Management Of irAEs Research Articles

Isolated Neutropenia Due to Immune Checkpoint Inhibitors.

In this article, we explore the correlation between immune checkpoint inhibitors (ICIs) and neutropenia. Immune checkpoint inhibitors have revolutionized cancer treatment and management by maximizing the innate abilities of the immune system. However, this therapeutic potential is accompanied by a range of immune-related adverse effects (irAEs), including neutropenia, which is a rare but potentially life-threatening side effect of this mode of cancer treatment. Through an in-depth analysis of various case reports, we have compiled a detailed table summarizing the occurrences of neutropenia associated with different ICIs, the grades of neutropenia, treatments used, and patient outcomes. Management of neutropenia must include an approach based on early diagnosis of the condition and a treatment based on its severity. This review discusses different therapeutic interventions, ranging from the administration of corticosteroids and intravenous immunoglobulin (IVIG) to the use of granulocyte colony-stimulating factor (filgrastim) and, in very severe cases, a stem cell transplant. We have also enlisted salient side effects caused by these interventions.Our findings emphasize that while neutropenia is a relatively rare adverse effect of ICIs, its severity necessitates increased awareness among healthcare professionals. As ICIs continue to be seen as an integral component of cancer therapy, a comprehensive understanding of neutropenia as a side effectand its management is critical for optimizing patient outcomes. A crucial purpose of this review is to highlight the need to achieve a balance between acquiring the therapeutic benefits of various treatment strategies for irAEs and considering their potential side effects, especially with the use of steroids. Achieving this equilibrium is very important in optimizing patient care during immunotherapy, as these irAE management options can bothmitigate the neutropenia triggered by ICIs and potentially give rise to secondary complications. Therefore, a careful assessment of the risks and benefits associated with each treatment approach is essential in tailoring irAE management.

Effects of immune-related adverse events (irAEs) and their treatment on antitumor immune responses.

Immune checkpoint inhibitors (ICIs) are potentially life-saving cancer therapies that can trigger immune-related adverse events (irAEs). irAEs can impact any organ and range in their presentation from mild side effects to life-threatening complications. The relationship between irAEs and antitumor immune responses is nuanced and may depend on the irAE organ, the tumor histology, and the patient. While some irAEs likely represent an immune response against antigens shared between tumor cells and healthy tissues, other irAEs may be entirely unrelated to antitumor immune responses. Clinical observations suggest that low-grade irAEs have a positive association with responses to ICIs, but the correlation between severe irAEs and clinical benefit is less clear. Currently, severe irAEs are typically treated by interrupting or permanently discontinuing ICI treatment and administering empirically selected systemic immunosuppressive agents. However, these interventions could potentially diminish the antitumor effects of ICIs. Efforts to understand the mechanistic relationship between irAEs and the tumor microenvironment have yielded meaningful insights and nominated therapeutic targets for irAE management that may preserve or even boost ICI efficacy. We explore the clinical and molecular relationship between irAEs and antitumor immunity as well as the role that irAE treatments may play in shaping antitumor immune responses.

Neurological adverse events associated with PD-1/PD-L1 immune checkpoint inhibitors.

Immunotherapy is a promising method for cancer treatment. Among them, immune checkpoint inhibitors targeting PD-1/PD-L1 are increasingly used for certain cancers. However, with the widespread use of such drugs, reports of immune-related adverse events (irAEs) are also increasing. Neurological adverse events (nAEs) are one of the irAEs that affect the peripheral and central nervous systems. They are characterized by low incidence, hard to diagnose, and life-threatening risks, which have a significant impact on the prognosis of patients. Biomarker-based early diagnosis and subsequent treatment strategies are worthy of attention, and comprehensive management of irAEs is important for optimizing patients' quality of life and long-term outcomes. In this review, we summarized the mechanisms, common symptoms, early biomarkers, treatments, and future research directions of nAEs, in order to provide a comprehensive overview of immune checkpoint inhibitor-related nAEs targeting PD-1/PD-L1.

Incidence and predictors of infections in patients with advanced non-small cell lung cancer treated with checkpoint inhibitor immunotherapies: A monocentric retrospective cohort study.

