Development Of Immune-related Adverse Events Research Articles

Kinetics of IFNγ-Induced Cytokines and Development of Immune-Related Adverse Events in Patients Receiving PD-(L)1 Inhibitors.

Immune checkpoint inhibitors (ICI) have the potential to trigger unpredictable immune-related adverse events (irAEs), which can be severe. The underlying mechanisms of these events are not fully understood. As PD-L1 is upregulated by IFN, the heightened immune activation resulting from PD-1/PD-L1 inhibition may enhance the IFN response, triggering the expression of IFN-inducible genes and contributing to irAE development and its severity. In this study, we investigated the interplay between irAEs and the expression of IFN-inducible chemokines and cytokines in 134 consecutive patients with solid tumours treated with PD-(L)1 inhibitors as monotherapy or in combination with chemotherapy or other immunotherapy agents. We compared the plasma levels of IFN-associated cytokines (CXCL9/10/11, IL-18, IL-10, IL-6 and TGFβ) at various time points (at baseline, at the onset of irAE and previous to irAE onset) in three patient groups categorized by irAE development and severity: patients with serious irAEs, mild irAEs and without irAEs after PD-(L)1 inhibitors. No differences were observed between groups at baseline. However, patients with serious irAEs exhibited significant increases in CXCL9/10/11, IL-18 and IL-10 levels at the onset of the irAE compared to baseline. A network analysis and correlation patterns highlighted a robust relationship among these chemokines and cytokines at serious-irAE onset. Combining all of the analysed proteins in a cluster analysis, we identified a subgroup of patients with a higher incidence of serious irAEs affecting different organs or systems. Finally, an ROC analysis and a decision tree model proposed IL-18 levels ≥ 807 pg/mL and TGFβ levels ≤ 114 pg/mL as predictors for serious irAEs in 90% of cases. In conclusion, our study elucidates the dynamic changes in cytokine profiles associated with serious irAE development during treatment with PD-(L)1 inhibitors. The study's findings offer valuable insights into the intricate IFN-induced immune responses associated with irAEs and propose potential predictive markers for their severity.

Effect of glucocorticoids for the management of immune-related adverse events on outcome in melanoma patients treated with immunotherapy – a retrospective and biomarker study

Immune-related adverse events (IRAEs) during therapy with immune checkpoint-inhibitors (ICIs) are common, and its management sometimes requires glucocorticoids (GC). Predictors for development of IRAEs and data about the impact of GC on clinical outcome are missing. We evaluated the impact of GC to treat IRAEs on clinical outcome, and plasmatic inflammatory proteins as predictors for IRAEs.Patients with melanoma (n=98) treated with ICIs at Karolinska University Hospital were included. Clinical information and data regarding prescription of systemic GC were collected. Baseline plasma samples (n=57) were analyzed for expression of 92 inflammatory proteins.Forty-four patients developed at least one IRAE requiring systemic GC and the most common was hypocortisolemia (n=11). A median overall survival (mOS) of 72.8 months for patients developing IRAEs requiring GC, 17.7 months for those who did not, and 1.4 months for individuals receiving GC at baseline was observed in Kaplan-Meier curves (p = 0.001). In immortal time bias adjusted analysis patients receiving steroids to treat IRAE survived slightly longer, even though this time trend was not statistically significant. The mOS was 29 months for those treated with GC within 60 days after ICIs start and was not reached for patients receiving GC later. The number of ICIs cycles was higher in subjects receiving GC after 60 days (p=0.0053). Hypocortisolemia occurred mainly in males (10/11) and correlated with favorable outcome. Male patients with hypocortisolemia had lower expression of IL8, TGF-alfa and FGF5 and higher expression of DNER.GC may be used to treat IRAEs without major concern. However, GC early during ICIs may impact clinical outcome negatively. The prognostic value of hypocortisolemia and inflammation proteins as biomarkers should be further investigated.

Antinuclear antibodies may predict the development of immune-related adverse events in asymptomatic patients treated with immune checkpoint inhibitors: results from a single-center cohort

We aim at investigating the association between subclinical autoimmunity and immune-related adverse events (irAEs) in a cohort of patients treated by immune checkpoint inhibitors for solid metastatic cancer. In the context of an oncology/rheumatology outpatient clinic, we evaluated patients treated with anti-PD-1 or anti-PD-L1. Before treatment, each patient underwent a physical evaluation and a blood sample to identify the presence of a set of autoantibodies. Indeed, all the patients were followed during treatment to identify irAEs and to assess the association with autoantibodies. Fifty-one patients (M/F 16/35; median age 70 years, IQR 16.5) were evaluated; 34.8% of patients showed ANA positivity, 6.5% ENA positivity (anti-SSA), 4.3% Ratest positivity, and 2.1% (one patient) ACPA positivity. During a median period of 21 months (IQR 38.75), 39.2% of patients developed irAEs. Musculo-skeletal manifestations, in particular arthritis, were the most frequent. We found a significant association between the positivity for ANA and the development of irAES (p = 0.03, RR 2.01, 95% CI 1.03–3.92). Furthermore, the progression-free survival was significantly longer in patients developing irAEs compared to those who are not experiencing these events (p = 0.007). This study underlines the potential role of ANA positivity as a predictive biomarker for the development of irAEs.

