Incidence Of irAEs Research Articles

Adverse events of neoadjuvant combination immunotherapy for resectable cancer patients: a systematic review and meta-analysis.

Neoadjuvant combination immunotherapy is changing the treatment landscape for patients with cancer. Exploring the incidence of immune-related adverse events (irAEs) in relation to this novel approach may provide valuable insights for future clinical investigations. This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Embase, Cochrane Library, American Society of Clinical Oncology (ASCO), and European Society of Medical Oncology (ESMO) websites were searched for all relevant literature from their inception to November 24, 2023. We then extracted the required data from the included studies and used the R software to analyze the pooled incidence of irAEs. Subgroup analyses examined the pooled incidence of irAEs according to cancer and combination types using a random-effects model. Sixteen studies involving 501 patients were included in the meta-analysis. Considering the heterogeneity of the study design, we analyzed the randomized controlled studies (RCTs) and the single-arm studies separately. In RCTs, the incidence of any-grade irAEs was 95.0% (95% confidence interval [CI] 87.3-99.3) and that of grade ≥3 irAEs was 24.0% (95% CI 13.7-36.0). In single-arm studies, the incidence of any-grade irAEs was 89.4% (95% CI 75.0-98.0) and grade ≥3 irAEs was 20.3% (95% CI 8.7-35.2). In both RCTs and single arms, the most common any- grade irAEs were rash and fatigue, while the most common grade ≥3 irAEs was abnormal liver function and colitis. Due to irAEs, 9.4% of patients in RCTs and 6.9% of patients in single-arm studies did not complete the prescribed neoadjuvant treatment cycle. This study comprehensively summarized the incidence of irAEs in neoadjuvant combination immunotherapy. The occurrence of irAEs varies depending on the cancer and combination types. Our meta-analysis provides clinicians with essential guidance for the management of patients with cancer. https://www.crd.york.ac.uk/prospero, identifier CRD42023387969.

Single Institution Experience with Immune Checkpoint Inhibitors in Vulvar and Vaginal Melanomas.

This study aimed to report clinical outcomes of patients with vaginal melanoma (VaM) or vulvar melanoma (VuM) who were treated with immune checkpoint inhibitors (ICI) and discuss the development of immune-related adverse events (irAE). This is a retrospective case series of patients diagnosed with VaM or VuM between July 2011 and September 2022 at the University of Virginia, Emily Couric Clinical Cancer Center. Patient demographics, disease characteristics, treatment outcomes, and adverse events were abstracted. The primary outcome was incidence of irAE. Eight patients were included in this study, four with VaM and four with VuM. Most (n = 6) had local or regional disease at first presentation, and 25% (n = 2) presented with distant metastasis. All patients received a CTLA-4 inhibitor and 75% (n = 6) received PD-1 inhibitor alone or in combination with a CTLA-4 inhibitor. Most (75%, n = 6) patients experienced irAE. Of those who had irAE, 83% (n = 5) required therapy interruption or discontinuation. Most (66%, n = 4) underwent ICI rechallenge of which 75% (n = 3) experienced subsequent irAE. Of all patients in the series, 75% of patients (n = 6) had partial or complete response to ICI. This series is the first to detail incidence of irAEs and ICI rechallenges in vulvovaginal melanoma. Our findings indicate that while ICIs are effective, their use is associated with significant irAE development. Rechallenge of ICI after irAE is feasible but associated with risk of recurrent/new irAE. Further studies are needed to better quantify this risk.

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.

PD-1/PD-L1 Inhibitor - Related Adverse Events and Their Management in Breast Cancer.

As the positive results of multiple clinical trials were released, the Programmed cell death 1 (PD-1) and Programmed cell death ligand 1 (PD-L1) inhibitors emerge as the focus of integrative breast cancer treatment. PD-1/PD-L1 inhibitors are often used as a sequential agent to be combined with other agents such as chemotherapeutic agents, targeted agents, and radiation therapy. As multiple therapies are administered simultaneously or in sequence, they are prone to a variety of adverse effects on patients while achieving efficacy. It is a challenge for clinicians to maintaining the balance between immune-related adverse effects(irAEs) and treatment efficacy. Previous literatures have paid lots of attention on the adverse effects caused by immunosuppressive agents themselves, while there is a dearth of the research on the management of adverse immune effects during the combination of immunotherapy with other treatments. In this review, we discuss the overall incidence of irAEs caused by PD-1/PD-L1 inhibitors in combination with various types of treatments in breast cancer, including chemotherapy, CTLA-4 inhibitors, targeted therapy, and radiotherapy, and systematically summarizes the clinical management to each organ-related adverse immune reaction. It is important to emphasize that in the event of irAEs such as neurological, hematologic, and cardiac toxicity, there is no alternative treatment but to terminate immunotherapy. Thus, seeking more effective strategy of irAEs' management is imminent and clinicians are urged to raise the awareness of the management of adverse immune reactions.

