. Serum NLR rose prior to and briefly after diagnosis (Figure 2). Conclusions: Peripheral cardiac and non-cardiac biomarkers change with ICI myocarditis. Further research on routine non-cardiac biomarkers associated with myocarditis and other ICI toxicities may help prevent high-grade adverse events.

Learning about and living with toxicity: A qualitative study of patients receiving immune checkpoint inhibitors for melanoma or lung cancer and their caregivers.

297 Background: Immune checkpoint inhibitors (ICIs) have revolutionized treatment for melanoma and lung cancer and are in widespread use. This study aims to describe how patients and caregivers learn about ICI toxicities and their lived experiences of receiving an ICI. Methods: We conducted a qualitative study of patients with advanced cancer receiving ICIs from a single academic center and their caregivers. We purposively sampled patients with stage IV non-small cell lung cancer (n=16) or stage III (n=9) or IV (n=17) melanoma who were initiating or discontinuing an ICI. We conducted semi-structured interviews to explore patients' and caregivers' experiences learning about and living with ICI toxicity. We used a framework approach to analyze interview transcripts, which included developing a codebook, double-coding transcripts, and synthesizing codes into themes with a multidisciplinary research team. Results: The median age of patients was 68 years, 31% were female and 49% had at least a college degree. We identified the following themes: i) Patients initiating ICIs received exhaustive counseling about side effects (“everything from rash to death,” “like a drug ad on television”), yet some patients lost details in the deluge of information (“I'm sure I was told of the risk, I just can't specifically recall what”); ii) Patients and caregivers identified several factors that helped them feel comfortable to proceed with treatment, namely that the oncology team emphasized the infrequency of serious side effects and that the team was ready to manage whatever toxicity occurred. In addition, patients perceived that ICI benefits outweighed the risks or felt that they had no alternative; iii) Among patients who discontinued ICIs, the association between ICI toxicity and efficacy was a source of hope (“I hope every day to find vitiligo... that might say that the immunotherapy is working”); iv) Patients’ and caregivers’ impressions of ICIs depended on patients’ outcomes. Patients tolerating ICIs well and their caregivers were surprised at how easy their treatment was, whereas patients who discontinued ICIs after experiencing severe side effects felt frustrated and surprised by toxicity, or worried their cancer would progress. Conclusions: Patients receiving ICIs for advanced cancer and their caregivers felt they received comprehensive education about ICI toxicity. They appreciated when their oncology team provided reassurance that side effects were rare and manageable, as well as messages that framed toxicity as a sign of efficacy once they occurred. Even with excellent preparation for the possibility of toxicity, patients who experienced severe toxicity were still surprised and disappointed. These perspectives highlight patient and caregiver preferences for learning about ICIs and opportunities to support patients in coping with advanced cancer.