Immune checkpoint inhibitors (ICIs) represent the cornerstone of the current treatment of non-small cell lung cancer (NSCLC). However, the occurrence of concomitant infections might hamper success. All consecutive patients with advanced NSCLC who started ICIs as a first- or second-line therapy from January 1, 2017 to June 30, 2020 were retrospectively evaluated. The occurrence of infectious events during ICIs was correlated with clinical characteristics, including previous Cytotoxic Chemotherapy (CC), occurrence of immune-related-adverse-events (irAEs). A total of 211 patients were included, 46 (22%) females, with a median (q1-q3) age of 69 (62-76) years. Overall, 85 patients (40%) received ICIs as a first treatment line and 126 (60%) as a second line; 40 patients (19%) had at least one infection during ICIs, and 17 (8%) more than one. Notably, autoimmune diseases (P < .005), neutropenia (P = .001) or infections during previous CC (P = .001), irAEs (P = .006), or steroid therapy for irAEs (P < .001) were associated with infection development. By multivariate Cox-regression, autoimmune diseases (aHR = 6.27; 95%CI = 2.38-16.48; P < .001) and steroid therapy for irAEs (aHR = 2.65; 95%CI = 1.27-5.52; P < .009) were associated with a higher risk of infection during ICIs. Interestingly, autoimmune diseases were confirmed as risk factors in patients treated with ICIs as a first line, while previous infections were the only independent predictor of infections in patients treated with ICIs as a second line. Patients with NSCLC treated with ICIs with concurrent autoimmune disease, receiving steroid therapy for management of irAEs, or having a history of previous infections during CC should be actively monitored for the risk of developing infectious complications.

Better Late Than Never: The Impact of Steroidal Treatment on the Outcome of Melanoma Patients Treated with Immunotherapy.

Successful treatment with Immune Checkpoint Inhibitors (ICI) requires the balanced activation of the immune system. Over-activation may result in immune-related adverse events (irAEs), which often require steroidal treatment. This study examined the possible impact of steroids on treatment efficacy in melanoma patients concerning initiation timing and dosage. A retrospective, single-center analysis of patients with advanced melanoma who underwent first-line ICI therapy during 2014-2020 was conducted. Among the 415 patients, two-hundred patients (48.3%) were exposed to steroids during the first line, most of them due to irAEs (n = 169, 84.5%). Nearly a quarter of them were exposed to steroids within the first four weeks of treatment. Surprisingly, steroidal exposure was associated with better progression-free survival (PFS; HR = 0.74, p = 0.015); however, early exposure (within four weeks of treatment) resulted in a significantly shorter PFS compared to late exposure (adjusted HR 3.2, p < 0.001). Early exposure to corticosteroids during the priming phase of ICI therapy could impede the establishment of an effective immune response. These results suggest that caution should be exercised when considering the use of steroids for the management of early-onset irAEs.

Management of immune related adverse events through electronic multidisciplinary consultation: Five years of experience from Peking Union Medical College Hospital.

