Immune Checkpoint Inhibitors Discontinuation Research Articles

Abstract PS14-03: Delayed and post-treatment immune toxicities in patients with breast cancer receiving immune checkpoint inhibitors

Abstract Background: Immune checkpoint inhibitors (ICI) have improved outcomes in patients (pts) with breast cancer, however identification and management of immune-related adverse events (irAE) remains challenging. Delayed irAE have been observed, occurring even after ICI cessation. Prior analyses of delayed irAE have focused on patients with melanoma, lung, and head & neck cancer but data in patients with breast cancer are lacking. Methods: We identified pts with breast cancer who received ICI at our institution between 2012 and 2022 using pharmacy administration records. Charts were reviewed for delayed and post-treatment irAE. Delayed irAE were defined as occurring >90 days after ICI start; post-treatment irAE were defined as occurring >60 days after ICI discontinuation. Events were categorized as irAE if provider notes indicated that the toxicity was related to or possibly related to ICI. Results: 320 consecutive pts with breast cancer (219 metastatic, 96 localized disease) underwent treatment with ICI, of which 79 (25%) developed delayed irAE (40 with metastatic disease, 39 with localized disease). 54 pts had triple negative breast cancer (TNBC), 22 had hormone receptor positive (HR+) disease, and 4 had HER2+ disease. 44 pts received ICI on a clinical trial. The median number of ICI doses was 8, and the median length of follow-up after the first ICI infusion with 29 months. For delayed iRAE, median time to onset was 183 days (range 91-1800 days) with a total of 103 delayed irAE events (see table). 24 pts (7.5%) developed a post-treatment irAE with a total of 27 events. For post-treatment irAE, median time to onset was 112 days after ICI cessation (range 69-1100 days) and median time on ICI was 63 days (range 22-1724 days). 11 of 24 patients who experienced a post-treatment irAE also experienced an irAE while on treatment. Hypothyroidism, colitis, adrenal insufficiency, and hepatitis were the most common irAE at all time points. Rash primarily occurred while still on ICI. All irAE at any time point either self-resolved, resolved with systemic steroids, or continued with indefinite hormone replacement. 45 irAE required systemic steroids, not including hydrocortisone replacement for adrenal insufficiency. There were no grade 4 or 5 irAEs. Conclusions: This is the first evaluation of delayed/post-treatment irAE in a large cohort of patients with breast cancer. 79 pts (25%) experienced delayed irAEs occurring ≥ 90 days after ICI start, with median time to onset of 183 days. 89% of patients with delayed irAE also experienced an irAE at an earlier time point, indicating that early irAE may be a risk for delayed irAE. 24 pts (7.5%) experienced post-treatment irAE with median onset of 121 days after ICI cessation. Diagnosis of delayed irAE requires heightened awareness and prompt treatment. Future work is needed to identify key clinical and molecular markers that predict risk for delayed irAE to better inform treatment & monitoring. Table. Parameter Number of pts (%) Total pts receiving an ICI 320 Delayed irAE 79 (25) >1 delayed irAE 21 (27% of pts with delayed irAE) Patients with delayed irAEs who also had irAE occurring < 90 days after ICI start 70 (89% of pts with delayed irAE) Post-treatment irAE 24 (7.5) Types of delayed irAE (>90 days after ICI start) Any Grade Grade 3 Hypothyroidism 24 (23) 1 (1) Colitis/Diarrhea 19 (18) 3 (3) Rash 14 (14) 0 Adrenal Insufficiency/Hypophysitis 11 (11) 4 (4) Hepatitis 10 (10) 3 (3) Pneumonitis 4 (4) 1 (1) Arthralgia 4 (4) 0 Diabetes mellitus 3 (3) 0 Mucositis 2 (2) 1 (1) Neuropathy 2 (2) 0 Neutropenia 2 (2) 1 (1) Bronchitis 1 (1) 0 Fever 1 (1) 0 Neuromuscular Weakness 1 (1) 0 Autoimmune Hemolytic Anemia 1 (1) 1 (1) Myocarditis 1 (1) 1 (1) Acid Reflux 1 (1) 0 Sarcoidosis 1 (1) 0 Vitiligo 1 (1) 0 Types of post-treatment irAE (>60 days post ICI cessation) Any Grade Grade 3 Hypothyroidism 7 (26) 2 (7) Colitis 7 (26) 3 11) Adrenal Insufficiency/Hypophysitis 6 (22) 1 (4) Hepatitis 4 (15) 3 (11) Arthralgia 1 (4) 0 Neuropathy 1 (4) 0 Neutropenia 1 (4) 1 (4) Rash 1 (4) 0 Citation Format: Saya Jacob, Samantha Fisch, Carolyn Face, Laura Huppert, Zoe Quandt, Laura Quintal, Michelle Melisko, Melanie Majure, Jo Chien, Anne Blaes, Hope Rugo. Delayed and post-treatment immune toxicities in patients with breast cancer receiving immune checkpoint inhibitors [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS14-03.

