Toxicity Of Checkpoint Inhibitors Research Articles

The Role of Aging and Senescence in Immune Checkpoint Inhibitor Response and Toxicity.

Cellular senescence accumulates with age and has been shown to impact numerous physiological and pathological processes, including immune function. The role of cellular senescence in cancer is multifaceted, but the impact on immune checkpoint inhibitor response and toxicity has not been fully evaluated. In this review, we evaluate the impact of cellular senescence in various biological compartments, including the tumor, the tumor microenvironment, and the immune system, on immune checkpoint inhibitor efficacy and toxicity. We provide an overview of the impact of cellular senescence in normal and pathological contexts and examine recent studies that have connected aging and cellular senescence to immune checkpoint inhibitor treatment in both the pre-clinical and clinical contexts. Overall, senescence plays a multi-faceted, context-specific role and has been shown to modulate immune-related adverse event incidence as well as immune checkpoint inhibitor response.

Reporting of immune-related adverse events (irAEs) in US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors.

e14693 Background: Evaluating immune checkpoint inhibitor (ICI) toxicity is complex given the interplay between the host immune system and tumor microenvironment leading to unpredictable timing and severity of irAEs. Monitoring of irAEs is critical as they can cause significant impact on morbidity and quality of life. Thus, we evaluated the consistency and pattern of reporting of irAEs in trials leading to FDA drug approvals. Methods: Using the FDA website, we identified 73 primary articles for ICI FDA approvals over a 10-year period (2011-2021). Data were collected independently by all authors as categorical variables for reporting of any grade and grade 3 or higher toxicity in the trial arm that led to FDA approval for 29 irAEs classified by the National Comprehensive Cancer Network Version 1.2024 guidelines. Our analyses were based on a binary classification of reported versus not reported, including the manuscript text, tables, and supplement, and reporting trends were analyzed based on the study year, phase, primary tumor, and monotherapy versus combination ICI therapy. Results: The majority of approvals were associated with Phase II (N=22) or Phase III (N=39) studies. Approvals included 14 primary tumors and 2 tumor agnostic approvals with the most common tumors including lung (N=22) and skin (N=14). irAE reporting ranged between 0% and 100% with a mean of 40% and a standard deviation of 35. Across the 29 irAEs, 45% were categorized as severely underreported with less than 25% reporting in trials, 17% were classified as underreported in 26-50% of trials, 17% were moderately reported in 51-75% of trials, and 21% were well reported in at least 75% of trials. For example, fatigue, diarrhea, and hypothyroidism were well reported at 100%, 99%, and 93%, respectively, while myocarditis, aseptic meningitis, and giant cell arteritis were severely underreported at 18%, 4%, and 1%, respectively. Additionally, certain systems were more reported than others, including gastrointestinal (100%) and endocrine (97%), while other systems were inconsistently reported such as cardiology (15%) and neurology (48%) (see Table). Conclusions: Our study identified significant inconsistencies in irAE reporting in clinical trials that led to ICI FDA approvals. In particular, rarer irAEs were reported infrequently while more common irAEs were well reported. Unified efforts are needed to standardize the irAE reporting in the primary literature to ensure reliable dissemination of information for timely recognition and treatment in clinical practice. [Table: see text]

Clinical nSights: A software platform to accelerate real world oncology analyses.