e14712 Background: The increasing occurrence of immune-related adverse events (irAEs) pose a growing challenge for patients receiving immunotherapy. We sought to evaluate the utility of telemedicine in improving access to the multidisciplinary service and to provide a comprehensive overview of practical issues in the diagnosis and management of irAEs. Methods: A virtual multidisciplinary service dedicated to the diagnosis and management of irAEs was launched in July 2018. Data were collected using a digital referral system. Results: Data were collected from 1 July 2018 to 30 June 2022. After excluding 11 consultations that were lost to follow-up or had incomplete medical records, 278 consultations were included in this study. 187 consultations related to the diagnosis and management of irAEs; 68 related to the management of irAEs; 23 related to the suitability of immunotherapy. The diagnosis of irAE was ruled out in 23% (43/187) of cases. The differential diagnosis included overlapping toxicity attributed to concurrent use of targeted therapy or chemotherapy (n = 16), comorbidities (n = 11), infection (n = 10), and cancer progression (n = 6). A diagnosis of irAE was confirmed in 206 cases. Of these, 131 cases were single organ/system irAEs and 75 cases were multiple organ/system irAEs. 83% of these were grade 3-4. The most common confirmed irAEs were interstitial lung disease (n = 45), diarrhoea/colitis (n = 41), liver dysfunction (n = 38) and myocarditis (n = 33). Initiation of corticosteroids was recommended in 100% (138/138) of treatment-naïve patients. The most commonly recommended corticosteroid dose was 1-4 mg/kg/d (n = 83, 45%). Corticosteroid dose adjustment was recommended in 90% (61/68) of treated patients, including dose escalation (n = 19), dose re-escalation or prolonged tapering (n = 30), and rapid tapering (n = 12). Cardiovascular, pulmonary, rheumatic and hepatic irAEs were the top four irAEs requiring immunosuppression in addition to corticosteroids. Intravenous immunoglobulin (n = 108), tocilizumab (n = 51), mycophenolate mofetil (n = 41), and infliximab (n = 21) were the four most commonly recommended immunosuppressants. Consultation recommendations were followed in 87% (166/191) of cases. Clinical improvement was observed in 83% (137/166) of cases. Conclusions: This study demonstrated the feasibility of the electronic multidisciplinary consultation in the diagnosis and management of irAEs. Common challenges in the diagnosis of irAEs were identified, mainly the differential diagnosis of non-immune toxicity, infection, cancer progression, or comorbidities. Awareness of differential diagnosis should also be raised in patients suspected of irAE flare. The use of corticosteroids and additional immunosuppressants needs to be further investigated.

Immune-mediated adverse event management at a tertiary care cancer center.

e14697 Background: Our understanding of immune-related adverse events (irAEs) has evolved rapidly with management guidelines constantly being updated. We aim to explore temporal changes in irAE management at a tertiary cancer care center to identify areas for potential improvement. Methods: This was a single-center, retrospective study including patients who developed a GI, pulmonary, renal, or cardiac irAE between 07/01/2019-10/01/2019 compared to a contemporary cohort from 2021. The follow-up window was for up to a year after diagnosis. Data collected included patient demographics and irAE management and outcomes. Results: Endoscopic evaluation and GI follow-up after discharge for patients with GI irAEs fell over the years. Despite this, there was a decline in symptom duration and steroid taper attempts. The pulmonary service showed improvements in consultation, hospital admission and re-admission, and ICU admission. However, follow up post-hospital discharge were consistently low ( &lt; 50%). Rate of cardiology consultation was consistently high across the years with an equally fast time to consultation, and myocarditis cohort in 2021 had a higher clinical response rate than the 2019 cohort. There were no major differences across the years for renal irAEs. We found that outpatient treatment and earlier GI consult improved outcomes in GI irAEs. For pulmonary irAEs, hospitalization, symptom recurrence, multiple steroid tapering courses, and hospital readmission were associated with less pneumonitis remission. Conclusions: This is one of the few qualitative studies exploring current practice in managing irAEs. We identified areas to improve the management on across all specialties, and found specific factors associated with better outcomes in GI and pulmonary irAEs. Together, these findings can help improve the quality of irAE management algorithms at our institution. [Table: see text]

Incidence, risk factors, and outcomes of immune-related adverse events (irAEs) in a prospective, pan-tumor population.