Longitudinal gut microbiome changes in immune checkpoint blockade-treated advanced melanoma

Multiple clinical trials targeting the gut microbiome are being conducted to optimize treatment outcomes for immune checkpoint blockade (ICB). To improve the success of these interventions, understanding gut microbiome changes during ICB is urgently needed. Here through longitudinal microbiome profiling of 175 patients treated with ICB for advanced melanoma, we show that several microbial species-level genome bins (SGBs) and pathways exhibit distinct patterns from baseline in patients achieving progression-free survival (PFS) of 12 months or longer (PFS ≥12) versus patients with PFS shorter than 12 months (PFS <12). Out of 99 SGBs that could discriminate between these two groups, 20 were differentially abundant only at baseline, while 42 were differentially abundant only after treatment initiation. We identify five and four SGBs that had consistently higher abundances in patients with PFS ≥12 and <12 months, respectively. Constructing a log ratio of these SGBs, we find an association with overall survival. Finally, we find different microbial dynamics in different clinical contexts including the type of ICB regimen, development of immune-related adverse events and concomitant medication use. Insights into the longitudinal dynamics of the gut microbiome in association with host factors and treatment regimens will be critical for guiding rational microbiome-targeted therapies aimed at enhancing ICB efficacy.

Uncovering the flip side of immune checkpoint inhibitors: a comprehensive review of immune-related adverse events and predictive biomarkers.

Immune checkpoint inhibitors (ICIs) have generated considerable excitement as a novel class of immunotherapeutic agents due to their remarkable efficacy in treating various types of cancer. However, the widespread use of ICIs has brought about a number of safety concerns, especially the development of immune-related adverse events (irAEs). These serious complications could result in treatment discontinuation and even life-threatening consequences, making it critical to identify high-risk groups and predictive markers of irAEs before initiating therapy. To this end, the current article examines several potential predictive markers of irAEs in important organs affected by ICIs. While retrospective studies have yielded some promising results, limitations such as small sample sizes, variable patient populations, and specific cancer types and ICIs studied make it difficult to generalize the findings. Therefore, prospective cohort studies and real-world investigations are needed to validate the potential of different biomarkers in predicting irAEs risk. Overall, identifying predictive markers of irAEs is a crucial step towards improving patient safety and enhancing the management of irAEs. With ongoing research efforts, it is hoped that more accurate and reliable biomarkers will be identified and incorporated into clinical practice to guide treatment decisions and prevent the development of irAEs in susceptible patients.

Establishment of CD8+ T Cell Thymic Central Tolerance to Tissue-Restricted Antigen Requires PD-1.

Highly self-reactive T cells are censored from the repertoire by both central and peripheral tolerance mechanisms upon receipt of high-affinity TCR signals. Clonal deletion is considered a major driver of central tolerance; however, other mechanisms such as induction of regulatory T cells and functional impairment have been described. An understanding of the interplay between these different central tolerance mechanisms is still lacking. We previously showed that impaired clonal deletion to a model tissue-restricted Ag did not compromise tolerance. In this study, we determined that murine T cells that failed clonal deletion were rendered functionally impaired in the thymus. Programmed cell death protein 1 (PD-1) was induced in the thymus and was required to establish cell-intrinsic tolerance to tissue-restricted Ag in CD8+ thymocytes independently of clonal deletion. In bone marrow chimeras, tolerance was not observed in PD-L1-deficient recipients, but tolerance was largely maintained following adoptive transfer of tolerant thymocytes or T cells to PD-L1-deficient recipients. However, CRISPR-mediated ablation of PD-1 in tolerant T cells resulted in broken tolerance, suggesting different PD-1 signaling requirements for establishing versus maintaining tolerance. Finally, we showed that chronic exposure to high-affinity Ag supported the long-term maintenance of tolerance. Taken together, our study identifies a critical role for PD-1 in establishing central tolerance in autoreactive T cells that escape clonal deletion. It also sheds light on potential mechanisms of action of anti-PD-1 pathway immune checkpoint blockade and the development of immune-related adverse events.