e23316 Background: Real world data analyses are critical to assess drug safety and effectiveness, including in patient populations underrepresented in clinical trials. Significant barriers to performing such analyses remain, including: (1) incomplete access to electronic health record (EHR) data due to patient privacy concerns, (2) lack of data harmonization within and across EHRs, (3) requirements for time- and labor-intensive data curation efforts, and (4) necessity of coding or data science expertise given the absence of user-friendly platforms. We present Clinical nSights, a software platform that addresses these challenges to enable researchers and clinicians to perform rapid, robust, and scalable real world oncology analyses. Methods: With input EHR data from multiple health systems, we developed intuitive user interfaces and a scalable researcher friendly programming environment for real world clinical analytics. We used (1) nCognito, a previously described HIPAA-compliant de-identification algorithm, to de-identify EHRs across data modalities; (2) the combination of a de novo knowledge graph, vector and distribution similarity metrics, and manual review to harmonize data types including but not limited to laboratory tests, disease codes, and drugs; and (3) a series of Bidirectional Encoder Representations from Transformers (BERT) models to perform augmented curation of variables of interest (e.g., cancer staging, tumor biomarkers) from unstructured clinical records. We developed a user interface for users to create and analyze defined patient cohorts. Results: Clinical nSights facilitates intuitive cohort creation via flexible specification of inclusion and exclusion criteria, including options to perform temporal linking between criteria and propensity score matching. The ability to specify criteria documented in de-identified clinical notes expands the repertoire of available features for cohort creation beyond those captured in structured EHR fields, including but not limited to cancer stage and tumor biomarker status (e.g., HER2 status, microsatellite instability). Data harmonization enables scalable longitudinal analyses of laboratory test data across cancer types, including changes in measurements in the years leading up to and following initial cancer diagnosis. Augmented curation improves the coverage of phenotypes including immune-related toxicities of checkpoint inhibitors and symptoms experienced by patients prior to a cancer diagnosis. Using the no-code interface, users can easily quantify and visualize outcomes such as overall survival and hospitalization rates. Conclusions: Clinical nSights addresses important challenges in the collection, curation, and analysis of real world oncology data. By enabling a broad range of users to rapidly generate and test hypotheses, this platform has the potential to significantly improve care delivery and patient outcomes.

Comparing rates of immune checkpoint inhibitor toxicity in different treatment settings (neoadjuvant, adjuvant, and palliative) in non-small cell lung cancer (NSCLC): A meta-analysis of phase III clinical trials.

8645 Background: Immunotherapy has created a paradigm shift in the treatment of NSCLC. There is growing interest in the utility of immunotherapy alone or in combination with chemotherapy for NSCLC in the peri-operative setting with practice changing results demonstrated in several pivotal phase III clinical trials. Nevertheless, immune related adverse events (irAEs) are the main barrier in the care of patients treated with immune checkpoint inhibitors (ICIs) with grade ≥ 3 irAEs seen in 10-15% of patients. The present meta-analysis aims to compare rates of irAEs across different treatment settings in NSCLC to aid in individual patient treatment decisions. Methods: We extracted data from selected published phase III clinical trials which have led to the approval of PD-1/PDL-1 ICIs in the neoadjuvant, adjuvant, peri-operative and in the palliative setting. We excluded trials which did not have supplemental data on irAEs included with published results and trials of CTLA-4 inhibitors. A sensitivity analysis was performed to assess whether number of cycles correlated with toxicity rates. Results: Pooled data from 15 published phase III NSCLC clinical trials including 5918 patients were included. This included 1 neoadjuvant, 2 peri-operative, 3 adjuvant, and 9 palliative studies. One of the peri-operative trials included data on irAEs which occurred during the neoadjuvant/surgery phase only and this data was pooled within the neoadjuvant group. The ICI drugs included nivolumab, pembrolizumab, atezolizumab, durvalumab, cemiplimab +/- chemotherapy. This included a total of 2523 stage 1B-3C and 3395 stage IV patients. We found a 9.5% rate of grade 3-5 and 35.8% rate of all grade irAEs in palliative trials (n=3395). In contrast, neoadjuvant ICI (n=572) had a 3.5% rate of grade 3-5 and 16.8% of all grades irAEs. Peri-operative ICI (n=797) had a 5.4% rate of grade 3-5 and 24.47% all grades irAEs. Adjuvant ICI (n=1550) had a 7% rate of grade 3-5 and 38.52% rate of all grade irAEs. The relative risk (RR) between the palliative and the neoadjuvant setting of a grade 3-5 irAE is 2.35 (95% CI:1.54 to 3.59; p = 0.0001) and the RR of any irAE is 2.03 (95% CI: 1.69 to 2.43; p=0.0001). The following median number of ICI cycles was seen: neoadjuvant = 3.5, adjuvant = 18, peri-operative = 18, palliative = 10. Lower number of cycles did correlate with lower toxicity in the neoadjuvant setting but this was not seen in other treatment settings. Conclusions: Neoadjuvant, peri-operative and adjuvant ICI’s are associated with a lower rate of irAEs than that seen in palliative trials. A neoadjuvant-only approach is associated with the lowest rates of irAEs and this may be due to the lower number of cycles received. These findings have implications for individual patient treatment decisions and support the use of neoadjuvant immunotherapy in NSCLC.

