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Bangalore Kumar, Anagha, Alan Bryce, Prakash Vishnu, Svetomir Markovic, and Marian McEvoy. "Associations of Cutaneous Immune-Related Adverse Effects of Immunotherapy With Treatment Response in Patients With Metastatic Melanoma." SKIN The Journal of Cutaneous Medicine 5, no. 2 (March 6, 2021): 108–17. http://dx.doi.org/10.25251/skin.5.2.5.
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Background: Dermatologic toxicity is the most common immune-related adverse effect of cancer immunotherapy.
Methods: We retrospectively reviewed the health records of adult (≥18 years) melanoma patients who received ipilimumab, nivolumab, or pembrolizumab from January 1, 2011, through September 15, 2017, at Mayo Clinic. The χ2 test was used to assess the association between development of a cutaneous immune-related adverse effect and antitumoral response to the immune checkpoint inhibitors. Odds ratios were calculated with logistic regression models and were adjusted for sex and immunotherapeutic drugs. We described the various cutaneous immune-related adverse effects and assessed the response to immunotherapy (each patient’s objective clinical response was categorized as favorable [complete or partial response] or unfavorable). We then determined whether development of a cutaneous immune-related adverse effect was associated with the clinical response.
Results: Of 690 melanoma patients, 232 (33.6%) had a cutaneous immune-related adverse effect. The most common effects were dermatitis (21.4%), pruritus (5.5%), and vitiligo (4.2%). Median (range) time to onset of dermatitis was 3 (0-7) weeks; lichenoid dermatitis, 12 (6-18) weeks; and vitiligo, 40 (12-96) weeks. Development of a cutaneous immune-related adverse effect was significantly associated with favorable clinical response.
Conclusions: Development of cutaneous immune-related adverse effects is associated with favorable responses to nivolumab, ipilimumab, pembrolizumab, and ipilimumab plus nivolumab therapy in patients with metastatic melanoma.
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Williams, Kiersten J., Dennis W. Grauer, David W. Henry, and Michelle L. Rockey. "Corticosteroids for the management of immune-related adverse events in patients receiving checkpoint inhibitors." Journal of Oncology Pharmacy Practice 25, no. 3 (December 9, 2017): 544–50. http://dx.doi.org/10.1177/1078155217744872.
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Introduction Due to enhanced T-cell activity, immune checkpoint inhibitors cause immune-related adverse effects. Corticosteroids are the mainstay of immune-related adverse effect management but the optimal strategy has not been determined, putting patients at risk for steroid-related adverse effects and potentially decreased efficacy of immunotherapy. This study aims to characterize the use of corticosteroids for the management of immune-related adverse effect. Methods and materials A retrospective, single-center evaluation of patients receiving checkpoint inhibitors was conducted. The primary objective was to evaluate corticosteroid use for immune-related adverse effects, including starting dose, taper strategy, total duration, and resumption of immunotherapy. Secondary objective was to describe the incidence and significance of hyperglycemia. Results One hundred and three patients met inclusion criteria and experienced 123 immune-related adverse effects. Prednisone was used most commonly (67%) at an average starting dose of 0.88 mg/kg (range 0.07–17.0). On average, steroid tapers began 9.2 days after initiation (range 0–89) and were continued for a total of 84.2 days (range 3–693). In 21.1% of cases, checkpoint inhibitor therapy was not delayed and 68.6% resumed checkpoint inhibitors, while the patient was taking steroids (30.4 mg prednisone on average, range 5–80). On average, checkpoint inhibitor therapy was resumed 18.6 days after detection of immune-related adverse effect (range 0–150). Clinically relevant hyperglycemia occurred in 8.9%. Conclusion Utilization of steroids for immune-related adverse effect at our institution is highly variable. The majority of patients received prolonged courses of steroids and resumed checkpoint inhibitor therapy with concomitant steroids above recommended doses. Additional monitoring for hyperglycemia and other steroid associated adverse effects should be considered.
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Muir, Christopher A., Roderick J. Clifton-Bligh, Georgina V. Long, Richard A. Scolyer, Serigne N. Lo, Matteo S. Carlino, Venessa H. M. Tsang, and Alexander M. Menzies. "Thyroid Immune-related Adverse Events Following Immune Checkpoint Inhibitor Treatment." Journal of Clinical Endocrinology & Metabolism 106, no. 9 (April 20, 2021): e3704-e3713. http://dx.doi.org/10.1210/clinem/dgab263.
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Abstract Context Thyroid dysfunction occurs commonly following immune checkpoint inhibition. The etiology of thyroid immune-related adverse events (irAEs) remains unclear and clinical presentation can be variable. Objective This study sought to define thyroid irAEs following immune checkpoint inhibitor (ICI) treatment and describe their clinical and biochemical associations. Methods We performed a retrospective cohort study of thyroid dysfunction in patients with melanoma undergoing cytotoxic T-lymphocyte antigen-4 (CTLA-4) and/or programmed cell death protein-1 (PD-1) based ICI treatment from November 1, 2009, to December 31, 2019. Thyroid function was measured at baseline and at regular intervals following the start of ICI treatment. Clinical and biochemical features were evaluated for associations with ICI-associated thyroid irAEs. The prevalence of thyroid autoantibodies and the effect of thyroid irAEs on survival were analyzed. Results A total of 1246 patients were included with a median follow-up of 11.3 months. Five hundred and eighteen (42%) patients developed an ICI-associated thyroid irAE. Subclinical thyrotoxicosis (n = 234) was the most common thyroid irAE, followed by overt thyrotoxicosis (n = 154), subclinical hypothyroidism (n = 61), and overt hypothyroidism (n = 39). Onset of overt thyrotoxicosis occurred a median of 5 weeks (interquartile range [IQR] 2-8) after receipt of a first dose of ICI. Combination immunotherapy was strongly associated with development of overt thyrotoxicosis (odds ratio [OR] 10.8, 95% CI 4.51-25.6 vs CTLA-4 monotherapy; P < .001), as was female sex (OR 2.02, 95% CI 1.37-2.95; P < .001) and younger age (OR 0.83 per 10 years, 95% CI 0.72-0.95; P = .007). By comparison, median onset of overt hypothyroidism was 14 weeks (IQR 8-25). The frequency of overt hypothyroidism did not differ between different ICI types. The strongest associations for hypothyroidism were higher baseline thyroid-stimulating hormone (OR 2.33 per mIU/L, 95% CI 1.61-3.33; P < .001) and female sex (OR 3.31, 95% CI 1.67-6.56; P = .01). Overt thyrotoxicosis was associated with longer progression free survival (hazard ratio [HR] 0.68, 95% CI 0.49-0.94; P = .02) and overall survival (HR 0.57, 95% CI 0.39-0.84; P = .005). There was no association between hypothyroidism and cancer outcomes. Conclusion Thyroid irAEs are common and there are multiple distinct phenotypes. Different thyroid irAE subtypes have unique clinical and biochemical associations, suggesting potentially distinct etiologies for thyrotoxicosis and hypothyroidism arising in this context.
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Bansal, Aditi, Ankur Singla, Davinder Paul, and Sukhjot Kaur. "Pembrolizumab-induced lichen planus: A rare immune-related adverse side effect." Indian Dermatology Online Journal 14, no. 3 (2023): 391. http://dx.doi.org/10.4103/idoj.idoj_377_22.
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Lima, Gian, Adriana Kahn, Shashank Sama, and Jacqueline Savage. "Aseptic Meningitis as an Immune-Related Adverse Event after Pembrolizumab." Case Reports in Oncological Medicine 2019 (November 4, 2019): 1–2. http://dx.doi.org/10.1155/2019/7183747.