2662 Background: IrAEs associated with immune checkpoint inhibitors (ICIs) can result in morbidity and mortality. The incidence, spectrum, and risk factors for irAEs are usually reported from retrospective studies and clinical trials, which typically exclude patients (pts) with pre-existing autoimmune disease (AD). The prevalence and risk factors for irAEs in a diverse, pan-tumor, real-world setting is not well understood. Methods: From 06/2021 to 2/2023, we prospectively enrolled pts receiving ICIs (alone or in combination as standard-of-care) at a tertiary care center in this imCORE network study. Univariate and multivariate logistic regressions and survival curves were used to interrogate risk factors for irAE development and the relationship between irAEs, graded using CTCAE v5.0, and clinical response by RECIST 1.1. Results: 132 pts with prior ICI therapy were prospectively followed. Median age was 65 years (IQR 56-72), 35% were female, 69% were white, and 24% were black. Most common tumor histologies were: hepatocellular, renal cell, bladder, non-small cell lung, and head and neck carcinoma. 23% (n=30/132) received dual ICI (nivolumab+ipilimumab). In the whole cohort, 36.4% (n=48/132) of pts developed any-grade irAE and 10.6% (n=14/132) developed a severe irAE (grades 3-5). There were 2 fatal irAEs (n=1 hepatitis, n=1 myocarditis) representing 1.5% of the total cohort. The median time to first irAE was 1.8 months (mos; IQR 1.2-3.1) for anti-PDL1 monotherapy, 1.2 mos (IQR 0.7-2.2) for dual ICI, 4.4 mos (0.2-8.7) for PDL1+chemotherapy, and 2.1 mos (1.3-3.1) for PDL1+other. A subgroup of pts (10.6%; n=14/132) had pre-existing AD and 50% (n=7/14) had ever received immunosuppression for their AD. Among pts with AD, the incidence of irAEs was 57% (n=8/14) vs 33.9% (n=40/118) among those without AD. Antitumor response for pts with AD was 27.3% vs 25.8% those without AD. Receipt of dual ICI therapy was associated with increased risk of any-grade irAE (OR 2.87 p=0.02) and severe irAE (OR 40.9 p=0.004). Pts with any grade irAEs were significantly more likely to experience a partial/complete response vs pts without irAEs (OR 4.14 p=0.02) and this relationship was preserved after adjustment for single vs dual ICI. Pts who did not develop irAEs had an overall response rate (ORR) of 18.2%, mPFS of 3.5 mos (IQR 1.6-7.3), and mOS 7.3 mos (IQR 3.8-9.9) vs pts who developed any grade irAE who had an ORR of 37.8%, mPFS of 5.9 mos (IQR 3.3-8.8), and mOS 8.6 mos (IQR 4.9-11.4). Conclusions: In this pan-tumor, prospective cohort study of pts receiving ICI therapy in a real world setting, we identified that pts with pre-existing AD and those on dual ICI had increased risk of irAE development. This signals the need for closer monitoring, early recognition, and management of irAEs in these pts. In addition, pts who developed irAEs were more likely to experience partial or complete response in a diverse tumor cohort.

Immune-related adverse events secondary to immunotherapy in oncology: A guide for general practice.

Immunotherapy has reshaped the prognoses for many cancers and is increasingly used in both metastatic andadjuvant settings. There is a high prevalence of immunotherapy side effects, or immune-related adverse events (irAEs), which can affect any organ. Some irAEs can cause permanent or prolonged morbidity and, in rare cases, may be fatal. irAEs can present with mild, non-specific symptoms, resulting in delays to identification and management. We aim to provide a general overview of immunotherapy and irAEs, highlighting common clinical scenarios and general principles of management. Cancer immunotherapy toxicity is an important clinical problem that is increasingly relevant to general practice, where patients with adverse events may first present. Early diagnosis and timely intervention are important in limiting the severity and morbidity of these toxicities. The management of irAEs should follow treatment guidelines, in consultation with patients' treating oncology teams.

Risk of immune-related adverse events (irAE) with immune checkpoint inhibitors (ICI) in patients (pts) with family history (FH) of autoimmune disease (AID).

2648 Background: Pts with personal history (PH) of AID are at increased risk of irAE following ICI. Risk of irAE in pts with FH of AID is unknown. Methods: In this retrospective cohort study, consecutive pts were recruited from 2 Australian melanoma cancer centers. Pts who received anti-PD-1 (PD1) based ICI with FH of AID were eligible. Pts with PH of AID were excluded. Toxicity data (CTCAE v5.0) was obtained and stratified by FH of AID (first/second/third degree relative). Descriptive statistics and Fisher’s Exact test were used for analysis. Results: 396 melanoma cases were screened, of which 44 (11.1%) were eligible for inclusion. Baseline characteristics are summarized. 57 irAE occurred in 44 pts. The most common irAE were dermatological (n=11; 19.3%), colitis (n=8; 14.0%), endocrinopathies (n=8; 14.0%), hepatitis (n=7; 12.3%) and arthritis (n=7; 12.3%). Among 57 irAE, frequency of Grade 1,2,3 and 4 irAE was 16 (28.1%), 26 (45.6%), 12 (21.0%) and 3 (5.3%) respectively. Corticosteroids were used for 31 (54.4%) irAE. Hospital admission for management of irAE occurred in 11 pts (25.0%). ICI was discontinued in 20 pts (45.5%) due to irAE. In pts with irAE, FH of that irAE/AID was present in 6 pts (13.6%) (n= 2 x arthritis, n= 2 x psoriasis, n= 1 x Crohn’s disease, n= 1 x Grave’s disease), and 4 of these patients had a first-degree relative with an AID. 3/6 pts had ICI ceased due to an irAE (peak toxicity Grade was 3) and 4/6 pts had RECIST response. There was no association in development of irAE between patients with FH of AID in a first-degree relative and those with FH of AID in second or third degree relative (p=0.17). Rate of irAE in pts with FH of AID was not statistically higher to that reported in registration trials of similar regimens (p=0.40). Conclusions: FH of AID is common in melanoma pts and was not associated with higher rate or morbidity of irAE. FH AID should be routinely collected, and larger scale studies need to be performed. [Table: see text]