Distinct autoantibody profiles across checkpoint inhibitor types and toxicities

ABSTRACT Immune checkpoint inhibitors (ICI) are increasingly used in combination. To understand the effects of different ICI categories, we characterized changes in circulating autoantibodies in patients enrolled in the E4412 trial (NCT01896999) of brentuximab vedotin (BV) plus ipilimumab, BV plus nivolumab, or BV plus ipilimumab-nivolumab for Hodgkin Lymphoma. Cycle 2 Day 1 (C2D1) autoantibody levels were compared to pre-treatment baseline. Across 112 autoantibodies tested, we generally observed increases in ipilimumab-containing regimens, with decreases noted in the nivolumab arm. Among 15 autoantibodies with significant changes at C2D1, all nivolumab cases exhibited decreases, with more than 90% of ipilimumab-exposed cases showing increases. Autoantibody profiles also showed differences according to immune-related adverse event (irAE) type, with rash generally featuring increases and liver toxicity demonstrating decreases. We conclude that dynamic autoantibody profiles may differ according to ICI category and irAE type. These findings may have relevance to clinical monitoring and irAE treatment.

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.

Abstract 5186: Spatial single-cell deconvolution of the bone marrow microenvironment to define predictive biomarker for response to immunotherapy in patients treated with a check point inhibitor in smoldering multiple myeloma, phase II trial of nivolumab in combination with lenalidomide and low dose dexamethasone

Abstract Background:The immune system is critical for response and resistance in all cancer types and therapies. Patients with Smoldering Multiple Myeloma (SMM) have altered immune cell composition in the bone marrow (BM). However, little is known about the role of BM spatial immune profiling in patients treated with checkpoint inhibitors in MM. Methods: We performed spatial profiling with imaging mass cytometry of trephine biopsies of the BM (n=15; pre-treatment n=7 and post-treatment n=8) from patients with high-risk SMM enrolled in a phase II trial of nivolumab in combination with lenalidomide and low dose dexamethasone (NCT02903381). Patients received 6 cycles of induction therapy of nivolumab (240mg) at days 1 and 15, in combination with lenalidomide (25mg) at days 1-21 and dexamethasone at days 1, 8, and 15. The induction phase was followed by nivolumab (240mg) and lenalidomide (25mg) maintenance for another 6 cycles. A treatment cycle was defined as 28 consecutive days for a total of 12 months period. Event monitoring was performed up to 3 years. The primary efficacy outcome was progression-free survival 2 years after treatment. Results: Eight patients were enrolled on this study from January 2017 to June 2017. The study was put on hold due to the toxicity of checkpoint inhibitors observed in other trials of MM. The median age for all patients at enrolment was 60 years (range 49 to 81), with 5 males (62%) and 3 females (38%). All patients met criteria for high risk SMM disease. Median follow-up for all 8 patients was 38.7 months. Median overall survival was not reached; median progression-free survival was 33.8 months. Seven total patients had a response of Minimal Response (MR) or better, and 4 patients who initially responded eventually progressed. The total number of patients who were followed for at least two years and remained progression-free was 4 of 8 evaluable patients (50%; 90% CI: 19 - 81%).Spatial profiling with a panel of 37 markers on the pre-treatment samples allowed us to assess the states and abundances of multiple immune subpopulations, including rare regulatory NK cells. To assess the accuracy of our cell type annotation, we correlated the proportion of malignant plasma cells identified per patient with the value determined by pathologists for clinical diagnosis. These measures were significantly positively correlated (R=0.92, p&amp;lt;0.01). Spatial neighborhood analysis revealed statistically significant interactions enriched in the responders, even with our small sample size (t-test; p &amp;lt; 0.05). Conclusions and future directions: This pilot study suggests that BM spatial immune profiling before receiving immune check point inhibitors can be a biomarker for response in patients with SMM. Citation Format: Yoshinobu Konishi, Giuseppe Tarantino, Yiwen He, Romanos Sklavenitis-Pistofidis, Sujal I. Shah, Katherine Towle, Christian J. Cea-Curry, Oksana Zavidij, Ruben D. Carrasco, Scott J. Rodig, Jon C. Aster, David Liu, Gad Getz, Irene M. Ghobrial. Spatial single-cell deconvolution of the bone marrow microenvironment to define predictive biomarker for response to immunotherapy in patients treated with a check point inhibitor in smoldering multiple myeloma, phase II trial of nivolumab in combination with lenalidomide and low dose dexamethasone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5186.