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Introduction. The management of patients with advanced malignancies is challenging, although recent advances with immunotherapy have shown better outcomes. Pembrolizumab has been associated with a variety of immune-related side effects, but the occurrence of aseptic meningitis is rare. Case. A 55-year-old male with a history of metastatic lung adenocarcinoma previously treated with pembrolizumab presented with persistent severe headaches and photophobia. Subsequent workup with cerebrospinal fluid analysis showed elevated opening pressure, increased nucleated cells with 30% lymphocytes, elevated protein levels, and normal glucose levels. The patient was started on high doses of IV steroids and progressed with significant improvement of his symptoms. Discussion. Given the rarity of this side effect, this case is a reminder that immune checkpoint inhibitors can cause aseptic meningitis and its early recognition is important for initiation of therapy with steroids and prompt discontinuation of the immunotherapy agent.
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Kim, Won Myung, Mun Su Park, Dong Hyun Seo, Jung Yun Lee, and Jung Yoon Pyo. "Immune-related Adverse Effect after BNT162b2 Vaccination with Parallel Immune Checkpoint Inhibitor Therapy: A Case Report." Korean Journal of Medicine 98, no. 2 (April 1, 2023): 93–97. http://dx.doi.org/10.3904/kjm.2023.98.2.93.
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COVID-19 vaccination is essential in cancer patients. However, there is limited evidence of the prognosis of these patients, especially for those taking immune checkpoint inhibitors (ICIs). We present a patient on pembrolizumab for advanced endometrioid adenocarcinoma experiencing continuous diarrhea and subsequent episodes of fever with pain in multiple joints following a second dose of the BNT162b2 mRNA COVID-19 vaccine. An ICI-induced immune-related adverse effect (irAE) was the main diagnosis; cytokine release syndrome and rheumatoid arthritis were also considered. Notably, the novel irAE occurred after the 19th pembrolizumab trial, highlighting the potential effect of changes in systemic immunogenicity after BNT162b2 vaccination. Ultimately, the patient was treated with steroid, which alleviated her symptoms. Here, we report a rare adverse effect after COVID-19 vaccination in an endometrioid carcinoma patient on ICI therapy. This report shows that there is a need to consider and investigate vaccine-related adverse events.
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Brinzevich, Daria, Virginia Falvello, Michael D. Green, and Alex Bryant. "Impact of commonly prescribed medications on immune-related adverse events." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): e14704-e14704. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.e14704.
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e14704 Background: Commonly used medications may have immune modulating properties that affect the risk of immune-related adverse events (irAEs) after immune checkpoint inhibitor (ICI) therapy. Methods: We identified 27,998 patients who received ICI from 2010 to 2023 in the national Veterans Affairs system, matched to 66,488 historical control patients treated with non-ICI systemic therapies. We extracted medication usage in the year before therapy start. We used propensity-weighted Cox regression analysis to assess the effect of each medication on severe irAE (treatment with prolonged course of high-dose steroids, adrenal insufficiency, or new insulin-dependent diabetes). To identify medication effects specific to ICI vs. other therapies, we report the adjusted hazard ratio (aHR) for each medication stratified by cohort (ICI vs. historical control) and the p-value for the interaction between each medication class and cohort. Results: Among ICI patients, 52% of patients were treated in the first line, 72% received ICI monotherapy, and 95% received PD-1/PD-L1 inhibitors alone. The most common cancer types were NSCLC (46%), melanoma (10%), and liver cancer (8%). Among 15 medication classes, metformin, loop diuretics, and PPIs were associated with small, marginally statistically significant differences in toxicity among ICI patients, but similar associations were observed in historical control patients (p for interaction >0.18; Table). After adjustment for multiple comparisons, no medication classes were associated with increased risk of severe irAE in ICI patients. Conclusions: Commonly prescribed medication classes have no significant effects on toxicity specific to ICI therapy. [Table: see text]
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Ou, Qiyun, Yunfang Yu, Haitao Zhong, Anlin Li, Yongjian Chen, HaiYu Zhou, Shaopeng Zheng, Luyu Huang, and Herui Yao. "Association of immune-related adverse events with immune checkpoint inhibitor efficacy in pancancer." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14087-e14087. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14087.
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e14087 Background: Immune-related adverse events (irAEs) have been shown to be associated with the efficacy of immune checkpoint inhibitors in patients with advanced cancer, but the reported effect sizes have varied greatly in previous trials. We did a meta-analysis to assess immune checkpoint inhibitors efficacy and further explored the correlation of irAEs with efficacy in cancer. Methods: We systematically searched database inception to January, 2019 for randomized trials of immune checkpoint inhibitor in patients with advanced cancer that had available data for overall survival (OS) and progression-free survival (PFS), and irAEs. We calculated the pooled hazard ratios (HRs) and 95% confidence intervals [CIs] using a random-effects model, and assessed the association between the irAEs and PFS or OS using coefficient of determination ( R²). The PROSPERO registry number is CRD42017075610. Results: Thirty eight trials with 19,521 patients were included. Compared with conventional therapy, anti-PD-1 or PD-L1 combined with conventional therapy significantly enhanced survival (HR = 0.62, 95% CI 0.53 to 0.72 for PFS; HR = 0.71, 95% CI 0.58 to 0.87 for OS), and anti-PD1 or PD-L1 combined with anti-CTLA4 (HR = 0.75, 95% CI 0.63 to 0.90 for PFS). Anti-CTLA4 plus conventional therapy prolonged PFS (HR = 0.80, 95% CI 0.72 to 0.89) and OS (HR = 0.80, 95% CI 0.66 to 0.96) than conventional therapy alone. Anti-PD1 or PD-L1 outperformed anti-CTLA4 on OS (HR = 0.68, 95% CI 0.57 to 0.81). Significant correlation between treatment efficacy and irAEs was only identified in pneumonitis ( R2 0.59, P = 0.026 for PFS) and diarrhea ( R2 0.22, P = 0.006 for OS). Conclusions: We recommended the concurrent use of immune checkpoint inhibitor and conventional therapy or dual immunotherapy as the most appropriate regimens for advanced cancer. Furthermore, development of pneumonitis and diarrhea were associated with survival outcome of immune checkpoint inhibitors in patients with advanced cancer.
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Hamatake, Kiyonori, and Kazuaki Kojima. "Initiatives for immune-related adverse events by the outpatient pharmacist clinic." Trends in Immunotherapy 6, no. 1 (January 10, 2022): 3. http://dx.doi.org/10.24294/ti.v6.i1.1385.
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Early detection is the key in managing side effects because immune-related adverse events (irAEs) are becoming more serious, and their onset time differs. In our hospital, we conducted an outpatient pharmacist clinic for early detection of irAEs by self-care practice for the cases of immune checkpoint inhibitor administration. As a result of a retrospective survey of 207 cases, the percentage of irAEs found by pharmacist’s suggestion of the outpatient pharmacist clinic increased over time, and a high detection ratio was obtained even for irAEs with a late onset time. The incidence of serious irAEs was higher than that in the immediate post-marketing surveillance, and different factors were considered. Although there were some problems, the outpatient pharmacist clinic had a certain effect.
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Sakai, Miho, Yuki Haga, Michiyo Kambe, Koji Nishimura, Ayako Shingyouchi, Tatsuo Miyamura, Kenji Ito, et al. "A case of immune-related adverse effect diffuse gastritis induced by nivolumab." Progress of Digestive Endoscopy 98, no. 1 (June 25, 2021): 91–92. http://dx.doi.org/10.11641/pde.98.1_91.