Blood Group Antigen A Carriers Exhibit an Extended Progression-Free Survival with no more Immune-Related Adverse Events.

Extensive investigations have been conducted regarding the potential correlation between blood type and the immune system, as well as cancer risk in the Southern Chinese population. However, the prognostic value of the blood group and its genetic determinants in the context of immune checkpoint inhibitor (ICI) treatment remains unclear. Therefore, the associations between the ABO blood group and its single nucleotide polymorphisms (SNPs) were examined in relation to ICI treatment outcomes in 370 eligible patients with cancer. This approach allowed us to derive the blood group from the SNPs responsible for blood group determination. In the discovery cohort (N = 168), antigen A carriers (blood types A and AB) exhibited an extended progression-free survival (PFS; hazard ratio (HR) = 0.58, 95% confidence interval (CI) = 0.34-0.98). The association results from the SNP-derived blood were consistent with those from the measured blood group. In the validation cohort (N = 202), Cox regression analysis revealed that the antigen A carriers (rs507666 AA+GA genotype carriers) experienced significantly extended PFS compared with the non-antigen A carriers (HR = 0.61, 95% CI = 0.40-0.93). Therefore, a longer PFS was observed in antigen A carriers (P value = 0.003, HR = 0.60, 95% CI = 0.44-0.84). Furthermore, haplotype 2 carriers (rs507666 GA and rs659104 GG) demonstrated both extended PFS and improved overall survival. Notably, the presence of antigen A was not associated with the occurrence of overall immune-related adverse events (irAEs) or organ-specific toxicity. In summary, our findings revealed that antigen A carriers did not experience a higher incidence of irAEs while exhibiting better immunotherapy efficacy.

Incidence and Timing of Immune-Related Adverse Events in Immune-Checkpoint Inhibitor-Treated Patients: A Retrospective Observational Study.

Immune-checkpoint inhibitors (ICIs) are effective against various cancers; however, immune-related adverse events (irAEs) have been reported and the timing and risk factors are unknown. Therefore, we examined the incidence and timing of irAE occurrence. Patients who received ICIs at our hospital between 1 April 2016 and 31 March 2020 were enrolled. Patients were classified into an irAE group or non-irAE group. In addition, we examined the onset time and symptoms of irAEs for each ICI type. A total of 80 patients received ICIs, of which 27 (33.8%) developed irAEs. The incidence of irAEs was 35.3% for nivolumab, 35.5% for pembrolizumab, and 28.6% for atezolizumab. The incidence of pneumonitis was 12.5%, 8.8% for dermatologic adverse events, and 6.3% for thyroid dysfunction. The earliest case of onset was after the 1st course, and the latest cases occurred after the 66th course. By the sixth course, 69% of the irAEs occurred. The positive rates for anti-thyroid peroxidase and anti-thyroglobulin antibodies were higher in the irAE group compared to the non-irAE group. Our findings suggest a high probability of irAEs occurring early in ICI treatment, with a diverse range of symptoms. This underscores the need for vigilant monitoring and tailored patient management during the initial courses of ICI therapy.

Serological response and immune-related adverse events following COVID-19 vaccination in cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis.