Development of myasthenia gravis: 4 years after durvalumab‐induced myositis

AbstractWe report a 74‐year‐old man diagnosed with myasthenia gravis (MG) accompanied by anti‐acetylcholine receptor antibody seroconversion and positive for anti‐titin antibody, with onset delayed by 4 years after the final durvalumab administration, which preceded myositis and organizing pneumonia (OP). Durvalumab, an anti‐programmed cell death ligand 1 antibody, is effective in patients with cancer and causes immune‐related adverse events (irAEs) retrospectively. Patients treated with immune checkpoint inhibitors require vigilant monitoring as irAEs can arise at any phase, regardless of the time after immune checkpoint inhibitor discontinuation.

Sarcoid-like reactions to immune checkpoint inhibitors: Incidence, treatment course, and impact on cancer progression and survival

IntroductionSarcoid-like reactions (SLRs) to immune checkpoint inhibitors (ICIs) are a rare but increasingly recognized immune-related adverse event of which the clinical significance is unclear. MethodsWe conducted a retrospective cohort study at a tertiary academic center of consecutive patients who received at least one dose of ICI from 2013 to 2020. Patient characteristics, risk factors, and outcomes were compared between patients with and without SLR following ICI treatment. ResultsA total of 2963 cancer patients received at least 1 dose of ICI between 2013 and 2020, and 7 patients (0.24 %) developed SLR. There were no significant demographic differences between patients with and without SLR following ICI. SLRs occurred in 5 of 451 (1.07 %) melanoma patients and 2 of 840 (0.24 %) non-small cell lung cancer patients. Two of the 7 patients had multi-organ SLR, and both were symptomatic requiring systemic corticosteroids and permanent ICI discontinuation, while single organ SLR patients did not require immune suppression. Development of SLR did not appear to have negative impact on cancer progression or overall survival; in fact, a trend towards improved progression-free and overall survival was observed (median time: 1363 days vs 127 days, p = 0.091; 1387 days vs 428.5 days, p = 0.19, respectively). ConclusionsSLRs are a known but understudied complication associated with ICI therapy. Multisystem SLR patients were more symptomatic and required ICI discontinuation and immune suppression. Larger studies are needed to fully evaluate the impact of SLR on cancer outcomes.

Clinical Manifestation, Risk Factors, and Immune Checkpoint Inhibitor Rechallenge of Checkpoint Inhibitor-Associated Pneumonitis in Patients With Lung Cancer.

Immune-related adverse effects can lead to damage to various systems of the body, checkpoint inhibitor-associated pneumonitis (CIP) is one of the potentially lethal immune-related adverse effects. However, evidence regarding the risk factors associated with CIP is limited. To timely and accurate identification and prompt treatment of CIP, understanding the risk factors for multimorbidity among diverse study populations becomes crucial. We retrospectively analyzed the clinical data of 1131 patients with lung cancer receiving immunotherapy to identify 110 patients with CIP, the clinical characteristics and radiographic features of patients with CIP were analyzed. A case-control study was subsequently performed to identify the risk factors of CIP. The median treatment cycle was 5 cycles and the median time to onset of CIP was 4.2 months. CIP was mainly grade I or II. Most cases improved after discontinuation of immune checkpoint inhibitors (ICIs) or hormone therapy. Severe CIP tended to occur earlier in comparison to mild to moderate cases. The recurrence rate was 20.6% in ICI-rechallenged patients, and patients with relapsed CIP were usually accompanied by higher-grade adverse events than at first onset. Among the 7 patients with relapse, ICI-associated deaths occurred in 2 patients (28.6%). For rechallenging with ICIs after recovery from CIP, caution should be practiced. Male [odds ratio (OR): 2.067; 95% CI: 1.194-3.579; P= 0.009], history of chest radiation (OR: 1.642; 95% CI: 1.002-2.689; P= 0.049) and underlying lung disease (OR: 2.347; 95% CI: 1.008-5.464; P=0.048) was associated with a higher risk of CIP.