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Margiotta, Philip, Mario Caldararo, Daniel Altman, Sheel A. Patel, Sharon Li, Sean Clark-Garvey, Reetu Mukherji, et al. "Effect of pretreatment steroids on the development of immune related adverse events." Journal of Clinical Oncology 36, no. 15_suppl (May 20, 2018): e15095-e15095. http://dx.doi.org/10.1200/jco.2018.36.15_suppl.e15095.
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Gleeson, Ferga C., Katie A. Dunleavy, Michael J. Levy, Ryan M. Carr, Mindy L. Hartgers, Lisa A. Kottschade, Robert R. McWilliams, Wen Wee Ma, Yogish C. Kudva, and Aoife M. Egan. "Incidence and Effect Duration of Immune Checkpoint Inhibitor-Related Pancreas Adverse Events." Pancreas 53, no. 7 (August 2024): e627-e629. http://dx.doi.org/10.1097/mpa.0000000000002337.
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Elsayed, Manar, and Carrie Ye. "Osteoporotic fractures: an unrecognized adverse event of immune checkpoint inhibitors?" Journal for ImmunoTherapy of Cancer 12, no. 7 (July 2024): e009309. http://dx.doi.org/10.1136/jitc-2024-009309.
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The widespread use of immune checkpoint inhibitors (ICIs) in clinical practice has broadened our understanding of their immune-related adverse events (irAEs). IrAEs, including musculoskeletal adverse events, remain a significant concern. While ICI-associated arthritis is a well-documented musculoskeletal side effect of ICI therapy, the direct effects of ICIs on bone in patients with cancer are poorly understood. There is emerging evidence to support the hypothesis that ICIs adversely impact bone turnover and can lead to osteoporosis and fragility fractures, which are not currently recognized as irAEs.
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El Bitar, Sandy, Chanudi Weerasinghe, Elie El-Charabaty, and Marcel Odaimi. "Renal Tubular Acidosis an Adverse Effect of PD-1 Inhibitor Immunotherapy." Case Reports in Oncological Medicine 2018 (2018): 1–3. http://dx.doi.org/10.1155/2018/8408015.
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Immune checkpoint blockade therapy is gaining popularity among oncologists for treatment of solid and hematologic malignancies. The widespread use of these agents resulted in increasing incidence of renal immune-related adverse events. Reported renal toxicity described so far includes acute interstitial nephritis, minimal change disease, and immune complex glomerulonephritis. We report the case of a 79-year-old female with metastatic non-small cell lung cancer on anti-PD-1 therapy nivolumab. After the 4th administration of nivolumab, the treatment course was complicated with normal anion gap metabolic acidosis. Urine and blood studies were in favor of distal renal tubular acidosis (RTA). Following a negative workup for an underlying etiology, immunotherapy-induced RTA was suspected. Withholding of the offending agent and initiation of steroid therapy resulted in adequate response. The present report provides the first presentation of RTA as a renal immune-related adverse event secondary to nivolumab. Nephrologists and oncologists should be familiar with potentially life-threatening renal side effects induced by immune checkpoint inhibitors.
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Osataphan, Soravis, Yu Jen Jan, Katherine A. Stafford, and Prudence B. Lam. "Effect of excess weight on immune-related adverse events from immune checkpoint inhibitor in lung cancer." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e21183-e21183. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e21183.
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e21183 Background: Immune checkpoint inhibitors (ICIs) are effective therapies for advanced lung cancer however they are also associated with immune-related adverse events (irAEs). Obesity has been shown to be correlated with both ICIs’ anti-tumor efficacy particularly in melanoma and non-small cell lung cancer (NSCLC). However, there have been conflicting reports between the relationship between BMI and the incidence of irAEs. Methods: We conducted a retrospective cohort study on the use of immune checkpoint inhibitor in advance lung cancer from Mount Auburn Hospital, a community-based teaching hospital in the United States, between 2016 to 2020. We studied the association between overweight (BMI of more than 25 kg/m2) versus normal weight patients (BMI 18.5 - 24.99 kg/m2) and incidence of irAEs or progression free survival. Results: A total of 51 patients with advanced lung cancer were treated with either Pembrolizumab, Nivolumab, Durvalumab or Atezolizumab. NSCLC accounted for 90.2% of the histological findings and adenocarcinoma represented 45.0% of the cohort. Among these patients 61.0% were classified as. There was a trend to increase in the incidence of irAEs in overweight compared to normal weight patients (48.3% vs. 25.0%, OR 1.91, 95% CI 0.56-6.99, p = 0.308). The most common irAEs in this cohort was thyroid dysfunction. The overweight group also had a higher baseline blood glucose level (120.5 ± 39.9 mg/dL vs. 92.9 ± 13.8 mg/dL, p < 0.01). However, no difference in progression free survival was found between the two groups (HR 1.19, 95%CI 0.58-2.42, p = 0.6). Conclusions: Although limited by sample size, here we reported a real-world experience where excessive weight may be an important predictor of irAEs development in patients with lung cancer.
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Rathmann, Joerg, James J. Vredenburgh, Racha Demesropian, Dorothy Wakefield, Kendra Williams, Archana Purushothaman, Jessica Bello, and Latha Dulipsingh. "Cancer-immune checkpoint inhibition and autoimmune-related adverse events." Journal of Clinical Oncology 37, no. 8_suppl (March 10, 2019): 107. http://dx.doi.org/10.1200/jco.2019.37.8_suppl.107.
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107 Background: Immunotherapies effect adaptive or innate immune responses. Programmed-death 1 (PD-1), a cell surface protein on activated T cells, which, when bound to its ligands PD-L1 and PD-L2, inhibits T-cell activation. Inhibition can be associated with complicating immune-related adverse events (IRAEs). Immune checkpoint inhibitors (ICIs) are FDA approved for advanced NSCLC. Study aims: (1) determine if the use of ICIs nivolumab (N) and pembrolizumab (P) is associated with development of autoimmune diabetes and thyroid disease and (2) determine the impact of (N) and (P) on pre-existing autoimmunity. Methods: Prospective, biological and clinical end-point-driven study in subjects with NSCLC considered for 1st or 2nd-line treatment with N or P. Subjects were assessed for thyroid stimulation hormone (TSH), hemoglobin A1c (HbA1c), thyroid peroxidase antibodies (TPO), glutamic acid decarboxylase (GAD) antibodies and islet cell antibodies (IC) at time of treatment start and wk 16 end point. Results: 29 subjects enrolled with base-line laboratory testing of which 14 subjects could be assessed at wk 16. At baseline, 1/14 subject had abnl TSH but at week 16 all subjects had a nl TSH (p 0.0687). Subjects had nl TPO at baseline and only 1/14 had an abnl TPO at 16 weeks (p 0.1634 ) but TSH remained nl. All 14 subjects had nl GAD and IC antibodies at baseline and at 16 wks; however, 2/14 of subjects had abnl IC antibodies at 16 wks but had nl HbA1c. 6/14 had nl HbA1c at baseline and 1/6 went on to develop pre-diabetes and 1/6 developed diabetes at the 16 wks. 5/14 subjects had pre-diabetes at baseline: 1/5 had nl HbA1c while 1/5 developed diabetes at 16 wks. 2 subjects developing diabetes had no positive GAD or IC antibodies. 3/14 had diabetes at study start with no worsening of the HbA1c or diabetes-related complications at wk 16. Conclusions: ICIs can cause IRAEs. Study result suggests that treatments with N and P can cause new onset of non-immune diabetes mellitus. Clinical awareness is important while managing NSCLC patients on ICIs. Patient should be screened for diabetes and thyroid disease prior to therapy and with repeat testing so as to avoid treatment complications. Longer follow-up and further study of ICI-mediated auto-immune endocrinopathies is needed.