With the popularity of Coronavirus disease 2019 (COVID-19) vaccine and the development of vaccination strategies, the impact of COVID-19 vaccine on cancer patients receiving immune checkpoint inhibitors (ICIs) is still unclear. In the systematic review and meta-analysis of patients with ICIs, we assessed the serological response of cancer patients receiving COVID-19 vaccine, and explored the risk of immune related adverse events (irAEs). We searched PubMed, EMBASE and Cochrane Library as of 10 June 2023, and included cancer patients who received ICIs and COVID-19 vaccine. The systematic review and meta-analysis include cohort study, cross-sectional study and case report. The outcome included the serological response, Spike-specific T-cell response, irAEs and rare adverse events. When possible, the data were analysed by random effect analysis, and the statistical heterogeneity was assessed by Q-test and I2 statistics. We explored the sources of heterogeneity through L'Abbe plots, Galbraith radial plots, and sensitivity analysis. The publication bias was evaluated by Egger's, Begg's linear regression test and funnel plot, and the impact of publication bias was further analysed by trim and fill method. 27 studies were eligible (19 cohort studies, 1 cross-sectional study and 7 case reports), involving 8331 patients (with 4724 receiving ICIs). Most studies used mRNA vaccine (BNT162b2 or mRNA-1273). Compared with cancer patients receiving chemotherapy, cancer patients receiving ICIs were significantly more likely to have seroconversion (RR=1.05, 95%CI 1.01-1.10, P=0.02). There were no statistically significant differences in seroconversion rates when comparing cancer patients receiving ICIs with controls without cancer (RR=0.95, 95% CI 0.89-1.01, P=0.09) or with cancer patients receiving targeted therapy (RR=1.05, 95% CI 0.79-1.39, P=0.75). The incidence of irAEs in patients receiving ICIs before and after COVID-19 vaccination was (21.96%, 95%CI 16.66%-28.94%) and (14.88%, 95%CI 8.65%-25.57%), respectively. The most common irAEs were endocrine abnormalities, skin disorders, etc. The certainty of evidence was low in cancer patients with ICIs, compared with those receiving chemotherapy, and very low versus controls without cancer. Cancer patients treated with ICIs seem to be able to receive COVID-19 vaccine safely without increasing the incidence of irAEs.

Comparison of clinical safety between standard versus extended interval dosing of immune checkpoint inhibitors: a real-world retrospective cohort study

Extended interval dosing (ED) for inhibitors of programmed cell death protein 1 (anti-PD-1) (nivolumab, pembrolizumab) or its ligand (anti-PD-L1) (durvalumab) were recently approved based on pharmacokinetic model results that predicted a benefit-risk profile comparable with the standard dosing (SD) regimen. However, safety data in real-world condition of use are lacking. The objective was to compare the incidence and the risk factors of serious immune-related adverse events (irAEs) and any-grade irAEs between the SD and ED regimens in patients treated with anti-PD-1 or anti-PD-L1. IrAEs were assessed from medical records in all new users of nivolumab, pembrolizumab, or durvalumab between 1 January 2019 and 31 December 2020 across two oncology centers in France. The incidence of irAEs was compared between both dosing regimens using Cox proportional hazards models adjusting for the main available confounders. Among 686 patients included, 63% were new users of an SD regimen, 14% of ED regimen, and 23% started with SD and switched to ED regimen during follow-up. Overall, 34.6% of patients experienced at least one irAE of any grade and 11.4% presented at least one serious grade ≥3 irAE. No statistical difference was found between the SD and ED regimen on the risk of grade ≥3 irAEs [adjusted hazard ratio (HR) 1.40, 95% confidence interval (CI) 0.71-2.76] but our results suggest an increased risk of any-grade irAEs with the ED regimen (adjusted HR 1.46, 95% CI 1.00-2.12, P= 0.048). IrAEs resolved without sequelae in 46.4% of cases, and they were fatal for three patients (0.4%). Autoimmune pre-existing condition was confirmed as a risk factor for grade ≥3 irAEs (HR 2.56, 95% CI 1.53-4.27) and for all-grade irAEs (HR 1.60, 95% CI 1.17-2.20). In a real-world setting, according to the regimen chosen by the oncologist based on clinical characteristics, we did not observe an increase in grade ≥3 irAE incidence between the SD and ED regimens.

Outcomes of weight-based vs. fixed dose of Pembrolizumab among patients with non-small cell lung cancer.

This study aims to assess outcomes among patients with non-small cell lung cancer (NSCLC) who received treatment with pembrolizumab on a weight-based dose (WBD) or fixed-dose (FD) regimen using a non-inferiority (NI) analysis. This retrospective cohort study included adult patients with NSCLC weighing under 100 kg who received pembrolizumab between 1 January 2015 and 31 December 2020. Patients were grouped into either WBD or FD cohort based on the initial pembrolizumab dose and dosing regimen. The primary effectiveness outcome was overall survival (OS), analyzed using NI analysis with a lower margin of 10% comparing WBD to FD. Safety outcomes were all-cause emergency room visits or hospitalizations and incidence of selected immune-related adverse events (irAEs) and analyzed using NI analysis with an upper margin of 10%. All patients were followed until the end of health plan membership, death, or 30 June 2022, whichever occurred first. A total of 1413 patients were evaluated. OS was observed in 36.6% of the FD group, and 37.7% in the WBD group (rate difference: 1%, 90% CI: -6%-8%, NI p-value < 0.01). NI was met in all three safety outcomes: proportion of all-cause emergency room visits (rate difference: 1.1%, NI p-value < 0.01); proportion of hospitalizations (rate difference: 2%, NI p-value < 0.01); and composite incidence of irAEs (rate difference: -2.2%, NI p-value = 0.03). These findings suggest that WBD of pembrolizumab may be as appropriate as FD for the treatment of lung cancer.