Safety and efficacy of immune checkpoint inhibitor cancer therapy in patients with preexisting type 1 diabetes mellitus.

Immune checkpoint inhibitors (ICI) produce dramatic tumor shrinkage and durable responses in many advanced malignancies, but their use is limited by the development of immune-related adverse events (IRAEs) that occur in up to 60% of patients and often affect endocrine organs. Concern for more severe IRAEs in patients with preexisting autoimmune diseases, including type 1 diabetes mellitus (T1DM), has led to the exclusion of such individuals from clinical trials of ICI therapy. As a result, little is known about the safety and efficacy of ICI in this population. Here, we report safety and treatments outcomes in ICI-treated patients with preexisting T1DM. This retrospective case-controlled study evaluated adult patients with T1DM who received ICI therapy for solid malignancies from 2015 to 2021 at four academic medical centers. Patients with prior ICI therapy, bone marrow transplantation, or pregnancy were excluded. We collected data on demographics, cancer diagnosis and treatment, IRAE incidence and severity, and diabetes management. Controls were matched 2:1 by age, sex, cancer diagnosis, and ICI therapy class. Of 12,142 cancer patients treated with ICI therapy, we identified 11 with a preexisting confirmed diagnosis of T1DM prior to starting ICI therapy. Mean age was 50.6 years, 63.6% were women, and most received anti-PD1/PDL1 monotherapy (10/11) compared with combination therapy (1/11). Grade 3/4 IRAEs were seen in 3/11 subjects with preexisting T1DM and were hepatitis, myositis, and myasthenia gravis. All three cases had interruption of ICI therapy and administration of adjunct therapies, including steroids, IVIG, or mycophenolate mofetil with resolution of the IRAE. The odds of all-grade IRAEs and of severe IRAEs were comparable between cases and controls matched for age, sex, cancer type, and ICI therapy [OR 0.83 (95% CI 0.2-3.56), p = 0.81, and OR 1.69 (0.31-9.36), p = 0.55, respectively]. Overall survival was not different between patients with T1DM and controls (p = 0.54). No patients had hospitalizations for diabetes-related complications during therapy. These data suggest that ICI monotherapy can successfully be used in patients with preexisting T1DM, with IRAE rates comparable with individuals without preexisting T1DM. Larger, prospective studies of these potentially life-saving ICI therapies that include patients with preexisting autoimmunity are warranted.

The Gut Microbiome from a Biomarker to a Novel Therapeutic Strategy for Immunotherapy Response in Patients with Lung Cancer.

The gastrointestinal microbiome has been shown to play a key role in determining the responses to cancer immunotherapy, including immune checkpoint inhibitor (ICI) therapy and CAR-T. In patients with non-small cell lung cancer (NSCLC), increasing evidence suggests that a microbiome composition signature is associated with clinical response to ICIs as well as with the development of immune-related adverse events. In support of this, antibiotic (ATB)-related dysbiosis has been consistently linked with the deleterious impact of ICI response, shortening the overall survival (OS) among patients on ATBs prior to ICI initiation. In parallel, several preclinical experiments have unravelled various strategies using probiotics, prebiotics, diet, and fecal microbiota transplantation as new therapeutic tools to beneficially shift the microbiome and enhance ICI efficacy. These approaches are currently being evaluated in clinical trials and have achieved encouraging preliminary results. In this article, we reviewed the recent studies on the gut microbiome as a potential biomarker and an adjuvant therapy to ICIs in NSCLC patients.

Significance of the autoantibody assay in predicting the development of immune-related adverse events in patients receiving atezolizumab plus bevacizumab combination therapy for unresectable hepatocellular carcinoma.

Atezolizumab plus bevacizumab (AB) combination therapy is the first-line treatment for unresectable hepatocellular carcinoma (u-HCC). The management of immune-related adverse events (irAEs) is an important issue associated with achieving a good therapeutic response in patients receiving AB therapy. However, few studies have reported irAE development in patients receiving AB therapy. This study focused on the association between irAE development and autoantibodies at baseline in patients receiving AB therapy. Sixty-one patients receiving AB therapy were enrolled. For autoantibodies, the following antibodies were tested before the start of AB therapy: antinuclear antibodies, rheumatoid factor (RF), anti-thyroglobulin antibodies, thyroid peroxidase antibodies, anti-thyroid stimulating hormone receptor antibodies, and acetylcholine receptor antibodies. A patient was considered to have pre-existing antibodies if any of the listed antibodies were present at baseline. Ten patients (16%) developed irAEs during the observation period. The irAEs included liver injury, hypothyroidism, adrenal insufficiency, adrenocorticotropic hormone deficiency, and rhabdomyolysis. Patients with irAE (n=10) were more likely to be positive for any autoantibody (hazard ratio [HR] 3.7, p=0.047) and RF at baseline (HR 5.4, p=0.035) and to achieve complete response (HR 5.8, p=0.027) than those without. The presence of autoantibodies at baseline was an independent factor associated with irAE development. In the real world, 16% of patients receiving AB therapy for u-HCC developed irAEs. Patients with autoantibodies at baseline are at high risk of developing irAEs and require cautious follow-up.