Neurological Adverse Events Related to Immune Checkpoint Inhibitors: A Practical Review.

The increasing use of immune checkpoint inhibitors (ICI) in cancer therapy has brought attention to their associated neurotoxicities, termed neurological immune-related adverse events (n-irAEs). Despite their relatively rare incidence, n-irAEs pose a significant risk, potentially leading to severe, long-lasting disabilities or even fatal outcomes. This narrative review aims to provide a comprehensive overview of n-irAEs, focusing on their recognition and management. The review addresses a spectrum of n-irAEs, encompassing myositis, myasthenia gravis, various neuropathies, and central nervous system complications, such as encephalitis, meningitis, and demyelinating diseases. The key features of n-irAEs are emphasized in this review, including their early onset after initiation of ICIs, potential association with non-neurological irAEs and/or concurrent oncological response, the significance of ruling out other etiologies, and the expected improvement upon discontinuation of ICIs and/or immunosuppression. Furthermore, this review delves into considerations for ICI re-challenge and the intricate nature of n-irAEs within the context of pre-existing autoimmune and paraneoplastic syndromes. It underscores the importance of a multidisciplinary approach to diagnosis and treatment, highlighting the pivotal role of severity grading in guiding treatment decisions.

Identification and Characterization of Immune Checkpoint Inhibitor-Induced Toxicities From Electronic Health Records Using Natural Language Processing.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet their use is associated with immune-related adverse events (irAEs). Estimating the prevalence and patient impact of these irAEs in the real-world data setting is critical for characterizing the benefit/risk profile of ICI therapies beyond the clinical trial population. Diagnosis codes, such as International Classification of Diseases codes, do not comprehensively illustrate a patient's care journey and offer no insight into drug-irAE causality. This study aims to capture the relationship between ICIs and irAEs more accurately by using augmented curation (AC), a natural language processing-based innovation, on unstructured data in electronic health records. In a cohort of 9,290 patients treated with ICIs at Mayo Clinic from 2005 to 2021, we compared the prevalence of irAEs using diagnosis codes and AC models, which classify drug-irAE pairs in clinical notes with implied textual causality. Four illustrative irAEs with high patient impact-myocarditis, encephalitis, pneumonitis, and severe cutaneous adverse reactions, abbreviated as MEPS-were analyzed using corticosteroid administration and ICI discontinuation as proxies of severity. For MEPS, only 70% (n = 118) of patients found by AC were also identified by diagnosis codes. Using AC models, patients with MEPS received corticosteroids for their respective irAE 82% of the time and permanently discontinued the ICI because of the irAE 35.9% (n = 115) of the time. Overall, AC models enabled more accurate identification and assessment of patient impact of ICI-induced irAEs not found using diagnosis codes, demonstrating a novel and more efficient strategy to assess real-world clinical outcomes in patients treated with ICIs.

Off-label prescribing of immune checkpoint inhibitor therapy at a single pediatric cancer center.

Immune checkpoint inhibitors (ICI) have improved outcomes in a variety of adult cancers and are prescribed with increasing frequency across oncology. However, patterns of off-label use of ICI in pediatrics remain unclear. This is a single-institution, retrospective cohort study evaluating off-label ICI use in pediatric and young adult patients with cancer treated at our institution from 2014 to 2022. Response was based on clinician assessment derived from clinical records. Immune-related adverse events (iRAEs) were classified according to CTCAE v5.0. We identified 50 unique patients treated with off-label ICI (28 with solid tumors, 20 with central nervous system (CNS) tumors, 2 with hematologic malignancies). At time of ICI initiation, only five patients (10%) had localized disease, and all but one patient was treated in the relapsed/refractory setting. All patients were treated with the FDA-approved weight-based dosing recommendations. Overall, there was disease control in 21 patients (42%), with best response including one complete response (melanoma), two partial responses (high-grade glioma, CNS nongerminomatous germ cell tumor), and 18 patients with stable disease. Forty-four patients (88%) eventually experienced disease progression. Among 22 patients (44%) experiencing iRAEs, 10 (20%) had a grade ≥3 irAE, 12 (24%) required corticosteroids, and 14 (28%) required ICI discontinuation. irAE occurrence was associated with significantly improved progression-free survival (HR 0.35; 95% CI: 0.18 to 0.68; p = 0.002) and overall survival (HR 0.33; 95% CI: 0.17 to 0.66; p = 0.002). At our institution, ICI was most commonly prescribed in the relapsed/refractory setting to patients with metastatic disease. The treatment was generally well-tolerated in the pediatric population. The overall response rate was low, and the majority of patients eventually experienced disease progression. A few patients, however, had durable treatment responses. Further studies are needed to identify which pediatric patients are most likely to benefit from ICI.