Clinical Impact of Pre-Existing Autoantibodies in Patients With SCLC Treated With Immune Checkpoint Inhibitor: A Multicenter Prospective Observational Study

IntroductionAlthough pretreatment autoantibodies have been associated with immune-related adverse events (irAEs) and immune checkpoint inhibitor treatment efficacy in some types of cancer, their importance has not been evaluated in patients with SCLC. MethodsA multicenter prospective observational study was conducted on a total of 52 patients with extensive-disease SCLC who received immune checkpoint inhibitors in combination with chemotherapy as the first-line treatment at either of the six participating centers in Japan. Pretreatment serum samples were collected and analyzed for autoantibodies (rheumatoid factor, antinuclear antibodies, and antithyroid). Moreover, 12 antineuronal antibodies (AMPH, CV2, PNMA2, Ri, Yo, Hu, Recoverin, SOX1, Titin, Zic4, GAD65, and Tr) were analyzed using immunoblot assays. The primary end point was the incidence of irAEs with or without autoantibodies. The secondary end points were progression-free survival (PFS) and overall survival (OS) on the basis of the presence or absence of autoantibodies. ResultsPFS and OS were 4.4 and 25.3 months, respectively. Autoantibodies (rheumatoid factor, antinuclear antibodies, and antithyroid antibodies) were detected in 29 patients (56%). In total, irAEs were observed in 18 patients (35%); irAE incidence was 48% in the autoantibody-positive group and 17% in the autoantibody-negative group (p = 0.039). There was no difference in PFS or OS between patients with and without autoantibodies (4.4 mo versus 4.6 mo, p = 0.36; 15.3 mo versus 18.2 mo, p = 0.36). Antineuronal antibodies were detected in 16 patients (31%). However, the development of neurologic irAEs was not observed in both groups. ConclusionsVigilance is required against the development of irAEs in pretreatment antibody-positive patients.

Emergence of immune-related adverse events correlates with pathological complete response in patients receiving pembrolizumab for early triple-negative breast cancer

ABSTRACT Based upon results of the KEYNOTE-522 trial and following approval by regulatory authorities, the addition of pembrolizumab to chemotherapy is now the standard-of-care for the treatment of early triple-negative breast cancer (eTNBC) (Clinical stage II-III). Pembrolizumab is a programmed cell death protein 1 monoclonal antibody, known to cause immune-related adverse events (irAEs) in a significant subset of patients. Real-world data on incidence, type and treatment strategies of irAEs in the setting of eTNBC treatment are sparse. In this multicenterretrospective analysis, we characterized real-world incidence of irAEs and treatment outcomes such as pathological complete response (pCR) from the combination of pembrolizumab and chemotherapy as neoadjuvant treatment for eTNBC. We found a rate of irAEs of all grades of 63.9% and of 20% for irAEs of grade 3 or higher. In the overall population, a pCR rate of 57.1% was observed. The emergence of irAEs correlated significantly with pCR (72.2% versus 30.8%; p =.03). Discontinuation of neoadjuvant chemotherapy before week 12 correlated significantly with a lower pCR rate. To our knowledge, this is the first study evaluating the real-world efficacy and safety of a neoadjuvant combination of chemotherapy and pembrolizumab in eTNBC, demonstrating a significant correlation between irAEs and pCR. Early discontinuation of neoadjuvant therapy due to AEs resulted in a lower pCR rate.

Out-of-hours admissions in patients treated with immune checkpoint inhibitors and their primary management with steroids.