OR18-05 Interleukin 21 Drives The Development Of Autoimmune Diabetes Mellitus During Immune Checkpoint Inhibitor Cancer Therapy

Abstract Disclosure: J.G. Ortega: None. L.N. Scott: None. S. Wang: None. S. Zhang: None. H. Chen: None. N. Huang: None. M. Lechner: None. Autoimmune diabetes mellitus is a rare but life-threatening side effect of immune checkpoint inhibitor (ICI) cancer therapy. Checkpoint inhibitors increase immune activation by blocking natural regulatory molecules on T cells, including programmed death protein (PD1) and cytotoxic T lymphocyte antigen (CTLA4). As a result of increased immune activation, up to 60% of patients may develop autoimmunity in healthy tissues. Endocrine tissues are among the most often affected by these immune related adverse events (IRAEs). ICI-associated diabetes mellitus (ICI-T1DM) results from autoimmune destruction of insulin-producing pancreatic beta-cells. Patients with ICI-T1DM frequently present in diabetic ketoacidosis and require life-long insulin therapy. Unfortunately, the cause of many IRAEs remains poorly understood. We recently developed a mouse model of IRAEs in which anti-PD1 + anti-CTLA4 antibody treatment of autoimmunity-prone non-obese diabetic mice leads to multi-organ autoimmune infiltrates, including acceleration of insulinitis and DM. ICI-treated mice had increased CD4+ T follicular (Tfh; PD1+ICOS+CXCR5+) and T peripheral helper (Tph; PD1+ICOS+CXCR5-) cells compared to isotype-treated controls. Such Tfh and Tph cells secrete interleukin (IL)-21 and can promote cytotoxic CD8+ T cell function in autoimmunity. Indeed, CD8+ T cells expressing Granzyme B, interferon gamma (IFNγ), and chemokine receptor CXCR6 ("CD8+ autoimmune mediators") were expanded in ICI-treated mice. Furthermore, in vitro, IL21 induced the autoimmune mediator phenotype in CD8+ T cells, with upregulation of IFNγ, cytotoxic and trafficking molecules. Using mice with genetic deletion of T cell receptor alpha (NOD.TCRa-/-), we showed that CD4+ and CD8+ T cells were required for the development of IRAEs in ICI-treated mice. In addition, adoptive transfer of CD4+ and CD8+ T cells into immunodeficient NOD.SCID mice confirmed that these populations were sufficient to cause DM during ICI treatment. Thus, we predicted that IL21 from Tfh and Tph cells contributes to the development of pancreas IRAEs by activating CD8+ autoimmune mediator T cells. Indeed, in our model, mice with genetic blockade of IL21 signaling (IL21R-/-) were protected from developing diabetes. After 4 weeks of ICI treatment, only one of 11 (9.1%) IL21R-/- mice developed DM with onset at day 28, compared to 80% of ICI-treated wild-type (WT) mice, with a median DM-free time of 10 days from start of ICI therapy (p&amp;lt;0.0001, Log Rank test); no isotype-treated WT or IL21R-/- mice developed diabetes. Histologic analyses of pancreatic tissue from ICI-treated mice also showed a significantly lower insulinitis index in IL21R-/- compared to WT mice (mean 0.19±0.06 vs. 0.7±0.14, p&amp;lt;0.01). In summary, we identify IL21+ CD4+ Tfh/Tph cells as drivers of pancreas IRAEs and a potential therapeutic target to prevent ICI-T1DM in cancer patients. Presentation: Saturday, June 17, 2023

Efficacy of immune checkpoint inhibitors in patients with anorectal melanoma in association with immune-related adverse events: a case series.

Anorectal melanoma (AM) is a rare subtype of mucosal melanoma with a poor prognosis. Given its rarity compared to its cutaneous counterpart, the benefits and side effects of immune checkpoint inhibitor (ICI) therapy and the relationship between side effects and prognosis remain unclear. Herein, we describe the clinical presentation of five patients with AM treated with ICI as well as their relationship to the treatment course and the development of immune-related adverse events (irAEs). Three patients received sequential or concurrent administrations of nivolumab and ipilimumab, one received nivolumab alone, and one received ipilimumab alone. The response rate (RR) and disease control rate (DCR) were 40% and 80%, respectively. Pituitary and hepatic dysfunctions were the most common irAEs observed (40% each), followed by thyroid, diarrhea, and renal dysfunctions (20% each). The RR was 67% in patients with irAEs while no response was observed in patients without irAEs. DCR was 100% and 50% in patients with and without irAEs, respectively. Overall survival was 34months in irAE and 8.75months in non-irAE cases, with a longer survival trend in irAE cases. ICI therapy was effective and well-tolerated by AM patients, with potentially better outcomes for those who experienced irAEs compared to those who did not.