Abstract 3460: Predicting cessation of immune checkpoint inhibitor therapy due to severe adverse events with an integrated autoimmune disease polygenic risk score

Abstract Background: Immune checkpoint inhibitors (ICIs), including anti-PD1/PD-L1 and anti-CTLA4 agents, have changed the landscape of cancer therapy. However, 6-30% of patients treated with ICIs can develop severe immune-related adverse events (irAEs) depending on the type of therapy used, often leading to cessation of treatment. Hundreds of genetic variants have been associated with autoimmune disorders, and recent genetic studies have developed polygenic risk scores (PRS) for composite risk of autoimmune disease (PRSAID). We used data from an ongoing observational study of patients with non-small cell lung cancer (NSCLC) treated with ICIs to evaluate the association between PRSAID and cessation of ICI therapy due to severe irAEs. Methods: Our cohort comprises 1,316 advanced NSCLC patients who received ICI therapy from four institutions between 2009 and 2022. Genotyping was performed using the Affymetrix Precision Medicine Array, and imputation was performed using 1000 Genomes Reference. To evaluate cessation of therapy due to severe irAEs, we conducted a thorough review of electronic health records. We identified permanent discontinuation of ICIs due to irAEs as cessation for at least 6 months without any disease progression. We tested the association of a previously published PRSAID (PMID: 35393596) with cessation of ICI due to any severe irAE. PRSAID was converted to a standard normal distribution. We conducted an unconditional logistic regression model to evaluate the association between a standardized PRSAID and discontinuation of ICI therapy due to severe irAEs. All models were adjusted for age at diagnosis, sex, type of ICI therapy, recruitment site, and 5 ancestry-informative principal components. Results: Of the 1,316 participants with genotype and outcome data, 171 (13.5%) of patients stopped ICI therapy due to severe irAEs. The most common irAEs leading to discontinuation were colitis, hepatitis, and pneumonitis. The PRSAID predicts the cessation of therapy due to severe irAEs with an odds ratio (OR) per standard deviation (SD) of 1.20 (95% confidence intervals [CI]=1.02-1.41, p=0.03). The association was stronger in individuals with high genetic risk (top 25th percentile compared to bottom 75th percentile of the PRSAID) (OR=1.60, 95% CI = 1.11-2.28, p=0.01). When we stratified the analysis by therapy type, we found an OR of 1.17 (95% CI-0.98-1.39, p = 0.08) for the anti-PD1/PD-L1 monotherapy groups and an OR of 1.48 (95% CI=0.94-2.40,p=0.09) for the dual anti-PD1/PD-L1 and anti-CTLA4 therapy group. Conclusions: An integrated PRS for autoimmunity can predict the cessation of ICI therapy due to severe irAEs in patients with advanced cancer. These findings suggest that PRS may help determine which patients may benefit from careful monitoring or even preventative measures for irAEs during ICI therapy. Citation Format: Pooja Middha, Rohit Thummalapalli, Zoe Quandt, Princess Margaret Lung Group, Matthew A. Gubens, Christine M. Lovly, Geoffrey Liu, Melinda C. Aldrich, Adam J. Schoenfeld, Elad Ziv. Predicting cessation of immune checkpoint inhibitor therapy due to severe adverse events with an integrated autoimmune disease polygenic risk score [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 3460.

Pregnancy and delivery in an advanced cancer survivor with immune checkpoint inhibitor-induced type 1 diabetes: a case report.