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Hunting, John, Eric Olson, Andrew Thomas Faucheux, Catherine A. Elko, Mary-Peyton Knapp, Sarah Price, Stephanie Brinton, and Thomas William Lycan. "Effects of pre-treatment on odds of immune-related adverse events." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): 2540. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.2540.
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2540 Background: For many tumor types, there is an option to start an immune checkpoint inhibitor (ICI) at the time of diagnosis or to sequence ICI after chemotherapies or targeted therapies. The risk of immune-related adverse events (irAE) may vary by the line of therapy. Prior systemic therapies might release cancer epitopes and increase the risk of an irAE through awakened subclinical autoimmunity. Conversely, prior systemic therapies may lead to residual immunosuppression and reduce the risk of irAEs. Methods: We created an IRB-approved retrospective registry of all patients who received at least one dose of an ICI for any indication between 2/1/2011 and 4/7/2022 at a comprehensive cancer center and its outreach clinics. Study personnel reviewed the electronic medical record and defined irAEs according to Common Terminology Criteria for Adverse Events. Research specialists at Vasta Global captured most clinical outcomes. Line of therapy was defined ordinal manner, with four or more combined into a single group due to data sparsity. A multivariable logistic regression model was built to assess effect of line of therapy on any irAE while controlling for confounders identified either a priori or in univariate analysis. Given potential for heterogeneity, interaction between tumor primary and line of therapy was tested. SAS v9.4 was used for all analyses. Results: Among the final cohort of 3,101 patients, 1,169 (38%) were noted to have an irAE of any grade. ICI were used as first-line therapy in 1,432 patients and second-, third-, or at least fourth-line in 1,119, 328, and 222 patients, respectively. The most common tumor type was non-small cell lung cancer (36%), followed by melanoma (14%). At baseline, any-grade irAE were more common among first-line ICI with 618 (43.2%) than for second-line (395, 35.3%), third-line (102, 31.1%), or at least fourth-line (54, 24.3%; p<0.01). After adjusting for age (over 65), sex, smoking history, and body mass index, the model revealed significant heterogeneity, indicated by a significant interaction between the ICI line and the primary tumor type (p=0.01). The impact of the ICI line on the odds ratio (OR) of irAE for each primary calculated: melanoma (OR) 0.54 (95% confidence interval [CI] 0.32-0.93), non-small cell lung cancer OR 1.14 (CI 0.96-1.35), head-neck cancer OR 0.82 (CI 0.58-1.14), and renal cell carcinoma OR 0.78 (CI 0.57-1.06). Conclusions: The effect of pre-treatment with prior systemic therapy was significantly associated with the odds of developing an irAE, though this effect was significantly heterogeneous between tumor primaries. Melanoma was significantly less likely to develop irAE when heavily pre-treated. In contrast, NSCLC suggested a trend of increased odds of irAE with more pre-treatment however it was not statistically significant. Further study is indicated to clarify the types of prior systemic therapy that may modulate the risk of irAE and better clarify the optimal sequencing of ICI.
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Liu, Mingyue, Xu Wang, Peng Zhang, Juanjuan Su, Xuexiang Du, Yan Zhang, Yang Liu, and Pan Zheng. "813 CD24Fc ameliorates immune-related adverse events while preserving anti-tumor therapeutic effect." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A849. http://dx.doi.org/10.1136/jitc-2021-sitc2021.813.
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BackgroundCombination therapy with anti-CTLA-4 and anti-PD-1 mAbs has emerged as the most potent and durable cancer immunotherapy, yet it is associated with frequent and severe immune-related adverse events (irAEs).1 2 A largely unmet medical need is to reduce irAEs. The CD24–Siglec 10/G interaction is an emerging immune checkpoint that regulates inflammation caused by danger-associated molecular patterns (DAMPs).3–5 It is of great interest to investigate whether CD24Fc can ameliorate severe irAEs, the hallmark of which is a severe inflammatory state in multiple organs.MethodsWe used a human CTLA-4 knock-in (Ctla4h/h) mice model that fully recapitulates human irAE in response to anti-PD-1 and anti-CTLA-4 antibodies to test if CD24Fc have therapeutic effect for irAE. We treated Ctla4h/h mice with Ipilimumab and anti-PD-1 Ab in conjunction with hIgFc or CD24Fc on day 10, 13, 16 and 19 after birth. The body weight was monitored over time, hematologic and histopathologic alterations were evaluated at 6 weeks of age. To evaluate the therapeutic effect of CD24Fc on ICIs induced tissue destruction, we performed histological analysis of internal organs and glands. Major organs were collected about 1 month after first treatment and fixed in 10% formalin, sectioned and stained with hematoxylin and eosin (H&E), and scored double blindly. To test whether CD24Fc immune modulation may interfere with the anti-tumor efficacy of the checkpoint inhibitors, we inoculated MC38 and B16-F10 tumor cells on Ctla4h/h mice, then treated with combination of Ipilimumab and anti-PD-1 Ab together with hIgFc or CD24Fc and monitored tumor growth.ResultsWe found that anti-CTLA-4 and anti-PD-1 therapy could induce growth retardation, anemia and severe inflammation in all organs examined. All of these adverse events were ameliorated by CD24Fc treatment. Moreover, in both tumor models tested CD24Fc modestly enhanced immunotherapeutic effect of anti-PD-1 and anti-CTLA-4 antibodies. CD24Fc treatment showed no effect on CD4+, CD8+ T cell or tumor associated macrophage (TAM) density intratumor. However, we observed significantly decreased Treg among CD4+T cells after CD24Fc treatment. CD24Fc treatment also decreased the TIM-3+ PD-1+ CD4+ and CD8+ T cells. These data suggest CD24Fc has the potential to optimize tumor microenvironment and augment antitumor immunity.ConclusionsOur data demonstrate that CD24Fc treatment ameliorates irAEs in multiple organs induced by combination of anti-CTLA-4 and anti-PD-1 Abs while modestly enhancing its anti-tumor activity, potentially by reducing the intratumor regulatory T cells and reverse exhaustion of tumor-infiltrating T cells.ReferencesWolchok JD, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2017;377:1345–1356.Larkin J, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2019;381:1535–1546.Chen GY, Tang J, Zheng P, Liu Y. CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science 2009;323:1722–1725.Liu Y, Chen GY, Zheng P. CD24-Siglec G/10 discriminates danger- from pathogen-associated molecular patterns. Trends Immunol 2009;30:557–561.Fang X, Zheng P, Tang J, Liu Y. CD24: from A to Z. Cell Mol Immunol 2010;7:100–103.
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Gleeson, Ferga C., Lisa Kottschade, Katie A. Dunleavy, Ryan M. Carr, Mindy Hartgers, Michael J. Levy, Wen Wee Ma, Robert McWilliams, and Aoife Egan. "Tu1420 INCIDENCE AND EFFECT DURATION OF IMMUNE CHECKPOINT INHIBITOR RELATED PANCREAS ADVERSE EVENTS." Gastroenterology 164, no. 6 (May 2023): S—1049. http://dx.doi.org/10.1016/s0016-5085(23)03438-8.
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Cautha, Sandhya, Kevin R. Jain, Pravash Budhathoki, Tobechukwu Joseph Okobi, Tanushree Bhatt, Valentina Moirangthem, Sorab Gupta, Thanh-Ha T. Luong, and Ahmad Hanif. "The study of immune-related adverse events in a community-based centre." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 2642. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.2642.