Atezolizumab-associated myositis in a patient with unresectable hepatocellular carcinoma.

Combination treatment with atezolizumab and bevacizumab is the preferred first-line treatment for patients with unresectable or metastatic hepatocellular carcinoma with a Child-Pugh Class A liver function. Reactivation of the antitumor immune response with atezolizumab can result in the development of immune-related adverse events including colitis, skin rash, endocrinopathies, pneumonitis, and nephritis with renal dysfunction. However, the occurrence of myositis with immune checkpoint inhibitors is rare. We report on a 67-year-old male patient with an initial diagnosis of hepatocellular carcinoma, stage IV, unresectable with underlying cirrhosis who experienced atezolizumab-associated myositis. Utilization of the American Society of Clinical Oncology guideline on managing immune checkpoint inhibitors adverse events helped guide the ordering of pertinent labs for monitoring and pharmacologic treatment. In our case, atezolizumab-induced myositis was resolved via a combination of corticosteroids, intravenous immunoglobulins, and plasmapheresis. Recognition of the signs and symptoms of atezolizumab-associated myositis is recommended and utilization of the American Society of Clinical Oncology guideline to guide management and treatment of associated symptoms.

Microbial Influences on Immune Checkpoint Inhibitor Response in Melanoma: The Interplay between Skin and Gut Microbiota.

Immunotherapy has revolutionized the treatment of melanoma, but its limitations due to resistance and variable patient responses have become apparent. The microbiota, which refers to the complex ecosystem of microorganisms that inhabit the human body, has emerged as a promising area of research for its potential role in melanoma development and treatment response. Recent studies have highlighted the role of microbiota in influencing the immune system and its response to melanoma, as well as its influence on the development of immune-related adverse events associated with immunotherapy. In this article, we discuss the complex multifactorial mechanisms through which skin and gut microbiota can affect the development of melanoma including microbial metabolites, intra-tumor microbes, UV light, and the immune system. In addition, we will discuss the pre-clinical and clinical studies that have demonstrated the influence of different microbial profiles on response to immunotherapy. Additionally, we will explore the role of microbiota in the development of immune-mediated adverse events.

The study of immune-related adverse events in a community-based centre.

2642 Background: The effectiveness of immunotherapy is often hindered by the development of immune-related adverse events (IrAE). Racial minorities were under-represented in the key clinical trials that led to the approval of different immune checkpoint inhibitors (ICI). In this study, we explore the side effect profile of immune checkpoint inhibitors in our patient population that comprises almost entirely of minorities, mostly African Americans (AA) and Hispanics. We hypothesize that due to race-based differences in immune milieu of the body and disease susceptibility, the timing and severity of immunotherapy-related IrAE would be different in AA and Hispanics compared to Caucasians. This can translate into a difference in clinical outcomes as well. There have been some suggestions of a positive association of the development of IrAE with cancer survival, although the data is limited and heterogeneous. The purpose of our study is to study the frequency and severity of IrAEs in racial minority groups, compare them with previous clinical trials population, and add valuable real-world data in this underrepresented group of patients. Methods: A retrospective chart review was performed on adult patients with solid malignancies treated with any ICI between January 1, 2015 and April 30, 2022. Patients were classified according to age (greater/equal to 65y or younger), sex, race (self-identified), primary cancer, and type of immunotherapy received. Outcome data using type and severity of IrAE, time to development of IrAE, and any association with clinical outcomes was collected and analyzed using descriptive statistics as well as univariate analysis. Results: A total of 78 patients were included in the final analysis. The mean age was 68 years; 51% were males; 42.3% were Hispanics, 37% were AA, 19.7% were others, and 1% were Whites. Most common malignancy was lung cancer (65.5%). Most common ICI agent used was Pembrolizumab (n = 52) and 2 patients were treated with combination therapy using Ipilimumab and Nivolumab. 41 (52.5%) patients had IrAE of any grade while 9 (11.5%) patients experienced grade 3 side effects. None of the patients experienced grade 4 side effects. Most common IrAE of any grade was hypothyroidism (n = 14) while most common grade 3 side effect was colitis (n = 6). 31 patients were less than 65y of age. There was no significant difference in IrAE in patients less than 65 years of age vs ≥ 65 years (51.6% vs 53.1%) or grade 3 IrAE (9.6% vs 12.7%). Conclusions: In our study population consisting mostly of AA and Hispanics, the rate of IrAE of any grade as well as grade 3 or 4 IrAE with ICI therapy was comparable to what was seen in clinical trials involving these drugs. This data and its potential effects on survival outcomes need to be analyzed in prospective studies involving a larger number of patients.