Given the rarity and elderly onset of immune checkpoint inhibitor (ICI)-induced type 1 diabetes (ICI-T1DM), cases leading to delivery are rare. To our knowledge, this is the first case report of childbirth in a patient with ICI-T1DM after cancer survival. A 32-year-old woman was started on Nivolumab for metastatic parotid cancers one year after total parotidectomy. The patient developed ICI-T1DM after 43 cycles and started multiple daily insulin therapy and self-monitoring of blood glucose. Complete response was maintained for 2 years by nivolumab, and she finished nivolumab in 77 cycles to attempt pregnancy. During the follow-up period, she began using a sensor-augmented pump (SAP). She had undetectable serum and urinary C-peptide when she started SAP. Her HbA1c level decreased from 7.8 to 6.6% without increasing hypoglycemia in one year. The patient remained in complete response after ICI discontinuation, and embryo transfer was initiated. Pregnancy was confirmed after a second embryo transfer (21 months after ICI discontinuation). At 36 weeks and 6 days, an emergency cesarean section was performed due to the onset of preeclampsia. The baby had hypospadias and bifid scrotum but no other complications or neonatal intensive care unit admission. Because ICI discontinuation and ICI-T1DM carry risks for the patient and child, the decision regarding pregnancy warrants careful consideration. Diabetologists should collaborate with patients and other clinical departments to develop a treatment plan for childbirth.

The Clinical Analysis of Checkpoint Inhibitor Pneumonitis with Different Severities in Lung Cancer Patients: A Retrospective Study.

Immune-related adverse events (irAEs) of immunotherapy would lead to the temporary or permanent discontinuation of immune checkpoint inhibitors (ICIs). Among them, checkpoint inhibitor pneumonitis (CIP) is a potentially life-threatening irAE. This study aimed to identify the differences between patients with low-grade CIPs (grades 1-2) and high-grade CIPs (grades 3-5) and to explore the prognostic factors. We retrospectively reviewed the medical records of 916 lung cancer patients who were treated with ICIs. Patients with CIPs were identified after multidisciplinary discussion, and their clinical, laboratory, radiological, and follow-up data were analyzed. Among the 74 enrolled CIP patients, there were 31 low-grade CIPs and 43 high-grade CIPs. Compared with low-grade CIP patients, patients with high-grade CIPs were older (65.8 years vs. 61.5 years) and had lower serum albumin (35.2 g/L vs. 37.9 g/L), higher D-dimer (5.1 mg/L vs. 1.7 mg/L), and more pulmonary infectious diseases (32.6% vs. 6.5%) during follow-up. In addition, complication with pulmonary infectious diseases, management with intravenous immunoglobulin, tocilizumab, and longer duration of large dosage corticosteroids might be associated with worse outcomes for patients with CIPs. This study highlights potential risk factors for high-grade CIP and poor prognosis among lung cancer patients who were treated with anti-cancer ICIs.

The efficacy of immune checkpoint inhibitors following discontinuation for long-term response or toxicity in advanced or metastatic non-small-cell lung cancers: A retrospective study.

The treatment of metastatic non-small-cell lung cancer (NSCLC) has been revolutionized by the arrival of immune checkpoint inhibitors (ICI). For patients without immune related adverse events (irAEs), it is recommended to continue the treatment as long as it provides clinical benefit or until unacceptable toxicity appears. The aim of our study was to evaluate survival data among patients with advanced or metastatic NSCLC following ICI discontinuation for reasons of long-term response or toxicity (irAEs). We included all patients with advanced or metastatic NSCLC treated with nivolumab and pembrolizumab at the Centre Jean Perrin, Clermont-Ferrand, France (January 1, 2016 to May 31,2019). We focused on two groups in this study population: "Voluntary treatment discontinuation" (medical decision as a result of long-term response and patient decision) and "Treatment discontinuation due to toxicity" (irAEs). The primary endpoint was to evaluate the postdiscontinuation outcomes of these two groups: progression-free survival (PFS) and overall survival (OS), and rechallenge in the "voluntary discontinuation" group. The final analysis concerned 146 patients, including 10 (7%) in the "discontinuation due to toxicity" group, 11 (8%) in the "voluntary discontinuation" group, 100 (68%) who discontinued treatment as a result of progression and 25 (17%) whose treatment was still on-going. The median PFS in the "discontinuation due to toxicity" group was not reached, and in the "voluntary discontinuation" group (n = 11) was 37 months (p = 0.4), versus 2 months in the progression group (p < 0.001). The median OS in "discontinuation due to toxicity,"and in the "voluntary discontinuation" groups was not reached (p = 0.5), versus 10 months in the progression group (p < 0.001). Treatment discontinuation following long-term response to ICI treatment showed sustained response and long-term survival after discontinuation. The incidence of irAEs was associated with better long-term survival, even after ICI discontinuation.