The incidence of immune-related adverse events (irAEs) from immune checkpoint inhibitors (ICI) is well described. However, the impact on emergency care services is not. This study investigated the incidence of irAEs out-of-hours, and the management used to mitigate symptoms and side effects. This retrospective cohort study reviewed all emergency presentations triaged by the acute oncology team between December 2021 and June 2022, between 5 pm and 9 am. Patients were identified from triage audit sheets and remaining data points were retrieved from electronic health records. Inclusion criteria included all adult patients admitted on an ICI at one tertiary centre. In 7 months, 970 patients called the acute oncology helpline 11% (n = 109) of patients were on an ICI treatment. After clinical review, 78% (n = 70) resulted in hospital admissions, with length of stay cumulating to 496 bed days. 56% (n = 39) of patients delayed reporting symptoms, ranging between 12 hours and 10 days from symptom onset to seeking support. 49% (n = 34) patients received steroids to manage suspected irAEs. Dexamethasone was the most common steroid used in 71% (n = 24) of patients, and variation was found in prescribed doses. These results underline the urgent need to address patient and staff education on adverse effects related to ICI. Patients require a comprehensive understanding of the symptoms and importance of prompt reporting. Staff education on recognition and treatment management is needed to reduce variation in practice. Further research is needed to identify barriers in symptom reporting and focus on realtime reporting to reduce the out-of-hours burden on services.

Pan-immune-inflammation and its dynamics: predictors of survival and immune-related adverse events in patients with advanced NSCLC receiving immunotherapy

ObjectivesPan-immune-inflammation value (PIV) is defined by the neutrophil, platelet, monocyte, and lymphocyte counts and is associated with immune-checkpoint inhibitor (ICI) therapy outcomes in advanced non-small cell lung cancer (aNSCLC). However, PIV is dynamic under therapy and its longitudinal assessment may help predict efficacy. This study investigated the impact of baseline PIV and its dynamics on ICI efficacy and its immune-related adverse events (irAEs). The study additionally attempted to understand the biological significance of PIV.Patients and methodsThis retrospective study analyzed the clinical data of 269 consecutive patients with aNSCLC. PIV was calculated at baseline and at weeks 3–4 to determine its association with overall survival (OS), progression-free survival (PFS), and irAEs.ResultsResults revealed that low baseline PIV was positively correlated with the incidence of irAEs. Moreover, a low PIV at baseline was significantly associated with a prolonged PFS (median PFS: 10 vs. 7 months, p = 0.0005) and OS (median OS: 29 vs. 21 months, p < 0.0001). When the PIV at baseline and weeks 3–4 was considered together, its low dynamics correlated with a higher incidence of irAEs (p = 0.001), a longer PFS (median PFS, 9 vs. 6 months, p = 0.012), and a longer OS (median OS; 28 vs. 21 months, p = 0.002).ConclusionThus, PIV at baseline and its dynamics are novel and potent predictors of irAEs, PFS, and OS in patients with aNSCLC receiving immunotherapy. Moreover, the PIV dynamics may be an effective, novel surrogate marker to dynamically observe the efficacy of immunotherapy.

FRI493 Immune Checkpoint Inhibitors: Effects On Thyroid Nodular Disease

Abstract Disclosure: D.L. Bignoli: None. N. Kalara: None. A.J. Manzano: None. Introduction: Immune checkpoint inhibitors (ICI) are more recent pharmacologic agents used to treat malignancies, linked to immune related adverse events (irAEs) especially involving the thyroid. Classically, a transient silent thyroiditis occurs followed by hypothyroidism, however the effects on multinodular goiter are not fully recognized. We report a patient with poorly differentiated colon adenocarcinoma, treated with Pembrolizumab and Ipilimumab with significant improvement in the size of her thyroid nodules. Pembrolizumab is a monoclonal antibody directed against PD-1 receptors and Ipilimumab is an anti-CTLA-4 antibody; combination therapy has a higher incidence of irAEs compared with monotherapy (54% versus 24%). Clinical Case: 71-year-old female with a history of nontoxic benign multinodular goiter and Hashimoto’s hypothyroidism began ICI therapy as adjunctive treatment for poorly differentiated colon adenocarcinoma with MSH 2 mutation. She was euthyroid on same dose of levothyroxine for years however developed subclinical hyperthyroidism after starting immunotherapy; reporting anxiety, palpitations, tremors, and anterior neck fullness. TSH then was 0.02 mIU/mL (reference range 0.40-4.50 mIU/mL), free T4 1 ug/dl (reference range 0.9-1.7 ng/dl), and T3 122 ng/dl (reference range 100-200 ng/dl) with positive TPO antibodies. Levothyroxine was stopped and her symptoms subsequently self-resolved at follow-up 4 weeks later. Ultrasonography (US) performed in 2018 prior to starting ICI revealed: left lobe 1.3 x 2.5 x 4.66 cm, right lobe 1.3 x1.4 x 4.6 cm, isthmus 0.7 cm. There were multiple nodules: 0.4 x 0.9 x 0.7 cm, 0.3 x 0.3 x 0.4 cm nodule at right lobe, and 0.9 x 2 x 2.1 cm over right isthmus. The left lobe had four nodules: 0.4 x 0.5 x 0.8 cm, 0.4 x 0.5 x 0.9 cm, 0.8 x 0.8 x 1.36 cm, and 1 x 1.1 x 1.5 cm. Repeat ultrasonography after immunotherapy in October 2022 revealed substantial decrease in thyroid size, and the previously reported isthmus nodule was no longer visualized. The left thyroid lobe measured 0.5 x 1.1 x 3.3 cm, the right lobe 0.92 x 0.6 x 3.4 cm, and isthmus measured 0.2 cm. The right lobe nodule measured 0.40 x 0.33 x 0.86 cm and the left lobe nodule 0.34 x 0.24 x 0.50 cm. TSH was 1.150 mIU/mL, free T4 1.61 ug/dl, T3 96 ng/dl; evidencing a drastic improvement of her multinodular goiter due to ICI therapy. Conclusion: To the best of the author’s knowledge at this point in time, this is one of the few cases demonstrating effects of ICI therapy on nontoxic multinodular goiter. As described, there was a significant change in size and a previously biopsied isthmus nodule was not seen on her last ultrasound. Although irAEs are well established, there is limited literature regarding changes in anatomy and thyroid nodule architecture. Presentation: Friday, June 16, 2023