Prognostic significance of immune-related adverse events and immunosuppression in patients with melanoma receiving adjuvant anti-PD-1 therapy.

9580 Background: Treatment with anti-Programmed Death-1 (PD-1) therapy reduces the risk of recurrence for patients (PT) with resectable Stage IIB-IV melanoma (MEL). This treatment is associated with the development of immune-related adverse events (irAEs), which may necessitate use of immunosuppressive therapy and treatment discontinuation. This project investigates the impact of irAE and immunosuppressive therapy in survival outcomes of PTs with MEL. Methods: PTs with stage IIB-IV resectable MEL who received adjuvant or neoadjuvant treatment with anti-PD-1 therapy were enrolled from the University of Pittsburgh Melanoma Center biospecimen repository. The association between irAEs/immunosuppressive therapy and recurrence-free survival (RFS) and overall survival (OS) were evaluated by univariate and multivariate Cox proportional hazards regression models. Results: A total of 6059 PT were consented to the repository: stage III = 1,328, stage IIB = 403, and stage IIC = 269 PT. Of these PT, 180 men and 93 women received adjuvant anti-PD-1 therapy. Average age at diagnosis was 61. BRAF mutation present in 94 PTs: V600E = 71 PT, V600K = 11 PT. Documented irAEs occurred in 50.9% of PTs. Cutaneous irAEs were most common (65/139, 46.8%), followed by endocrine (45/139 32.4%), and visceral organ (37/139, 26.6%). Of the 32 visceral organ irAEs, 15 were gastrointestinal, 10 pulmonary, 5 hepatic, and 1 renal. Systemic corticosteroids &gt; 10mg of prednisone equivalent were administered during adjuvant therapy for 24.9% of PT. In the univariate model, development of irAEs was associated with improved OS (HR = 0.38; CI 0.18-0.83, p = 0.015). In a multivariate analysis after adjusting for age and sex, irAE development continued to be associated with improved OS (HR = 0.38; CI 0.17-0.82, p = 0.014). RFS did not differ for patients that developed irAEs (HR = 0.9; CI 0.59-1.4, p = 0.67). Steroid treatment was not associated with a change in OS (HR = 1.04; CI 0.46-2.4, p = 0.93) or RFS (HR = 0.96; CI 0.59-1.56, p = 0.87). Conclusions: Half of stage IIB-IV resectable MEL PT receiving adjuvant anti-PD1 therapy developed irAEs, of which 24% required steroid therapy. Development of irAE was associated with improved OS and corticosteroid use for irAE did not mitigate adjuvant therapy outcome benefits.

The exploratory case-control study on prediction of immune checkpoint inhibitor-induced thyroiditis by human leukocyte antigen types.

2558 Background: Given the function of human leukocyte antigen (HLA) in immunity, variation of the HLA type could affect the development of immune-related adverse events (irAEs) that is induced by immune checkpoint inhibitors (ICIs). In this study, we examined whether HLA types of cancer patients could be a marker for the development of irAE thyroiditis. Methods: In the present case-control study, we randomly selected 20 cancer patients who received ICIs and developed thyroiditis (irAE thyroiditis group) and 51 who did not develop thyroiditis (No irAE thyroiditis group). The 51 patients were subdivided into 31 who did not develop any irAEs (No irAEs group) and 20 who developed irAEs other than thyroiditis (irAEs other than thyroiditis group). HLA types were classified at the amino acid sequence level (Field 2 resolution). Frequency of the HLA types of each group was compared. Results: There was no significant difference in HLA type prevalence, comparing the irAE thyroiditis group and the No irAE thyroiditis group. When comparing the irAE thyroiditis group with the No irAEs group, the irAE thyroiditis group had significantly higher HLA-X, HLA-Y, and HLA-Z (Tentative names are used here, and actual HLA types will be announced at the time of publication). This result suggested that irAEs other than thyroiditis in the control group could be noise. HLA-X had a specificity of 96.8% for the development of irAE thyroiditis. HLA-Y had a sensitivity of 80.0%. Patients carrying both HLA-X and HLA-Y had the highest specificity of 100.0%. There was a significant difference in frequency of HLA-Y between irAEs other than the thyroiditis group and the No irAEs group. HLA-Y may be a universal marker for any irAEs. On the other hand, HLA-X is a specific marker for thyroid irAE. The median time of onset of irAE thyroiditis in all patients was 72 days after ICI administration. Patients with both HLA-X and HLA-Y tended to have an earlier onset with a median onset time of 53 days. Conclusions: We found an association between specific HLA types and the development of irAE thyroiditis. The present study indicates that HLA types could be a predictive marker for the development of irAE thyroiditis.