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2642 Background: The effectiveness of immunotherapy is often hindered by the development of immune-related adverse events (IrAE). Racial minorities were under-represented in the key clinical trials that led to the approval of different immune checkpoint inhibitors (ICI). In this study, we explore the side effect profile of immune checkpoint inhibitors in our patient population that comprises almost entirely of minorities, mostly African Americans (AA) and Hispanics. We hypothesize that due to race-based differences in immune milieu of the body and disease susceptibility, the timing and severity of immunotherapy-related IrAE would be different in AA and Hispanics compared to Caucasians. This can translate into a difference in clinical outcomes as well. There have been some suggestions of a positive association of the development of IrAE with cancer survival, although the data is limited and heterogeneous. The purpose of our study is to study the frequency and severity of IrAEs in racial minority groups, compare them with previous clinical trials population, and add valuable real-world data in this underrepresented group of patients. Methods: A retrospective chart review was performed on adult patients with solid malignancies treated with any ICI between January 1, 2015 and April 30, 2022. Patients were classified according to age (greater/equal to 65y or younger), sex, race (self-identified), primary cancer, and type of immunotherapy received. Outcome data using type and severity of IrAE, time to development of IrAE, and any association with clinical outcomes was collected and analyzed using descriptive statistics as well as univariate analysis. Results: A total of 78 patients were included in the final analysis. The mean age was 68 years; 51% were males; 42.3% were Hispanics, 37% were AA, 19.7% were others, and 1% were Whites. Most common malignancy was lung cancer (65.5%). Most common ICI agent used was Pembrolizumab (n = 52) and 2 patients were treated with combination therapy using Ipilimumab and Nivolumab. 41 (52.5%) patients had IrAE of any grade while 9 (11.5%) patients experienced grade 3 side effects. None of the patients experienced grade 4 side effects. Most common IrAE of any grade was hypothyroidism (n = 14) while most common grade 3 side effect was colitis (n = 6). 31 patients were less than 65y of age. There was no significant difference in IrAE in patients less than 65 years of age vs ≥ 65 years (51.6% vs 53.1%) or grade 3 IrAE (9.6% vs 12.7%). Conclusions: In our study population consisting mostly of AA and Hispanics, the rate of IrAE of any grade as well as grade 3 or 4 IrAE with ICI therapy was comparable to what was seen in clinical trials involving these drugs. This data and its potential effects on survival outcomes need to be analyzed in prospective studies involving a larger number of patients.
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Zyablova, E. I., L. N. Nefedova, and V. A. Porkhanov. "Radiological Imaging of Adverse Events to Immunotherapy." Journal of oncology: diagnostic radiology and radiotherapy 3, no. 3 (September 30, 2020): 44–53. http://dx.doi.org/10.37174/2587-7593-2020-3-3-44-53.
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At present, immunotherapy is successfully used for the treatment of multiple malignant diseases, especially in the late stages of metastatic tumors, which until now, were difficult to treat using standards protocols. Positive therapeutic effects of immunotherapy were demonstrated in treatment of many common oncological diseases. However, despite the expressed positive effect, in some patients immunotherapy can demonstrate non-typical forms of the answer. To establish accurate diagnosis it is necessary to know radiological manifestations of immune-related adverse events (irAE), mainly, immune-mediated pneumonitis, colitis, hypophysitis, hepatitis and myositis. Early identification and the corresponding treatment of irAE may improve patient's outcomes.
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Fragulidis, Georgios, Eirini Pantiora, Vasiliki Michalaki, Elissaios Kontis, Elias Primetis, Antonios Vezakis, and Andreas Polydorou. "Immune-related intestinal pseudo-obstruction associated with nivolumab treatment in a lung cancer patient." Journal of Oncology Pharmacy Practice 25, no. 2 (October 25, 2017): 487–91. http://dx.doi.org/10.1177/1078155217738325.
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Immune checkpoint inhibition therapy using targeted monoclonal antibodies is a new therapeutic approach with significant survival benefit for patients with several cancer types. However, their use can be associated with unique immune-related adverse effects as a consequence of impaired self-tolerance due to loss of T-cell inhibition via a nonselective activation of the immune system. Nivolumab is an anti-PD-1 immune checkpoint inhibitor that was recently developed for cancer immunotherapy with remarkable responses in nonsmall cell lung cancer patients. We present a 62-year-old Caucasian male with recurrent lung adenocarcinoma and currently under third-line therapy with nivolumab, who was admitted in our hospital with abdominal distension. Radiologic findings were consistent with small bowel ileus. After four days of conservative treatment, the patient underwent exploratory laparotomy where no cause of ileus was discovered. Postoperative the ileus persisted and considering that an adverse effect of the immune checkpoint inhibition therapy occurred, the patient received high-dose prednisone resulting in gradual improvement of symptoms. Immune checkpoint inhibitors may induce adverse effects to unaffected organ systems and tissues including the skin, gastrointestinal, hepatic, pulmonary, and endocrine system. The mainstay treatment consists of immunosuppression with corticosteroids in the majority of cases. As the clinical use of immune checkpoint inhibitors is expanding rapidly, there is an emergence of unique immune-related adverse effects in a growing patient population. Gaining early awareness is essential in these patients in order to ensure prompt diagnosis and management.
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Rai, Manoj P., Prabhjot Singh Bedi, Rohanlal Vishwanth, Fawzi Abu Rous, Shiva Shrotriya, and Prajwal Dhakal. "Immune-related adverse events in melanoma: A nationwide analysis 2016." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e18253-e18253. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e18253.
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e18253 Background: Melanoma is an aggressive skin cancer. Immunotherapy is currently used as a first-line treatment for unresectable metastatic disease. Combination immunotherapy has been shown to improve overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) compared to single-agent immunotherapy. However, immunotherapy related adverse events (irAE's) are being increasingly seen. This study analyses the incidence of irAE's and the variation in the length of stay, and mortality. Methods: This is a retrospective cohort analysis of the 2016 NIS database. We identified hospitalizations with either primary or secondary diagnosis of Melanoma. Logistic regression of irAE's such as pneumonitis, colitis, hypophysitis, adrenal insufficiency, encephalitis, myocarditis was performed. We evaluated the association between irAE's and various parameters. Results: We identified 13170 hospitalizations with primary or secondary diagnosis of melanoma. Univariate logistic regression showed pneumonitis (OR: 1.39; p value: < 0.01), hypophysitis (OR: 20.61; p value < 001), adrenal insufficiency (OR: 10.36, p value = < 0.01), colitis (OR 23.94, p value < 001), myocarditis (OR: 1; p value was n/a), encephalitis (OR 1.71; p value was 0.5). Univariate logistic regression for LOS showed colitis (OR 1.23; p value: 0.01), adrenal insufficiency (OR 0.20; p value: 0.748), hypophysitis (OR -2.50; p value: 0), myocarditis no admissions, encephalitis (OR -2.15; p value 0.01). Univariate logistic regression for mortality showed pneumonitis (OR 6.07; p value: < 0.01), colitis (OR 0.86 p value: 0.721), adrenal insufficiency (OR 1; p value: 0.996). Conclusions: The above results suggest that the incidence of colitis is the highest among irAE’s in melanoma patients likely due to immunotherapy. Hypophysitis is the next most common side effect, it’s followed by adrenal insufficiency which can be life-threatening. A high index of suspicion and anticipation of the above complications can lead to their timely detection and treatment.
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Gandhi, Shipra, Manu Pandey, Nischala Ammannagari, Chong Wang, Mark J. Bucsek, Lamya Hamad, Elizabeth Repasky, and Marc S. Ernstoff. "Impact of concomitant medication use and immune-related adverse events on response to immune checkpoint inhibitors." Immunotherapy 12, no. 2 (February 2020): 141–49. http://dx.doi.org/10.2217/imt-2019-0064.