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.

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?

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.

The Conundrum of Normal Kidney Endothelial HLA-DR Clarified by Checkpoint Inhibitor Toxicity: A Role for Microvascular Endothelium in Peripheral Tolerance

The Conundrum of Normal Kidney Endothelial HLA-DR Clarified by Checkpoint Inhibitor Toxicity: A Role for Microvascular Endothelium in Peripheral Tolerance

Text intervention to minimize time burden of cancer care (TIME).

301 Background: Innovative strategies to mitigate the time toxicity of cancer therapy are desperately needed. We have shown that a text-based e-triage can utilize patient-reported outcomes to identify patients without immune checkpoint inhibitor (ICI) toxicity who could safely fast-track to ICI infusion without a pre-infusion office visit. We report the efficacy of e-triage versus usual care to minimize the time toxicity of cancer care. Methods: This hybrid type 1 effectiveness-implementation randomized controlled trial was conducted at Penn Medicine between December 2021 and December 2022. Eligible patients spoke English, were receiving single agent ICI for a solid tumor, and had access to a mobile device with text messaging. The e-triage arm included ICI toxicity symptom assessment via two-way text messaging 96 hours prior to scheduled ICI and routine laboratory testing. Patients on the e-triage arm with normal bloodwork and no symptoms identified by the e-triage were eligible to fast-track to ICI infusion, bypassing the pre-treatment office visit. Usual care was standard office visits. Primary endpoint was care time (total time per ambulatory encounter including commute-, wait-, infusion-, and lab-times). Secondary endpoints were patient wait time per encounter, incident emergency department (ED) or hospital visits during follow-up, health related quality of life (HRQOL) measured by The Functional Assessment of Cancer Therapy-General, and patient satisfaction measured by PSQ-18. Differences in proportions of ED or hospital visits between arms were evaluated by the Fisher’s exact test. Linear mixed-effects models with random intercepts for each individual evaluated differences in all other endpoints between arms, accounting for within-patient correlation. Implementation outcomes were adoption (# patients who participated in the trial out of # approached) and fidelity (# patients on the intervention arm who followed their triage assignment). Acceptability, feasibility, and appropriateness outcomes were reported previously. Results: Among 152 eligible patients, 51 consented onto study (adoption rate 33.6%) and 40 were randomized (n=21, usual care; n=19, e-triage). Patient characteristics will be presented. Of 52 encounters on the e-triage arm, 23 adhered to their e-triage assessment (fidelity rate 44.2%). Compared with the usual care arm, patients on the e-triage arm had an average of 70 minutes less care time per encounter (95% CI -123.7 to –8.08 minutes, p=0.03) and 30.1 minutes less wait time (95% CI -61 to 1.1 minutes, p=0.08). The incidence of ED or hospital visits did not differ by treatment arm (usual care, n=2, 12.5% vs. intervention, n=3, 20%, p=0.65). HRQOL and patient satisfaction scores were similar by treatment arm. Conclusions: Results from this pilot trial support further work to optimize the design and implementation of a mobile e-triage program to personalize cancer care delivery and minimize time toxicity. Clinical trial information: NCT05134636 .

The need for ambulatory emergency oncology: exemplified by the management of immune checkpoint inhibitor toxicity.

Cancer patients seeking emergency care can be vulnerable in increasingly overcrowded Emergency Departments and timely delivery of care is often aspirational rather than reality in many acute care systems. Ambulatory emergency care and its various international models are recognized as contributing to the safety and sustainability of emergency care services. This schema can logically be extended to the emergency oncology setting. The recent proliferation of immune checkpoint inhibitors (ICIs) has led to another opportunity for the management of oncologic complications in the ambulatory emergency care setting. More nuanced risk stratification of currently perceived high-risk toxicities may also afford the opportunity to personalize acute management. Virtual wards, which predominantly provide virtual monitoring only, and hospital at home services, which provide more comprehensive in-person assessment and interventions, may be well suited to supporting care for ICI toxicity alongside hospital-based assessment. Emergency management guidelines for immune-mediated toxicities will increasingly need to be both pragmatic and deliverable, especially as larger numbers of patients will present outside cancer centers. Identifying and modelling those suitable for emergency ambulatory care is integral to achieving this.