FRI508 A Case Of Durvalumab Induced Hypothyroidism

Abstract Disclosure: E.D. Cecilio La Riva: None. C. Acosta: None. A.J. Manzano: None. Background: Immune checkpoint inhibitors (ICIs), like Durvalumab, have become a mainstay in cancer treatment as they have significantly improved survival rates, especially for lung cancer. These treatments, however, have been associated with immune-related adverse events (irAEs) including dermatological manifestations, gastrointestinal symptoms, and endocrinopathies. Clinical Case: A 62-year-old male was diagnosed with a poorly differentiated adenocarcinoma with signet ring cell features stage IIIA of the right upper lobe with concurrent prostate cancer who was initially started on chemotherapy with Cisplatin/Pemetrexed for two months (four cycles) and radiation. He was subsequently started on Durvalumab. Thyroid function tests were performed after starting Durvalumab and TSH was 3.46 mlU/L (reference range: 0.40-4.50), Free T4 was 1.2 ng/dL (reference range: 0.8-1.8) and Free T3 was mildly elevated at 4.3 pg/mL (reference range: 2.3-4.2). The patient remained asymptomatic until about 12 weeks later when he began feeling occasional episodes of anxiety and shortness of breath with fatigue that was brought on at random instances. Thyroid function tests at that time showed an undetectable TSH at &amp;lt;0.01, an elevated free T3 at 4.9, and a normal free T4 at 1.6. Immunotherapy was continued and the patient was referred to endocrinology. Repeat thyroid function tests 8 weeks later showed an elevated TSH at 19.55, decreased free T4 at 0.7, and a normal free T3 at 3.1. The patient was started on levothyroxine at that time with improvement of his symptoms. Upon follow-up 4 weeks later, TSH was found at 30.56 and free T4 at 0.9 which improved with levothyroxine dose adjustment. Conclusion: The case of a patient with thyroiditis beginning as transient hyperthyroidism on Durvalumab is described. Hypothyroidism occurs in about 1.82% of patients on ICIs, with more common occurrences on Nivolumab (51.38%) and Pembrolizumab (24.44%). The incidence of hypothyroidism and thyroiditis on Durvalumab is about 3.11% and 2.04% respectively. Thyroid dysfunction with ICIs occurs with PD-1/PD-L1 blockade and an inflammatory, destructive thyroiditis can be seen. Routine monitoring of thyroid function should be performed before and throughout treatment with an ICIs. Preexisting autoimmune thyroid disease may be a risk factor for developing thyroid disease during treatment, but this has not been well studied. Meta-analysis has shown that preexisting autoimmune disease was a risk factor for irAE incidence. This case highlights the importance of proactive monitoring of thyroid function during treatment. Presentation: Friday, June 16, 2023

Prognostic Impact of Immune-Related Adverse Events as First-Line Therapy for Metastatic Renal Cell Carcinoma Treated With Nivolumab Plus Ipilimumab: A Multicenter Retrospective Study