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Aim: Patients receiving checkpoint inhibitors (CPI) are frequently on other medications for co-morbidities. We explored the impact of concomitant medication use on outcomes. Materials & methods: 210 metastatic cancer patients on CPI were identified and association between concomitant medication use and immune-related adverse events with clinical outcomes was determined. Results: Aspirin, metformin, β-blockers and statins were not shown to have any statistically significant difference on clinical benefit. 26.3% patients with clinical benefit developed rash versus 11.8% without clinical benefit (p < 0.05) on multivariate analysis. Conclusion: Use of common prescription and nonprescription medications in patients with multiple co-morbidities appears safe and does not have an adverse effect on CPI efficacy. The presence of rash predicted for a better response.
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Kulkarni, Ajinkya, Mrunal Kulkarni, Vinay Edlukudige Keshava, Rithikaa Ellangovan, and Rajesh Thirumaran. "Awareness of immune-related adverse events among medical residents in a community hospital." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15154-e15154. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15154.
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e15154 Background: Immunotherapy has paved the way for new frontiers in the management of certain advanced cancers. Immune checkpoint inhibitors (ICI) have substantially improved prognosis in patients with advanced malignancy. Primary targets for ICIs include programmed cell death receptor 1 (PD-1), programmed cell death ligand 1 (PD-L1) and Cytotoxic T-lymphocyte-associated antigen 4(CTLA-4). These treatments have a wide range of adverse effects distinct from traditional chemotherapy regimens. We conducted a survey to assess the awareness of immune-related adverse events (IRAE) among medical residents in a community hospital. Methods: Internal medicine residents in a community hospital were given a survey of 10 questions related to IRAEs. A total of 40 responses were collected and analyzed. Results: 22.50% respondents were aware that nephrotoxicity is not a common side effect of immunotherapy. 35% were aware that cutaneous toxicities are the most common IRAEs. 42.50% were aware that hair loss is not a common side effect of ICIs. 42.50% were aware that patients do not need pretreatment with anti-emetics before immunotherapy. 45% were aware that the onset of hepatotoxicity is usually not seen within the first week of starting immunotherapy. 50% were aware that immunotherapy is associated with the development of pneumonitis. 62.5% were aware that steroids formed mainstay of treatment in IRAEs. 65% were aware that immunotherapy is associated with thyroid-related side effects. 67.5% were aware that patients with pre-existing autoimmune conditions are at greater risk for immune-related adverse effects. 70% were aware that immune related colitis was not treated with antibiotics. Conclusions: With the rapid advancement and use of immunotherapy the incidence of IRAEs is increasing. Involvement of single or multiple organ systems as well as flare of previously well controlled autoimmune disease can add to the challenge. As we gain more experience, long term data will emerge to help predict at-risk patients. This is a dynamic area of research and new treatments are under development. 6/10 questions were answered correctly by less than 50% respondents and 4/10 were answered correctly by 50-70% respondents. At present no data is available to gauge awareness regarding IRAEs among internists. Our survey suggests a lack of awareness among medical residents on many fronts. Lack of awareness leads to inappropriate treatment and prolonged hospital stay. Active efforts need to be taken to educate residents regarding immunotherapy and IRAEs to achieve better patient outcomes.
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Luo, Jia, Jason Beattie, Paige Fuentes, Hira Rizvi, Jacklynn V. Egger, Jeffrey Kern, Donald Y. M. Leung, et al. "Beyond steroids: Immunosuppressants in steroid-refractory/resistant immune related adverse events." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 9092. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.9092.
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9092 Background: The optimal management for immune related adverse events (irAEs) in patients who do not respond or become intolerant to steroids is unclear. Guidelines suggest additional immunosuppressants based on case reports and expert opinion. Methods: We examined patients with advanced lung cancers at MSK treated with immune checkpoint blockade (ICB) from 2011-2020. Pharmacy records were queried to identify patients who received systemic steroids as well as an additional immunosuppressant (eg TNFα inhibitor, mycophenolate mofetil). Patient records were manually reviewed to examine baseline characteristics, management, and outcomes. Results: Among 2,750 patients with lung cancers treated with ICB, 51 (2%) received both steroids and an additional immunosuppressant for a severe irAE (TNFα inhibitor (73%), mycophenolate mofetil (20%)). The most common events were colitis (53%), pneumonitis (20%), hepatitis (12%), and neuromuscular (10%). At 90 days after start of an additional immunosuppressant, 57% were improved from their irAE, 18% were unchanged, and 25% were deceased. Improvement was more common in hepatitis (5/6) and colitis (18/27) but less common in neuromuscular (1/5) and pneumonitis (3/10). All patients with hepatitis received mycophenolate mofetil 500-1000mg BID for a median of 3 months, range 2-5 months. Of the 18 patients with colitis who improved with a TNFα inhibitor, 10 needed just one dose. Of 13 patients who died, 4 were related to toxicity from immunosuppression (3, infection-related deaths; 1, drug-induced liver injury leading to acute liver failure). Those who died from immunosuppressive therapy received higher amounts of systemic steroids than those who did not (max median 525 vs 132 mg prednisone equivalent, Mann Whitney U p = 0.004, total median 5.9k vs 2.3k mg prednisone equivalent, p = 0.004). Of 31 patients who received at least 3 weeks of prednisone ≥ 20mg, most (90%, 28/31) had at least one side effect that was brought to clinical attention (most commonly altered mood/ sleep, 52%, increase in BMI > 1kg/m2, 45%, and infection, 32%). Conclusions: Steroid-refractory/resistant immune related adverse events are rare. While existing treatments help patients with hepatitis and colitis, most patients with other irAEs remain refractory and/or experience toxicities from immunosuppression. Systemic steroid use likely contributed to side effects and mortality. A more precise understanding of the pathophysiology of specific irAEs is needed to guide biologically informed treatment regimens for severe irAEs to realize the true benefit of ICB therapy.
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Shalata, Walid, Sarah Weissmann, Sapir Itzhaki Gabay, Kim Sheva, Omar Abu Saleh, Ashraf Abu Jama, Alexander Yakobson, and Keren Rouvinov. "A Retrospective, Single-Institution Experience of Bullous Pemphigoid as an Adverse Effect of Immune Checkpoint Inhibitors." Cancers 14, no. 21 (November 5, 2022): 5451. http://dx.doi.org/10.3390/cancers14215451.
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Immune checkpoint inhibitors are a class of cancer treatment drugs that stimulate the immune system’s ability to fight tumor cells. These drugs are monoclonal antibodies targeting im-mune-inhibiting proteins on cancer cells, such as CTLA-4 and PD-1/PD-L1. Immune checkpoint inhibitors cause many immune-related adverse events. Cutaneous toxicities are of the most common adverse effects and occur with a range of severity. Bullous Pemphigoid is a rare adverse event with a high impact on quality of life that may occur after immune checkpoint inhibitor treatment. In this article, we investigate current research on immune checkpoint inhibitors, cutaneous adverse events, and common presentations and treatments, with a specific focus on Bullous Pemphigoid, its characteristics, onset timing, and treatment. Significant findings include a negative skew in the onset of presentation. Furthermore, we describe exclusive cases.
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Khalid, Ahmed Bilal, Shadia Ibrahim Jalal, and Greg Andrew Durm. "Physician awareness of immune-related adverse events from checkpoint inhibitors." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 6571. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.6571.