Biomarkers of immune checkpoint inhibitor response and toxicity: Challenges and opportunities.

Immune checkpoint inhibitors have transformed cancer therapy, but their optimal use is still constrained by lack of response and toxicity. Biomarkers of response may facilitate drug development by allowing appropriate therapy selection and focusing clinical trial enrollment. However, aside from PD-L1 staining in a subset of tumors and rarely mismatch repair deficiency, no biomarkers are routinely used in the clinic. In addition, severe toxicities may cause severe morbidity, therapy discontinuation, and even death. Here, we review the state of the field with a focus on our research in therapeutic biomarkers and toxicities from immune checkpoint inhibitors.

Prospective Clinical Trials to Advance the Study of Immune Checkpoint Inhibitor Toxicity.

Immune checkpoint inhibitors (ICIs) are a class of drug that produces durable and sustained anti-tumour responses in a wide variety of malignancies. The exponential rise in their use has been mirrored by a rise in immune-related adverse events (IrAEs). Knowledge of such toxicities, as well as effective management algorithms for these toxicities, is essential to optimize clinical efficacy and safety. Currently, the guidelines for management of the IrAEs are based largely on retrospective studies and case series. In this article, we review the current landscape of clinical trials investigating the management of IrAEs with an aim to develop standardised, randomised controlled trial-based management algorithms for ICI-related toxicities.

De-correlating immune checkpoint inhibitor toxicity and response in melanoma via the microbiome.

9569 Background: Immune-checkpoint inhibitor (ICI) immunotherapy increases survival in patients with melanoma. Yet only half of the patients respond, and 10-40% of patients experience immune-related adverse events (irAEs). Previous studies have found a correlation between the development of an irAE and treatment response. Modifying the gut microbiome could positively affect response to ICIs and reduce toxicities. We sought to determine if the microbiome at the onset of treatment, during an irAE, and at 12 weeks, can predict the response or toxicity during ICI treatment for metastatic melanoma. Methods: Melanoma patients (pts) &gt; 18 yo treated with ICI enrolled in a prospective observational cohort study at The Ohio State University Comprehensive Cancer Center Skin Cancer Clinic. Excluded were patients on corticosteroids at the start of ICI cycle 1, except for adrenal physiologic replacement. Stools were collected at baseline, within 2 days of an adverse event assessed by physician chart review using CTCAE (Common Terminology Criteria for Adverse Events) v5.0, and at 12 weeks. Response (ORR) to ICIs was assessed by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) q12 weeks and progression-free survival recorded. Metagenomic whole-genome shotgun sequencing was performed on an Illumina NovaSeq 6000 and classified using HUMAnN3. The effect of microbe relative abundances on irAEs was modeled by logistic regression with the R package glmm. Results: Of the 88 patients enrolled, 48 had metastatic disease with 32 assessable for response. ORR at 12 weeks was 28% (1 CR, 8 PR, 17 SD, and 6 PD) and 24 patients showed PFS at 12 months. Grade &gt; 2 irAEs were observed in 11/48 pts. Abundance of Bacteroides dorei (False Discovery Rate Corrected p-value = 9.5E-07) and Blautia species CAG:257 (padj = 0.001) were enriched in responders, Prevotella Stercorea (padj = 1.1E-07) and a phage with a predicted target of Salmonella (padj = 8.3E-09) in non-responders. Responders with an irAE had enrichment of Bacteroides plebeius (padj = 4.2E-13) and Bacteroides coprophilus (padj = 0.0002) whereas responders without irAE had enrichment of Eubacterium siraeum (padj = 7.2E-05). Conclusions: Longitudinal and event-driven biospecimen collection in patients treated with ICIs showed several bacteria and viruses but no fungi associated with response, with and without the development of an irAE. The abundance of the two high-taxonomic rank microbe groups is significantly associated with irAEs. The association with the Bacteroides Genus is consistent with previous studies and is associated with response to ICIs. A microbiome abundant in Bacteroides and lacking Prevotella is associated with response to ICI. An abundance of Bacteroides could be a biomarker for irAEs, and an abundance of Eubacterium, a biomarker for response without irAEs. Future analyses are necessary to assign causal roles for microbe biomarkers with specific irAEs. Clinical trial information: NCT05102773 .