Association of immune-related adverse events and improved treatment outcomes across race/ethnicity in a diverse patient population.

e21220 Background: The development of immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors (ICIs) has been associated with improved clinical outcomes in advanced non-small cell lung cancer (NSCLC). However, how this association extends across race and ethnicity remains uncertain. In this study, we evaluated the association between the development of irAEs and treatment outcomes across different racial and ethnic groups treated at a single institution. Methods: We performed a retrospective chart review to identify irAEs and treatment outcomes in patients with advanced NSCLC who had received treatment with ICIs at our institution between 2015-2020. The incidence of irAEs across racial subgroups was compared using logistic regression analysis. Cox regression analysis was carried out to evaluate the associations between the development of irAEs and treatment outcomes [Overall Survival (OS) and Progression Free Survival (PFS)] in these subgroups. Results: We identified a total of 138 NSCLC patients who received treatment with ICIs, of whom 50% (69) identified as non-Hispanic Black (NHB) and 50% (69) as others, including 34% (47) as non-Hispanic White. The overall incidence of irAEs in the cohort was 28%, with no significant difference between NHB and other racial groups (29% vs. 27.5%). However, females [OR 2.3 (1.1-4.8)] and patients who did not have Medicare or private insurance (i.e had Medicaid or MassHealth) were found to have a higher incidence of irAEs [OR 2.7 (1.2-5.7)]. With a median follow-up time of 363 days, the proportion of patients who were progression-free was greater in patients who had experienced irAEs than in those who did not experience irAEs [HR for time to progression 0.46 (0.23 – 0.92)]. The association between irAEs and improved PFS in NHB patients was similar to the overall population [median PFS 246 vs. 181; HR 0.87 (0.58-1.29)]. Higher ECOG status, higher Charlson Comorbidity Index and receiving ICIs as 2nd or subsequent line therapy were independently associated with worse PFS. Conclusions: Our single-institution study demonstrated a similar incidence of irAEs in patients with NSCLC across different racial and ethnic groups. As in prior studies, patients undergoing treatment with ICIs and experiencing irAEs had significantly better outcomes. We found that the association between the development of irAEs and improved treatment outcomes was independent of race and ethnicity, supporting the importance of making unbiased treatment recommendations without regard to these factors. [Table: see text]

Efficacy and safety of durvalumab + chemotherapy vs. atezolizumab + chemotherapy in the treatment of small‑cell lung cancer: a retrospective comparative cohort study.

Durvalumab and atezolizumab have recently been approved in extensive small cell lung cancer (SCLC) with moderate median overall survival (OS) improvements. However, only limited data exist regarding the impact of immunotherapy in real-world SCLC patients. This study sought to assess the efficacy and safety of atezolizumab plus chemotherapy and durvalumab plus chemotherapy in the treatment of SCLC in a real-world setting. A retrospective cohort study of all patients treated for SCLC with chemotherapy with PD-L1 inhibitor, at 3 centers in China between February 1, 2020 and April 30, 2022. Patient characteristics, adverse-events and survival analyses were conducted. A total of 143 patients were enrolled in this study, 100 were treated with durvalumab and the remainder with atezolizumab. The baseline characteristics of the two groups were fundamentally balanced before using PD-L1 inhibitors (P>0.05). The median OS (mOS) of the patients who received durvalumab or atezolizumab as the first-line treatment were 22.0 and 10.0 months, respectively (P=0.03). Survival analysis of patients with brain metastasis (BM) revealed that the median progression-free survival (mPFS) of patients without BM treated with durvalumab plus chemotherapy (5.5 months) was longer than that of those with BM (4.0 months) (P=0.03). In contrast, in the atezolizumab plus chemotherapy regimen, BM did not affect survival. In addition, the addition of radiotherapy to treatment with PD-L1 inhibitors in combination with chemotherapy has a tendency to improve long-term survival. As for safety analysis, there was no significant difference in the incidence of immune-related adverse events (IRAEs) during PD-L1 inhibitor therapy between the 2 groups (P>0.05). And during treatment with immunochemotherapy, radiotherapy was not associated with the development of IRAE (P=0.42) but increased the risk of immune-related pneumonitis (P=0.026). The implication of this study for clinical practice is a preference for durvalumab in first-line immunotherapy for SCLC. In addition, appropriate radiotherapy during treatment with PD-L1 inhibitors in combination with chemotherapy may prolong long-term survival, but the occurrence of immune-related pneumonitis should be vigilant. Data from this study are limited and the baseline characteristics of the two populations still need to be more finely classified.