Safety and Efficacy Outcomes in Immune Checkpoint Inhibitor-Treated Patients With Metastatic Urothelial Carcinoma Requiring Treatment Interruption or Discontinuation Due to Immune-Related Adverse Events

IntroductionAs most patients with metastatic urothelial carcinoma (mUC) will be treated with immune checkpoint inhibitors (ICI), familiarity with their associated immune-related adverse events (irAEs) is critical. We describe the characteristics and outcomes of ICI-treated mUC patients who experienced irAEs requiring treatment interruption (TI) or permanent discontinuation. Materials and MethodsICI-treated mUC patients who developed grade ≥2 irAEs were reviewed. Clinical-, treatment-, and toxicity-related data were evaluated. Toxicity was graded per common terminology for categorization of adverse events v5.0. Cohorts were divided into patients who underwent ICI rechallenge and those who required permanent ICI discontinuation. Time to treatment interruption (TTI), time to next treatment, and duration of clinical benefit were assessed descriptively. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier methodology. ResultsOf 200 ICI-treated mUC patients at Cleveland Clinic between October 2015 and October 2020, 16 (8%) experienced ≥ grade 2 irAEs necessitating TI. Median TTI among all patients was 6.5 months (range, 1-19). Eleven patients (69%) required corticosteroids. ICI were held and rechallenged in 10 patients (62%) and permanently discontinued in 6 patients (38%). Of the 10 ICI-rechallenged patients, 7 (70%) experienced another irAE upon rechallenge with median time to irAE recurrence of 2.9 months (range, 0.1-10.9); 3 (30%) eventually discontinued ICI due to recrudescent irAEs. Four (40%) of the 10 ICI-rechallenged patients received subsequent therapy. Five (83%) of the 6 patients who permanently discontinued ICI demonstrated durable clinical benefit off therapy with median duration of clinical benefit 17.7 months (range, 14.2-55.2). Two-year OS was 40% (95% CI: 19%-86%) in the ICI rechallenge cohort and 67% (95% CI: 38%-100%) in the permanent discontinuation cohort. ConclusionICI-treated mUC patients who developed irAEs requiring TI had a high rate of subsequent irAEs upon ICI rechallenge. Importantly, patients who permanently discontinued ICI due to irAE demonstrated durable clinical benefit off treatment.

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

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

Recurrence of Checkpoint Inhibitor Pneumonia More than Three Years after Discontinuation of an Immune Checkpoint Inhibitor

Many immune‑related Adverse Events (irAEs) resolve after discontinuation of Immune Checkpoint Inhibitors (ICIs) and treatment with immunosuppression, most commonly corticosteroids. However, some irAEs can recur or persist after discontinuation of ICIs.

Baseline neutrophil-lymphocyte ratio and platelet-lymphocyte ratio appear predictive of immune treatment related toxicity in hepatocellular carcinoma

BACKGROUND A well-recognized class effect of immune checkpoint inhibitors (ICI) is immune-related adverse events (IrAEs) ranging from low grade toxicities to life-threatening end organ damage requiring permanent discontinuation of ICI. Deaths are reported in &lt; 5% of patients treated with ICI. There are, however, no reliable markers to predict the onset and severity of IrAEs. We tested the association between neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) at baseline with development of clinically significant IrAEs (grade ≥ 2) in hepatocellular carcinoma (HCC) patients treated with ICI. AIM To test the association between NLR and PLR at baseline with development of clinically significant IrAEs (grade ≥ 2) in HCC patients treated with ICI. METHODS Data was extracted from an international database from a consortium of 11 tertiary-care referral centers. NLR = absolute neutrophil count/absolute lymphocyte count (ALC) and PLR = platelet count/ALC. Cutoff of 5 was used for NLR and 300 for PLR based on literature. We also tested the association between antibiotic and steroid exposure to IrAEs. RESULTS Data was collected from 361 patients treated between 2016-2020 across the United States (67%), Asia (14%) and Europe (19%). Most patients received Nivolumab (n = 255, 71%). One hundred sixty-seven (46%) patients developed at least one IrAE, highest grade 1 in 80 (48%), grade ≥ 2 in 87 (52%) patients. In a univariable regression model PLR &gt; 300 was significantly associated with a lower incidence of grade ≥ 2 IrAEs (OR = 0.40; P = 0.044). Similarly, a trend was observed between NLR &gt; 5 and lower incidence of grade ≥ 2 IrAEs (OR = 0.58; P = 0.097). Multivariate analyses confirmed PLR &gt; 300 as an independent predictive marker of grade ≥ 2 IrAEs (OR = 0.26; P = 0.011), in addition to treatment with programmed cell death ligand 1 (PD-1)/cytotoxic T lymphocyte-associated protein-4 (OR = 2.57; P = 0.037) and PD-1/tyrosine kinase inhibitor (OR = 3.39; P = 0.01) combinations. Antibiotic use was not associated with IrAE incidence (OR = 1.02; P = 0.954). Patients treated with steroids had a &gt; 2-fold higher incidence of grade ≥ 2 IrAEs (OR = 2.74; P &lt; 0.001), although 74% were prescribed steroids for the treatment of IrAEs. CONCLUSION Given that high baseline NLR and PLR are associated with a decreased incidence of IrAEs, lower baseline NLR and PLR may be predictive biomarkers for the appearance of IrAEs in HCC treated with ICI. This finding is in keeping with several studies in solid tumors that have shown that baseline NLR and PLR appear predictive of IrAEs.