BackgroundImmune checkpoint inhibitors can cause various immune-related adverse events (irAEs). This study aimed to evaluate the association between the incidence of irAEs and oncological outcomes of metastatic renal cell carcinoma (mRCC) treated with nivolumab plus ipilimumab as first-line therapy. Patients and MethodsWe retrospectively analyzed data from 69 patients with mRCC treated with nivolumab plus ipilimumab as first-line therapy between September 2018 and September 2021 at 4 institutions. Cox regression analyses were performed to investigate the important factors affecting overall survival (OS) in patients with mRCC treated with nivolumab plus ipilimumab as first-line therapy. ResultsDuring observation with a median follow-up of 9.1 months, the median OS was not reached, while the median progression-free survival was 6.0 months. Patients with irAEs had significantly prolonged OS and progression-free survival than those without irAEs (p = .012 and .002, respectively). Multivariate analysis showed that 3 independent factors, including C-reactive protein (CRP), irAEs, and performance status (PS), were significantly associated with OS (p = .04, .02, and .01, respectively). The patients were subsequently divided into 3 groups as follows: group 1, 20 patients with all 3 independent OS predictors; group 2, 18 patients with irAE predictors alone or 2 positive independent OS predictors (irAEs + CRP or irAEs + PS); group 3, 31 patients with 3 negative independent S predictors. OS varied significantly among the 3 groups (p = .004). ConclusionThe appearance of irAEs could predict OS in patients with mRCC treated with nivolumab plus ipilimumab as the first-line therapy.

Occurrence of irAEs after Immune Checkpoint Inhibitor Rechallenge: An Updated Meta-Analysis

What Is Known? and Objective. Immune checkpoint inhibitors (ICIs) play an important role in various cancers. The efficacy and safety of rechallenge with ICIs after immune-related adverse events (irAEs) were not well known. Accumulating studies report inconsistent findings. Thus, we conducted an updated meta-analysis by including more studies. Methods. We searched PubMed, Web of Science, Embase, and Cochrane Library for studies reporting the rechallenge of ICIs after irAEs. The evaluation outcomes included the incidence of irAEs, objective response rate (ORR), and disease control rate (DCR). Results and Discussion. A total of 896 ICI rechallenge cases from 24 studies were included. Compared to the initial treatment with ICIs, rechallenge showed a higher incidence of all-grade irAEs (OR, 2.78; 95% CI, 1.51–5.10; p = 0.001 ) and high-grade irAEs (OR, 1.88; 95% CI, 1.27–2.78; p = 0.002 ), but ORR (OR, 1.01; 95% CI, 0.55–1.84; p = 0.97 ) and DCR (OR, 1.21; 95% CI, 0.68–2.15; p = 0.52 ) were not further improved after the rechallenge of ICIs. What Is New? and Conclusion. More studies are included in this paper to compare and analyze the efficacy and safety of ICIs after rechallenge, so as to update the previous meta-analyses, and finally get different conclusions from the previous meta-analyses in terms of safety. Our results suggest that rechallenged ICIs after irAEs showed similar efficacy and lower safety than initial ICIs. However, these results need to be further verified by high-quality studies with large samples. In addition, we added subgroup analysis not available in previous meta-analyses to explore the association of cancer type, age, and gender factors with the incidence of irAE after ICI rechallenge.

P06.18.B OVERVIEW OF THE GLITIPNI TRIAL - LOCAL ADMINISTRATION OF IMMUNE CHECKPOINT INHIBITION AND/OR DENDRITIC CELLS FOLLOWING RESECTION OF RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Intravenous (IV) administration of the Immune checkpoint inhibitor (ICI) nivolumab (NIVO) for recurrent glioblastoma (rGB) has proven mostly ineffective, and the combination of IV ipilimumab (IPI) plus nivolumab (NIVO) is associated with a high incidence of irAE. Combinatorial immunotherapy strategies are likely to be more effective, and direct Intracerebral (iCE) administration following the resection of rGB could be a more effective and safer alternative to iv-dosing METHODS We previously demonstrated that intra-operative intracerebral (iCE) administration of the Immune checkpoint inhibitors (ICI) ipilimumab (IPI) and nivolumab (NIVO) after resection of recurrent glioblastoma (rGB) is safe and resulted in encouraging survival. The adaptive phase I Glitipni trial was further expanded with more cohorts (C) exploring the implantation of an Ommaya reservoir for intracavitary (iCav) administration of escalating doses of ICI, complementary iCE injection of increasing numbers of myeloid dendritic cells (myDC). We provide an overarching overview of all patients included in the program. RESULTS 102 patients have been included in the Glitipni trial. In C1 and 2 (3 and 24 patients) iCE IPI and IPI+NIVO were followed by IV NIVO every two weeks. Next, we combined this peroperative backbone with postoperative iCav injection of NIVO 1-/5-/10 mg every two weeks through an Ommaya reservoir following stereotactic biopsy (C3, 16 patients) or resection (C4, 16 patients). No dose-related toxicity was seen for iCav NIVO. iCE injection of BDCA-1 and BDCA-3+ myDC (escalating from 1-/10- to 20.10E6) was added to the backbone of C3/4 with adjuvant 10mg iCav NIVO (resection in C5, 11 patients, biopsy in C6, 2 patients). In C7 (27+patients), patients had resection, iCE IPI+NIVO, and postoperative IV NIVO with iCav NIVO 10mg and IPI escalating 1/5/10mg. Dose limiting toxicity (aseptic neutrophilic pleocytosis) was encountered with iCav IPI (5-10mg Q2w). Median Overall Survival (mOS) was 38 weeks (C1/2), 23 weeks (C3), 42 weeks (C4), 44 weeks (C5/6) and 40 weeks (C7) CONCLUSION Peroperative iCer administration of IPI and NIVO is feasible and associated with an acceptable safety profile. A potential beneficial effect on overall survival was restricted to patients with resectable recurrences. Addition of myDC my improve PFS and OS. There is no indication for an additional benefit of adjuvant iCav IPI or NIVO. Further research will expand on iCer myDC administration and investigate complementary neo-adjuvant ICI administration.