Challenges and Limitations of Endocrine Toxicity Evaluation in Non-Small Cell Lung Cancer Patients Treated with Immunotherapy-Retrospective Study from a Tertiary-Level Hospital in Romania.

(1) Background: The endocrine system has become a prominent target to autoimmune damage during treatment with immune checkpoint inhibitors (ICIs) in cancer patients. Real-world data regarding endocrine immune-related adverse events (irAEs) are needed to explore their impact in cancer patients. An analysis was conducted to evaluate endocrine irAEs caused by ICIs, besides the challenges and limitations of daily medical practice in oncology in Romania. (2) Methods: This was a retrospective cohort study of lung cancer patients treated with ICIs at Coltea Clinical Hospital, Bucharest, Romania, from 1 November 2017 to 30 November 2022. Endocrine irAEs were identified through endocrinological assessment and were distinguished as any occurring endocrinopathy during treatment with ICIs and related to immunotherapy. Descriptive analyses were performed. (3) Results: Of 310 cancer patients treated with ICIs, we identified 151 with lung cancer. From this cohort, 109 NSCLC patients qualified for baseline endocrine estimation and 13 patients (11.9%) developed endocrine irAEs, such as hypophysitis (4.5%), thyroid disorder (5.5%) and primary adrenal insufficiency (1.8%), with one or more endocrine glands being affected. There might be a correlation between endocrine irAEs and duration of ICI treatment. (4) Conclusions: Early diagnosis and adequate management of endocrine irAEs may be challenging in lung cancer patients. A high incidence of endocrine irAEs is expected with the growing use of ICIs, and because not all endocrine events are immune-related, cooperation between oncologists and endocrinologists is crucial in the management of these patients. More data are needed to confirm the correlation between endocrine irAEs and the efficacy of ICIs.

Systematic surveillance of immune-related adverse events in clinical practice and impact of subsequent steroid medication on survival outcomes.

Recent advances in immune-checkpoint inhibitors (ICIs) have highlighted the need for effective management of immune-related adverse events (irAEs). This study aimed to conduct a systematic surveillance of real-world development of irAEs for understanding their characteristics and examine the prognostic impact of steroid use for these events. We retrospectively investigated cancer patients treated with ICIs between 2014 and 2021 and collected information about irAEs throughout their development, management, and clinical outcomes. Overall, 458 patients (45.4%) developed 670 irAEs. The prevalence of irAEs varied by cancer type, but it was increased in regimens with longer treatment durations. Severe irAEs were more common in the nivolumab + ipilimumab and pembrolizumab + axitinib regimens. Patients who received steroids for irAEs at a dosage of < 2mg/kg had comparable prognosis to those who did not receive steroids; however, patients who received methylprednisolone pulse therapy, primarily for severe pneumonitis and hepatitis, had shorter overall survival than those who did not receive steroids (7.8 versus 23.4months, p = 0.016). Furthermore, methylprednisolone pulse therapy for irAEs was a poor prognostic factor in multivariate analysis (hazard ratio: 2.19, 95% confidence interval: 1.34-2.86, p < 0.001). Steroid treatment for irAE does not affect prognosis and should thus be used promptly to control inflammation. However, pulse therapy for severe cases is a poor prognostic factor, and early detection remains the key to managing such irAEs. The irAE characteristics in each regimen should be clarified to establish and provide more sophisticated irAE management, and the current findings will be beneficial to this goal.