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6571 Background: Immune checkpoint inhibitors (ICIs) have been one of the most significant developments in Oncology over the last decade. Despite being very effective for certain patient subsets, they have a unique side effect profile different from conventional chemotherapy that can manifest as immune-related adverse events (IRAEs). With increasing ICI use, clinicians will increasingly encounter these adverse events and thus, adequate knowledge on recognition and management of IRAEs is very important. Methods: To assess physician knowledge on IRAEs of ICIs, an online survey was administered to resident physicians in internal medicine (IM), emergency medicine (EM) and family medicine (FM) as well as to faculty physicians in IM, and FM at 3 tertiary care hospitals in Indiana. Results: We sent the survey to 413 physicians out of which 155 responded with a response rate of 38%. Out of 155 physicians, 110 were residents and 45 were faculty (27 hospitalists and 17 primary care physicians). Pembrolizumab was identified as a checkpoint inhibitor correctly by 79% of physicians, nivolumab by 64% and ipilimumab by 55%. Twenty-five percent of physicians incorrectly believed infliximab and adalimumab were ICIs. Most physicians (93%) were able to identify the gastrointestinal tract as an IRAE site whereas only 57% and 67% were able to identify cardiovascular and renal systems as an IRAE site, respectively. Fifty-nine percent of physicians believed steroids negatively affect efficacy of ICIs and should be used with caution to treat IRAEs. Sixty-five percent of physicians incorrectly thought endocrinopathies due to IRAEs are usually reversible. Most physicians (79%) believed IRAEs most commonly manifest in the first 6 months of treatment. Forty-five percent of FM residents considered antibiotics as the mainstay of treatment in ICI associated immune mediated colitis; this was significantly different from EM (15%) and IM (8%) residents(p = 0.0004). When comparing between residency programs, on a scale of 0-100, IM residents felt significantly more comfortable identifying IRAEs secondary to ICIs (27.1±24.2) when compared to EM (12.2±12.7) and FM residents (9.4±13.8; p = 0.0009). There was no significant difference among IM (19.8±20.1), EM (11.9±13.6), and FM residents (11.6±18.9; p = 0.11) when comparing how comfortable they were in treating IRAEs. When asked what the best way would be to learn about IRAEs, 36% chose printed material and algorithms, 30% picked online teaching module and 30% chose one time in-person lecture from an Oncologist. Conclusions: Resident and faculty physicians in multiple specialties are not comfortable in the management and treatment of IRAEs due to ICIs. Given that most of these physicians are usually the first point of contact with patients, physician education on identification and treatment of IRAEs is needed. Early detection of these toxicities is critical for their resolution.
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Khalid, Ahmed Bilal, Shadia Ibrahim Jalal, and Greg Andrew Durm. "Physician awareness of immune-related adverse events from checkpoint inhibitors." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 6571. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.6571.
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6571 Background: Immune checkpoint inhibitors (ICIs) have been one of the most significant developments in Oncology over the last decade. Despite being very effective for certain patient subsets, they have a unique side effect profile different from conventional chemotherapy that can manifest as immune-related adverse events (IRAEs). With increasing ICI use, clinicians will increasingly encounter these adverse events and thus, adequate knowledge on recognition and management of IRAEs is very important. Methods: To assess physician knowledge on IRAEs of ICIs, an online survey was administered to resident physicians in internal medicine (IM), emergency medicine (EM) and family medicine (FM) as well as to faculty physicians in IM, and FM at 3 tertiary care hospitals in Indiana. Results: We sent the survey to 413 physicians out of which 155 responded with a response rate of 38%. Out of 155 physicians, 110 were residents and 45 were faculty (27 hospitalists and 17 primary care physicians). Pembrolizumab was identified as a checkpoint inhibitor correctly by 79% of physicians, nivolumab by 64% and ipilimumab by 55%. Twenty-five percent of physicians incorrectly believed infliximab and adalimumab were ICIs. Most physicians (93%) were able to identify the gastrointestinal tract as an IRAE site whereas only 57% and 67% were able to identify cardiovascular and renal systems as an IRAE site, respectively. Fifty-nine percent of physicians believed steroids negatively affect efficacy of ICIs and should be used with caution to treat IRAEs. Sixty-five percent of physicians incorrectly thought endocrinopathies due to IRAEs are usually reversible. Most physicians (79%) believed IRAEs most commonly manifest in the first 6 months of treatment. Forty-five percent of FM residents considered antibiotics as the mainstay of treatment in ICI associated immune mediated colitis; this was significantly different from EM (15%) and IM (8%) residents(p = 0.0004). When comparing between residency programs, on a scale of 0-100, IM residents felt significantly more comfortable identifying IRAEs secondary to ICIs (27.1±24.2) when compared to EM (12.2±12.7) and FM residents (9.4±13.8; p = 0.0009). There was no significant difference among IM (19.8±20.1), EM (11.9±13.6), and FM residents (11.6±18.9; p = 0.11) when comparing how comfortable they were in treating IRAEs. When asked what the best way would be to learn about IRAEs, 36% chose printed material and algorithms, 30% picked online teaching module and 30% chose one time in-person lecture from an Oncologist. Conclusions: Resident and faculty physicians in multiple specialties are not comfortable in the management and treatment of IRAEs due to ICIs. Given that most of these physicians are usually the first point of contact with patients, physician education on identification and treatment of IRAEs is needed. Early detection of these toxicities is critical for their resolution.
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Jiang, Ning, Yue Yu, Dawei Wu, Shuhang Wang, Peiwen Ma, Huilei Miao, Yu Tang, and Ning Li. "Association between germ-line HLA and immune-related adverse events." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 2658. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.2658.
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2658 Background: In recent years, great progress has been made in immune checkpoint inhibitors (ICIs), opening a new chapter for cancer treatment. However, accompanied by remarkable efficacy, immune-related adverse events (irAEs) also arose. Though some pilot studies have explored the possible factors that may influence the development of irAEs, the mechanism of irAEs remains unclear. Previous studies indicated a positive association between certain HLA types and irAEs. To uncover the relationship between irAEs and divergent HLA types, we initiated a large cohort study. Methods: We screened 626 patients who have been treated in the clinical research ward, Cancer Hospital of Chinese Academy of Medical Sciences. All participants included should be diagnosed with malignant tumors and have received at least 2 cycles of ICIs with complete security follow-up data in the original electronic medical records. The blood samples were collected before the first cycle of treatment. Sequencing libraries were generated using a customized panel. Six digit formatted HLA alleles were extracted from HLA-HD (v1.4.0) results for further analysis. Fisher-exact test was used to perform association analysis between HLA and different irAEs. To control the type I error, we introduce two external reference groups as well as the non-irAE control group. In addition, false discovery rate (FDR) correction was performed with the resulting p-values when comparing the HLA allele frequency between patients with irAEs and the MHC-han Chinese reference cohort. We also explored the relationship between zygosity of HLA genes, evolutionary divergence of HLA class I genotype (HED) and irAEs. Results: Of the 626 participants, 530 received at least 2 doses of ICIs. The median follow-up time was 10.3 months. 97% patients received anti-PD-1/PD-L1 treatment. Of all participants, 78% reported irAEs of any grade, with 10.2% reporting grade 3 and above irAEs. The occurrence of overall irAEs showed no significant difference between homozygous group and heterozygous group. We did not find any significant association between irAEs and HED. We found that some HLA types are associated with irAEs of different organs, including the significant association between HLA-DRB3*01:01 and thrombocytopenia (OR 3.48 (1.19,9.42), p = 0.011), HLA-DPB1*04:02 and hypokalemia/ hyponatremia (OR 3.44 (1.24,9.1), p = 0.009), leukopenia (OR 2.1 (0.92,4.8), p = 0.037) as well as anemia (OR 2.33 (1.0,5.41), p = 0.026), HLA-A*26:01 and bilirubin elevation (OR 2.67 (0.92,8.31), p = 0.037). Conclusions: IrAEs in specific organs and tissues may be associated with certain HLA types, while HLA heterogeneity have no significant influence on the happening of irAEs. More research is needed to explore the role of germline genetic changes in the risk assessment of irAEs, and potential therapies targeting irAE-inducing HLA types without influencing the anticancer effect may be considered to benefit the patients.