High level of C-reactive protein as a predictive factor for immune-related adverse events of immune checkpoint inhibitors in non-small cell lung cancer: a retrospective study.

Several risk factors for the immune-related adverse events (irAEs) during treatment with immune checkpoint inhibitors (ICIs) have been reported, of which include high levels of C-reactive protein (CRP). In this study, we aim to evaluate CRP levels before ICIs treatments as potential predictive biomarkers of irAEs incidence rate and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC). Between December 1, 2015 to December 31, 2019, we retrospectively collected all adult patients with NSCLC who received at least one dose of an ICI targeting the PD-1/PD-L1 axis at the Iwate Medical University Hospital in Japan. In this study the patients were categorized into low and high groups with a cut-off value of 10 mg/L as the baseline level of CRP before the ICI treatment. The primary endpoint was relationship between CRP levels at baseline and incidence of irAEs. The secondary endpoints were the relationship of progression-free survival (PFS) and OS. A total of 101 irAEs, and 25 severe irAEs were observed. The incidence of the most irAEs was higher in the high CRP group compared to the low CRP group (54.4% vs. 34.5%, respectively, P=0.003). The most frequent irAEs were skin rush (28.8%), followed by pneumonitis (19.2%), hypothyroidism (15.4%), and hepatotoxicity (9.6%). The most common grade 3 or 4 irAEs was pneumonitis (7.9%), which tended to be more frequent in the high CRP group. In multivariate analysis, patients with high CRP levels had an adjusted OR of 2.41 and were associated with an increased risk of developing irAEs (95% CI: 1.16-4.43, P=0.020). The high CRP group was related with shorter PFS compared to the low CRP group (2.2 vs. 3.3 months, respectively, P=0.006). The high CRP group were also related with shorter OS compared to the low CRP group (8.9 vs. 39.1 months, respectively, P<0.001). The results suggest that higher level of pretreatment CRP is involved in the development of irAE and poor prognosis. Identification of patients at high risk of irAEs would be of great help. Future multicenter prospective studies are needed to expand on this study.

Adverse events associated with postoperative outcomes of adjuvant anti-PD-1 antibody therapy in both acral and non-acral cutaneous melanomas: A multicenter, observational, post hoc analysis study.

Since anti-PD-1 Abs can cause irreversible immune-related adverse events (irAEs), the associations between their efficacies and the incidence of irAEs are important to evaluate the use of anti-PD-1Abs for the treatment of melanoma, especially in the adjuvant setting. The purpose of this post hoc analysis study was to retrospectively analyze the associations between recurrence-free survival (RFS) at 12 months and the onset of any irAEs in 31 non-acral cutaneous and 30 acral melanoma cases treated with anti-PD-1 Abs therapy at the adjuvant setting in Asians. There were 20 cases with greater than grade 1 AEs in both the acral and non-acral cutaneous groups. Of the acral melanoma, 10 cases were nails or toes, and 20 cases were soles and heels. The log-rank test showed that RFS was better in cases with AEs than in cases without AEs. The present study suggested that the different profiles of irAEs between non-acral cutaneous and acral melanoma might correlate with the different response to anti-PD1 Abs of melanoma in the adjuvant setting.