Endocrine Dysfunction From Immune Checkpoint Inhibitors: Pearls and Pitfalls in Evaluation and Management.

Immune checkpoint inhibitors (ICPis) have proven extremely efficacious in cancer therapy but also lead to a plethora of immune-related adverse events (irAEs). The endocrine irAEs are not only quite common but also may pose a challenge to the clinician while managing a patient with cancer treated with ICPis. The clinical features of endocrine dysfunction are usually nonspecific and may overlap with concurrent illnesses, underlying the importance of accurate hormone testing and efforts toward case-finding. The management of endocrine irAEs is unique in the focus being on hormone replacement rather than curtailing the autoimmune process. Although the management of thyroid irAEs appears straightforward, adrenal insufficiency and insulin-dependent diabetes can be life-threatening if not promptly recognized and treated. This clinical review synthesizes the studies to provide pearls and pitfalls in the evaluation and management of endocrine irAEs with specific reference to guidelines from oncologic societies.

Role-Specific Curricular Needs for Identification and Management of Immune-Related Adverse Events.

Immune checkpoint inhibitors (ICIs) activate the immune system against cancer and have become standard of care for many cancers. With increased ICI use, their toxicitiesknown as immune-related adverse events (irAEs) are becoming more common, but it is unclear how prepared relevant clinicians feel to diagnose and treat irAEs. The objective of this study was to assess irAE knowledge, confidence, and experience among generalists and oncology clinicians to guide future curricular interventions related to irAEs. A 25-item survey with questions assessing knowledge, experience level, confidence, and resource utilization regarding irAE diagnosis and management was sent to University of Chicago-affiliated(UChicago) internal medicine residents and hospitalists (inpatient irAE management)along with UChicago oncology fellows, attendings, nurse practitioners (NPs), andphysician assistants (PAs) (inpatient and outpatient) as well as Chicago community oncologists (outpatient) in June 2022. Overall response rate was 37% (171/467). Knowledge scores averaged below 70% for all clinicians. "No idea" responses were most common with knowledge questions on steroid-sparing agent use and ICI use for patients with preexisting autoimmune disease. IrAE experience correlated with higher knowledge for oncology attendings (p = 0.015) and hematology/oncology NPs/PAs (p = 0.031). IrAE experience correlated with higher confidence for residents (p = 0.026), oncology fellows (p = 0.047), and hematology/oncology NPs/PAs (p = 0.042). Most commonly utilized resources were colleagues and UpToDate, and most clinicians were very likely to use online resources in the future. Knowledge and confidence gaps exist, and they were somewhat mitigated by experience. Future irAE curricula can fill these needs through online role-specific resources: irAE identification for generalists versus irAE identification and management for oncologists.

Abstract 4387: Total toxicity burden of FDA approved immune checkpoint inhibitors in USA

Abstract Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for multiple cancers, demonstrating effective and durable responses and becoming the standard of care for a variety of malignancies. However, ICI-based treatment has resulted in the rise of unique immune-related adverse events (irAEs). To date, very little information is available on the frequency, significance, and management of single-organ or multiorgan irAEs in clinic. In this study, the irAEs associated with the treatment of seven FDA-approved ICIs, including three PD-1 inhibitors (cemiplimab, nivolumab and pembrolizumab), three PD-L1 inhibitors (atezolizumab, avelumab and durvalumab), and one CTLA4 inhibitor (ipilimumab), were analyzed based on the data of 149,303 report cases (January 1, 2015 - June 30, 2022) collected from FDA Adverse Events Reporting System (FAERS) public dashboard. Our data reveal that irAEs associated with the treatment of anti-PD-1 ICIs (e.g., pembrolizumab) require less hospital care resources compared with anti-PD-L1 and anti-CTLA4 ICIs. Tissue and organ toxicity of ICIs are age and gender specific. ‘Cardiac disorders’ is the main disorder caused by these ICIs in cancer patients aged 65-85, while ‘reproductive system and breast disease’ is the main disorder in cancer patients aged 18-64. There are risks of respiratory and urinary system toxicity in male patients and reproductive system toxicity in female patients when they receive the treatment of ICIs. Studies such as this one provide the statistical data for understanding patients at risk of developing irAEs, which will underscore the importance of further exploring research strategies to predict, detect, and mitigate toxicities from ICIs. Citation Format: Fan Yang, Chloe Shay, Zhaohui Qin, Nabil Saba, Yong Teng. Total toxicity burden of FDA approved immune checkpoint inhibitors in USA. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4387.