Immune checkpoint inhibitor rechallenge in patients who previously experienced immune-related inflammatory arthritis: a multicentre observational study

ObjectiveAnother course of immune checkpoint inhibitors (ICIs) is often considered in patients with cancer progression and previous immune-related adverse events, including inflammatory arthritis (ICI-IA), but there are limited data regarding...

Effects of Early Short-Course Corticosteroids on Immune-Related Adverse Events in Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors

Introduction: In real-world practice, most non-small cell lung cancer (NSCLC) patients receiving combined immunochemotherapy are exposed to short-course corticosteroids following immune checkpoint inhibitor (ICI) infusion to prevent chemotherapy-related adverse events. However, whether this early short-course corticosteroid use prevents immune-related adverse events (irAEs) remains unknown. Methods: Between January 1st, 2015, and December 31st, 2020, NSCLC patients who received at least one cycle of ICI with or without chemotherapy were enrolled. Early short-course corticosteroids were defined as corticosteroids administered following ICI injection and before chemotherapy on the same day and no longer than 3 days afterward. The patients were categorized as either “corticosteroid group” or “non-corticosteroid group” depending on their exposure to early short-course corticosteroid. The frequencies of irAEs requiring systemic corticosteroid use and irAEs leading to ICI discontinuation were compared between the two groups, and exploratory survival analyses were performed. Results: Among 252 eligible patients, 137 patients were categorized as “corticosteroid group” and 115 patients as “non-corticosteroid group.” The corticosteroid group enriched patients in the first-line setting (n = 75, 54.7%), compared to the non-corticosteroid group (n = 28, 24.3%). Thirty patients (21.9%) in the corticosteroid group and 35 patients (30.4%) in the non-corticosteroid group developed irAEs requiring systemic corticosteroid use (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.35–1.18; p = 0.15). Eight patients (5.8%) in the corticosteroid group, as compared with 18 patients (15.7%) in the non-corticosteroid group, permanently discontinued ICI due to irAEs (OR, 0.34; 95% CI, 0.12–0.85; p = 0.013). Conclusion: Early short-course corticosteroids following each ICI injection may reduce the rate of irAEs that lead to ICIs discontinuation, warranting further investigation of its prophylactic use to mitigate clinically significant irAEs.

Extended duration of treatment using reduced-frequency dosing of anti-PD-1 therapy in patients with advanced melanoma and Merkel cell carcinoma.

Optimal duration of treatment (DoT) with immune checkpoint inhibitors (ICI) in metastatic cancers remains unclear. Many patients, especially those without radiologic complete remission, develop progressive disease after ICI discontinuation. Extending DoT with ICI may potentially improve efficacy outcomes but presents major logistical and cost challenges with standard frequency dosing (SFD). Receptor occupancy data supports reduced frequency dosing (RFD) of anti-PD-1 antibodies, which may represent a more practical and economically viable option to extend DoT. We conducted a retrospective study of patients with metastatic melanoma and Merkel cell carcinoma (MCC), who received ICI at RFD administered every 3months, after initial disease control at SFD. We evaluated efficacy, safety, and cost-savings of the RFD approach in this cohort. Between 2014 and 2021, 23 patients with advanced melanoma (N = 18) or MCC (N = 5) received anti-PD-1 therapy at RFD. Median DoT was 1.1years at SFD and 1.2years at RFD. The 3year PFS after start of RFD was 73% in melanoma and 100% in MCC patients, which compare favorably to historical control rates. In the subset of 15 patients who received at least 2years of therapy, total savings amounted to $1.1 million in drug costs and 384h saved despite the extended DoT (median 3.4years), as compared to the calculated cost of 2years at SFD. ICI administration at RFD can allow extension of treatment duration, while preserving efficacy and reducing logistical and financial burden. RFD approach deserves further exploration in prospective clinical trials.