Cardiovascular toxicity of checkpoint inhibitors: review of associated toxicity and design of the Spanish Immunotherapy Registry of Cardiovascular Toxicity.

Immune checkpoint inhibitors (ICI) have changed the prognosis of many tumors. However, concerning associated cardiotoxicity has been reported. Little is known about the real-life incidence-specific surveillance protocols or the translational correlation between the underlying mechanisms and the clinical presentation of ICI-induced cardiotoxicity. The lack of data from prospective studies led us to review the current knowledge and to present the creation of the Spanish Immunotherapy Registry of Cardiovascular Toxicity (SIR-CVT), a prospective registry of patients receiving ICI that aims to examine the role of hsa-miR-Chr8:96, (a specific serum biomarker of myocarditis) in the early diagnosis of ICI-induced myocarditis. An exhaustive prospective cardiac imaging study will be performed before and during the first 12months of treatment. The correlation between clinical, imaging, and immunologic parameters may improve our understanding of ICI-induced cardiotoxicity and enable simpler surveillance protocols. We assess ICI-induced cardiovascular toxicity and describe the rationale of the SIR-CVT.

Patient-reported outcomes in immunotherapy for head and neck cancer.

Data about patient-reported outcomes (PROs) among patients with head and neck squamous cell carcinoma (HNSCC) treated with immune checkpoint inhibitors are sparse. Our exploratory study evaluated PROs in patients with HNSCC starting treatment with immune checkpoint inhibitor monotherapy or combination therapy with cetuximab. Patients were recruited prior to receipt of their first checkpoint inhibitor therapy infusion. Participants completed measures of checkpoint inhibitor toxicities and quality of life (QOL) at on-treatment clinic visits. Among patients treated with checkpoint inhibitor monotherapy (n = 48) or combination therapy (n = 38) toxicity increased over time (p < 0.05), while overall QOL improved from baseline to 12 weeks, with stable or declining QOL thereafter (p < 0.05). There were no group differences in change in toxicity index or QOL. Toxicity index scores were significantly higher in the combination group at 18-20 weeks and 6 months post-initiation of immune checkpoint inhibitor (p < 0.05). There were no significant group differences at baseline, the 6-8 week (p = 0.13) or 3-month (p = 0.09) evaluations. The combination group reported better emotional well-being at baseline than the monotherapy group (p = 0.04), There were no other group differences QOL at baseline or later timepoints. Despite increasing patient-reported toxicity, checkpoint inhibitor monotherapy and combination therapy were associated with similar transient improvements, then worsening, of QOL in patients with HNSCC.

Immune-related pulmonary toxicities of checkpoint inhibitors in non-small cell lung cancer: Diagnosis, mechanism, and treatment strategies.

Immune checkpoint inhibitors (ICI) therapy based on programmed cell death-1 (PD-1) and programmed cell death ligand 1 (PD-L1) has changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC) and improved the survival expectancy of patients. However, it also leads to immune-related adverse events (iRAEs), which result in multiple organ damage. Among them, the most common one with the highest mortality in NSCLC patients treated with ICI is checkpoint inhibitor pneumonitis (CIP). The respiratory signs of CIP are highly coincident and overlap with those in primary lung cancer, which causes difficulties in detecting, diagnosing, managing, and treating. In clinical management, patients with serious CIP should receive immunosuppressive treatment and even discontinue immunotherapy, which impairs the clinical benefits of ICIs and potentially results in tumor recrudesce. Therefore, accurate diagnosis, detailedly dissecting the pathogenesis, and developing reasonable treatment strategies for CIP are essential to prolong patient survival and expand the application of ICI. Herein, we first summarized the diagnosis strategies of CIP in NSCLC, including the classical radiology examination and the rising serological test, pathology test, and artificial intelligence aids. Then, we dissected the potential pathogenic mechanisms of CIP, including disordered T cell subsets, the increase of autoantibodies, cross-antigens reactivity, and the potential role of other immune cells. Moreover, we explored therapeutic approaches beyond first-line steroid therapy and future direction based on targeted signaling pathways. Finally, we discussed the current impediments, future trends, and challenges in fighting ICI-related pneumonitis.

77 - Evaluating safe prescribing with long-term steroid usage for checkpoint inhibitor (IO) toxicity in oncology patients

77 - Evaluating safe prescribing with long-term steroid usage for checkpoint inhibitor (IO) toxicity in oncology patients