The impact of immunosuppressive agents on immune checkpoint inhibitor efficacy in patients with advanced melanoma: A real-world, multicenter, retrospective study.

Immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) are often managed via immunosuppressive agents (ISAs); however, their impact on ICI efficacy is not well studied. The impact of the use of ISAs on ICI efficacy in patients with advanced melanoma was therefore investigated. This is a real-world, multicenter, retrospective cohort study of patients with advanced melanoma who received ICIs (n=370). Overall survival (OS) and time to treatment failure (TTF) from the time of ICI initiation were compared among patients in subgroups of interest by unadjusted and 12-week landmark sensitivity-adjusted analyses. The association of irAEs and their management with OS and TTF were evaluated using univariate and multivariable Cox proportional hazards regression models. Overall, irAEs of any grade and of grade ≥3 occurred in 57% and 23% of patients, respectively. Thirty-seven percent of patients received steroids, and 3% received other ISAs. Median OS was longest among patients receiving both (not reached [NR]), shorter among those receiving only systemic steroids (SSs) (84.2months; 95% CI, 40.2 months to NR), and shortest among those who did not experience irAEs (10.3months; 95% CI, 6-20.1 months) (p<.001). Longer OS was significantly associated with the occurrence of irAEs and the use of SSs with or without ISAs upon multivariable-adjusted analysis (p<.001). Similar results were noted with anti-programmed death 1 (PD-1) monotherapy and combination anti-PD-1plusanti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy, and with 12-week landmark sensitivity analysis (p=.01). These findings in patients with melanoma who were treated with ICIs suggest that the use of SSs or ISAs for the management of irAEs is not associated with inferior disease outcomes, which supports the use of these agents when necessary.

Application of PD-1 and PD-L1 inhibitors in immunotherapy of cancer

Cancer is a disease that developed from uncontrolled cells and has become one of the most medical problems that endanger human health. Currently, immunotherapy has replaced traditional treatment acts as the major therapy for cancer patients. The immune checkpoint inhibitor (ICI), which is highly specific and affinity to the immune checkpoint that suppress immune response during tumorigenesis, shows promising result during the clinical study and research. PD-1 and its ligand PD-L1 are the major targets for ICI development, there already have six FDA-approved inhibitors that target PD-1 and PD-L1 are used as a first-line treatment for many cancers. The clinical study of PD-1 and PD-L1 inhibitor application in patients with different cancers not only reveals their efficacy and safety but also indicates the onset of many adverse effects, which are usually called immune-related adverse events (irAE) and could be fatal in particular conditions. However, some research suggests the presence of irAE is a marker for effective of ICI therapy. Therefore, this essay will mainly focus on the application of PD-1 and PD-L1 inhibitors and the efficacy of each inhibitor has been testified via multiple clinical research. The common PD-1 and PD-L1 blockade-associated irAEs also have been discussed and their degree of risk is assessed. This essay also discussed the method that is frequently used in the management of irAEs.

Rheumatic Immune-Related Adverse Events due to Immune Checkpoint Inhibitors—A 2023 Update

With the aging of the population, malignancies are becoming common complications in patients with rheumatoid arthritis (RA), particularly in elderly patients. Such malignancies often interfere with RA treatment. Among several therapeutic agents, immune checkpoint inhibitors (ICIs) which antagonize immunological brakes on T lymphocytes have emerged as a promising treatment option for a variety of malignancies. In parallel, evidence has accumulated that ICIs are associated with numerous immune-related adverse events (irAEs), such as hypophysitis, myocarditis, pneumonitis, and colitis. Moreover, ICIs not only exacerbate pre-existing autoimmune diseases, but also cause de novo rheumatic disease-like symptoms, such as arthritis, myositis, and vasculitis, which are currently termed rheumatic irAEs. Rheumatic irAEs differ from classical rheumatic diseases in multiple aspects, and treatment should be individualized based on the severity. Close collaboration with oncologists is critical for preventing irreversible organ damage. This review summarizes the current evidence regarding the mechanisms and management of rheumatic irAEs with focus on arthritis, myositis, and vasculitis. Based on these findings, potential therapeutic strategies against rheumatic irAEs are discussed.