P06.14.A DIAGNOSIS AND MANAGEMENT OF NEUROPATHIES RELATED TO IMMUNE CHECKPOINT INHIBITORS: A CASE SERIES

Abstract BACKGROUND Immune checkpoint inhibitors (ICIs) are associated with a wide range of neurotoxicities. Several types of neuropathies have been associated to immune checkpoint inhibitors (ICIs), from length-dependent sensory neuropathies to radiculoneuropathies similar to Guillain-Barré syndromes, with an overall incidence estimated to be between 0.1-1.2% of patients. Guidelines recommend prompt ICI discontinuation and the INTRODUCTION of steroids depending on the severity of the adverse event. However, the usage of IVIG or plasmapheresis (alternatively or in addition to steroids) has been reported in cases of Guillain-Barré-like syndromes. MATERIAL AND METHODS In this study, we report a retrospective consecutive series of patients with an ICI-related neuropathy referred to our department between 2016 and 2021, with the intent to describe their clinical and para-clinical features and the outcome after ICI discontinuation and steroids. RESULTS We identified 12 cases of acute peripheral nervous system involvement, with a predominant sensory pattern. The median onset of symptoms from ICI initiation was 18 weeks, and the median number of ICIs doses was 3. Electrophysiological studies, done in 11 patients, showed a radiculopathy in 9 cases, associated with an axonal neuropathy in 3, and a demyelinating neuropathy in 2 cases. Altogether, these findings are consistent with Guillain-Barré-like syndrome. ICIs were stopped in all patients and steroids started in 7 patients, leading to a favourable outcome (complete recovery =7, partial recovery =4, stability =1). CONCLUSION This consecutive retrospective series identifies Guillain-Barré-like syndrome as the main clinical pattern of immune related neuropathies. We did not observe any case of length-dependent axonal neuropathy without an associated root involvement. Our systematic management, consisting of ICI discontinuation in all patients and steroids in more severe cases, seems a valid strategy. On the other hand, our results do not support the use of IVIG or other treatments.

The preventive effects of early short-course corticosteroids on immune-related adverse events in non-small cell lung cancer patients receiving immune checkpoint inhibitors.

144 Background: Corticosteroid is effective in treating immune checkpoint inhibitor (ICI)-induced immune-related adverse events (irAEs). However, whether its earlier use prevents irAEs remains unknown. In real-world practice, non-small cell lung cancer (NSCLC) patients receiving combined immunochemotherapy are often given corticosteroids right after ICI injection to reduce subsequent chemotherapy-related adverse events. It is thus an ideal model to examine whether this earlier use of corticosteroid also reduce irAEs following immunotherapy. Methods: NSCLC patients receiving at least one cycle of ICI with or without chemotherapy were enrolled. Patients receiving ICI with corticosteroid corticosteroid premedication exposure were categorized as “corticosteroid group (CS)”, whereas patients receiving ICI without corticosteroids premedication exposure were categorized as “non-corticosteroid group (non-CS)”. Frequency of irAEs prompting systemic corticosteroid or leading to ICI discontinuation were compared between the two groups. Exploratory survival analysis was performed. Results: Among 252 eligible patients, 137 patients were categorized as CS group, and 115 patients as non-CS group. 21.9% of patients in the CS group and 30.4% of patients in the non-CS group developed irAEs prompting systemic corticosteroid use (Odds ratio [OR], 0.64; 95% confidence interval [CI], 0.35 to 1.18; p=0.15). 5.8% of patients in the CS group and 15.7% of patients in the non-CS group developed irAEs leading to ICI discontinuation (OR, 0.34; 95% CI, 0.12 to 0.85; p=0.013). In the exploratory survival analysis, early short-course corticosteroids was not associated with a higher risk for death in first-line patients (hazard ratio [HR], 1.06; 95% CI, 0.56–2) or patients receiving immunochemotherapy (HR, 0.72; 95% CI, 0.37–1.45). Conclusions: Early short-course corticosteroids following each ICI injection may reduce the rate of irAEs that leads to ICIs discontinuation. The use of prophylactic corticosteroids on irAEs in cancer patients receiving ICIs should be evaluated in future prospective studies. [Table: see text]