Comparison of peripheral blood markers in predicting the occurrence of immune-related adverse events in patients with metastatic genitourinary cancer treated with cabozantinib + nivolumab +/- ipilimumab.

e16506 Background: Peripheral blood markers (PBM) have been demonstrated to be prognostic and/or predictive for cancer patients (pts) treated with immune checkpoint inhibitors (ICI). Initial evidence has shown their potential role in predicting the occurrence of immune-related adverse events (IrAE) in pts treated with single-agent ICI. We explored the potential role of different PBM in predicting IrAE in metastatic genitourinary cancer (mGU) pts treated with an ICI-based combination. Methods: We retrospectively evaluated 60 mGU pts treated with Cabozantinib + Nivolumab +/- Ipilimumab (CaboNivo +/- Ipi) in a phase I study at the National Cancer Institute. We retrieved their demographics, the occurrence of IrAE, and the baseline values of different PBM (neutrophil/lymphocyte ratio [NLR], neutrophil/eosinophil ratio [NER], lymphocyte/monocyte ratio [LMR], monocyte/lymphocyte ratio [MLR], platelet/lymphocyte ratio [PLR], systemic immune-inflammation index [SII] [N/L*P], and HALP score [albumin*hemoglobin*L/P]). We evaluated PBM based on the presence or absence of IrAE using the Wilcoxon rank sum test followed by multivariable logistic regression analysis. Receiver operating characteristic (ROC) curve analyses were used to investigate an optimal cut-off for PBM suitable for prediction. Results: The median age of pts was 58.5 years (interquartile range [IQR] 46 - 67), and 13 (21.7%) were female. Twenty (33.3%) pts developed at least one IrAE. Baseline median values of PMB are summarized in the Table. A multivariable logistic regression model showed after backward elimination that only NER had the potential to predict IrAE (p = 0.033; Odds Ratio = 0.989 per unit [95% Confidence Interval 0.979 - 0.999]) and thus, we further investigated the predictive potential of NER for the development of IrAE following CaboNivo +/- Ipi. The ROC curve suggested that an optimal cut-off value for NER was 30.647 (area under the ROC = 0.6351). Accordingly, we classified pts with high NER ( &gt; 30.647) as not having IrAE vs low NER (≤ 30.647) as having IrAE. Using this classification, 24/37 (64.9%) of those without (w/o) IrAE and 14/20 (80%) of those with an IrAE could simultaneously be correctly predicted by NER alone. Conclusions: A baseline low NER value was an independent factor associated with a higher probability of developing IrAE in mGU pts treated with CaboNivo +/- Ipi. Prospective validation on a larger cohort of pts is needed. [Table: see text]

Predicting immune-related adverse events using a simplified frailty score in cancer patients treated with checkpoint inhibitors: A retrospective cohort study.

Checkpoint inhibitors (CPIs) are in widespread clinical use. Little is known about which patients are at risk for developing toxicity. It is essential being able to identify patients with higher risk of experiencing immune-related adverse events (IRAEs) before initiation of CPI treatment to optimize treatment decisions and follow-up strategy. The aim of this study was to investigate whether a simplified frailty score based on performance status (PS), age, and comorbidity expressed as Charlson comorbidity index (CCI) could predict development of IRAEs. We performed a retrospective cohort study at three Swedish centers. All patients (n = 596) treated with PD-L1 or PD-1 inhibitor for advanced cancer between January 2017 and December 2021 were included. In total, 361 patients (60.6%) were classified as nonfrail and 235 (39.4%) as frail. The most common cancer type was non-small cell lung cancer (n = 203; 34.1%) followed by malignant melanoma (n = 195; 32.7%). Any grade of IRAE occurred in 138 (58.7%) frail and in 155 (42.9%) non-frail patients (OR: 1.58; 95% CI: 1.09-2.28). Age, CCI, and PS did not independently predict the occurrence of IRAEs. Multiple IRAEs occurred in 53 (22.6%) frail and in 45 (12.5%) nonfrail patients (OR: 1.62; 95% CI: 1.00-2.64). In conclusion, the simplified frailty score predicted all grade IRAEs and multiple IRAEs in multivariate analyses whereas age, CCI, or PS did not separately predict development of IRAEs suggesting that this easy-to-use score may be of value in clinical decision making but a large prospective study is needed to assess its true value.