Immune Checkpoint Inhibitor Related Rheumatological Complications: Cooperation between Rheumatologists and Oncologists

In cancer, immune checkpoint inhibitors (ICIs) improve patient survival but may lead to severe immune-related adverse events (irAEs). Rheumatic irAEs are a distinct entity that are much more common in a real-life than in clinical trial reports due to their unspecific symptoms and them being a rare cause of hospitalization. This review focuses on an interdisciplinary approach to the management of rheumatic irAEs, including cooperation between oncologists, rheumatologists, and immunologists. We discuss the immunological background of rheumatic irAEs, as well as their unique clinical characteristics, differentiation from other irAEs, and treatment strategies. Importantly, steroids are not the basis of therapy, and nonsteroidal anti-inflammatory drugs should be administered in the front line with other antirheumatic agents. We also address whether patients with pre-existing rheumatic autoimmune diseases can receive ICIs and how antirheumatic agents can interfere with ICIs. Interestingly, there is a preclinical rationale for combining ICIs with immunosuppressants, particularly tumor necrosis factor α and interleukin 6 inhibitors. Regardless of the data, the mainstay in managing irAEs is interdisciplinary cooperation between oncologists and other medical specialties.

Immune-related adverse events associated with immune checkpoint inhibitors for advanced gastric and gastroesophageal junction cancer: A meta-analysis.

Immune checkpoint inhibitors (ICIs) have shown promising efficacy in treatment and clinical management of advanced gastric and gastroesophageal junction cancer. However, the inhibitors also cause immune-related adverse events (irAEs). The current systematic review and meta-analysis study aimed to investigate the incidence and nature of irAEs caused by ICIs. To investigate the incidence and nature of irAEs in advanced gastric and gastroesophageal junction cancer. This systematic review was registered with PROSPERO (Reg. number: CRD42020152291). Data included in this study were collected from patients diagnosed with advanced gastric cancer or gastroesophageal junction cancer and treated with ICIs. A systematic literature search was conducted using the PubMed, EMBASE, and Cochrane Library databases. Meta-analysis was carried out using the single sample rate method. Synthesis and analysis of the data was conducted using Stata/SE and Review Manager Software. The patients enrolled in the present study included 14 patients from 14 case reports, 326 patients from 6 case series, and 1249 patients from 8 clinical trials. It was found that the overall incidence of irAEs was 16% [95% confidence interval (CI): 11-20] for all grades and 3% (95%CI: 2-4) for the severe grade. It was evident that the incidence of irAEs varied with the type of inhibitor and organs. A comparative study of the anti-programmed cell death receptor-1 (PD-1) and anti-programmed death receptor-ligand 1 (PD-L1) treatments showed that the anti-PD-1 group had a higher overall incidence of irAEs (20%) as compared with that of the anti-PD-L1 group (13%). Results of this study showed that the endocrine system experienced the highest incidence of organ-specific irAEs (7.4%), including hypothyroidism, hyperthyroidism, thyroiditis, diabetes, and adrenal insufficiency, followed by gastroenterology (2.2%), pulmonology (1.8%), neurology (1.4%), dermatology (1.4%), hematology (0.8%), and hepatology (0.7%). In clinical trials, it was found that the incidence of death related to irAEs was 1% (95%CI: 0-2.0), whereby colitis and interstitial lung diseases were the leading causes of death. It was evident that the incidence and nature of irAEs are both organ- and inhibitor-specific. The anti-PD-1 group had the highest incidence of all irAEs grades including the severe grades of irAEs. Early identification and management of irAEs allows clinical oncologists to effectively consider the pros and cons and hence enables them to strike a balance.