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Soman, Biji, Maria Cecilia Dias, Syed Azhar J. Rizvi, and Attila Kardos. "Myasthenia gravis, myositis and myocarditis: a fatal triad of immune-related adverse effect of immune checkpoint inhibitor treatment." BMJ Case Reports 15, no. 12 (December 2022): e251966. http://dx.doi.org/10.1136/bcr-2022-251966.
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Pembrolizumab, a humanised monoclonal antibody and immune checkpoint inhibitor (ICI) that blocks programmed death receptor 1 and its ligands, is an effective immunotherapy for malignancies such asmelanoma, lung, head and neck, cancers, and Hodgkin’s lymphoma. It has an overall response rate between 73% and 83%, with complete response rate of 27%–30%. It is well tolerated with minor side effects in 70% of cases characterised by fatigue, rash, pruritus and diarrhoea. In rare cases, more serious and life-threatening complications can occur at a rate of 0.3%–1.3%. We report a case of a woman in her 70s with non-small-cell lung cancer treated with ICI. She presented to the emergency department with left-sided ptosis and muscle weakness 3 weeks of her first dose of pembrolizumab infusion as a treatment plan of her cancer. She was diagnosed with myasthenia gravis, myocarditis and myositis as ICI-induced immune-related adverse effects resistant to medical intervention. We wish to raise awareness of the triad of life-threatening complication of ICI therapy that accounts for 30%–50% of fatal complications.
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Inagaki, Yuichiro, Hirofumi Yokota, Yuki Takeuchi, Hitomi Sawa, Takashi Seki, Hidetoshi Akita, Mamiko Takeuchi, et al. "The therapeutic effect and immune-related adverse event of nivolmab in Anjo Kosei Hospital." Annals of Oncology 30 (October 2019): vi135. http://dx.doi.org/10.1093/annonc/mdz343.079.
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Nakai, Masahiro, Yoshiro Kai, Kentaro Suzuki, Masayuki Matsuda, Shoma Kikukawa, Hiroyuki Masuda, Masahiro Soga, et al. "A case of perforated immune-related colitis complicated by cytomegalovirus infection during treatment of immune-related adverse effect in lung cancer immunotherapy." Respiratory Medicine Case Reports 41 (2023): 101794. http://dx.doi.org/10.1016/j.rmcr.2022.101794.
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Rahman, Md Mominur, Tapan Behl, Md Rezaul Islam, Md Noor Alam, Md Mohaimenul Islam, Ali Albarrati, Mohammed Albratty, Abdulkarim M. Meraya, and Simona Gabriela Bungau. "Emerging Management Approach for the Adverse Events of Immunotherapy of Cancer." Molecules 27, no. 12 (June 13, 2022): 3798. http://dx.doi.org/10.3390/molecules27123798.
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Immunotherapy, which stimulates the body’s immune system, has received a considerable amount of press in recent years because of its powerful benefits. Cancer immunotherapy has shown long-term results in patients with advanced disease that are not seen with traditional chemotherapy. Immune checkpoint inhibitors, cytokines like interleukin 2 (IL-2) and interferon-alpha (IFN), and the cancer vaccine sipuleucel-T have all been licensed and approved by the FDA for the treatment of various cancers. These immunotherapy treatments boost anticancer responses by stimulating the immune system. As a result, they have the potential to cause serious, even fatal, inflammatory and immune-related side effects in one or more organs. Immune checkpoint inhibitors (ICPIs) and chimeric antigen receptor (CAR) T-cell therapy are two immunotherapy treatments that are increasingly being used to treat cancer. Following their widespread usage in the clinic, a wave of immune-related adverse events (irAEs) impacting virtually every system has raised concerns about their unpredictability and randomness. Despite the fact that the majority of adverse effects are minimal and should be addressed with prudence, the risk of life-threatening complications exists. Although most adverse events are small and should be treated with caution, the risk of life-threatening toxicities should not be underestimated, especially given the subtle and unusual indications that make early detection even more difficult. Treatment for these issues is difficult and necessitates a multidisciplinary approach involving not only oncologists but also other internal medicine doctors to guarantee quick diagnosis and treatment. This study’s purpose is to give a fundamental overview of immunotherapy and cancer-related side effect management strategies.
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Chang, Michael, Nira A. Krasnow, Amy E. Blum, Vartan Pahalyants, William S. Murphy, Jaewon Yoon, Kerry Lynn Reynolds, Leah L. Thompson, and Steven T. Chen. "Relationship between insurance status and diagnosis of cutaneous immune-related adverse events." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e18535-e18535. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e18535.
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e18535 Background: Cutaneous immune-related adverse events (cirAEs) are among the most common side effects of immune checkpoint inhibitor (ICI) therapy. While insurance status has been shown to influence outcomes in patients treated with ICIs, its impact on cirAE management remains underexplored. We therefore evaluated insurance status in patients with cirAEs, examining its effect on rate of and time to cirAE diagnosis. Methods: Using billing data, we retrospectively identified patients who initiated anti-PD-1/PDL-1 and/or anti-CTLA-4 therapy at Massachusetts General Hospital between January 1, 2016 and March 8, 2019 (n = 2,459) for possible cirAE. Eligible cirAEs included reactions attributed to ICI by the clinician, consistent with established morphologic categories. For each patient with confirmed cirAE (n = 358), we abstracted oncologic history, cirAE features, and insurance status. Associations between insurance and cirAE diagnosis outcomes were assessed via logistic and linear regression, and adjusted for age, sex, race, ICI type, cancer diagnosis, cirAE type, and significant covariates ( P< 0.05). Results: Of the 2,459 patients who received ICIs, 2,419 (98.4%) had documented insurance status. Most ICI recipients had Medicare (n = 1,119; 46.3%) or private insurance (n = 1,156; 47.8%) relative to Medicaid (n = 104; 4.3%) or other government insurance (e.g. Tricare) (n = 40; 1.7%). We found that 358 (median age 64 years, 40.5% female) developed a cirAE. Among cirAE patients, 175 had Medicare (48.9%), 174 had private insurance (48.6%), 6 had Medicaid (1.7%), and 3 had other government insurance (0.8%). The most common cirAEs across insurance types were maculopapular rash, pruritus, and eczematous and lichenoid eruptions. In the multivariable analysis, ICI patients with Medicare insurance had a higher rate of cirAE diagnosis (adjusted odds ratio: 2.41, 95% CI: 1.00, 5.90, P= 0.05) relative to Medicaid patients. In addition, in terms of time to cirAE diagnosis at dermatology visit, Medicare insurance was associated with longer delays, with a linear regression coefficient of 132.2 (95% CI: 4.78, 259.6; P= 0.04). No significant associations were found between other insurance types and cirAE diagnosis outcomes. Conclusions: Our study shows that patients with Medicaid are less likely to be diagnosed with cirAE relative to those with Medicare, despite delays in diagnosis, when controlling for all other demographic/oncologic factors. Ultimately, these findings are reassuring that despite insurance differences, patients with cirAEs are receiving suitable care and appropriately seen by dermatologists. As insurance coverage for specialists can vary widely, these initial findings are a promising indicator that patients with cirAEs are well-connected within healthcare systems.
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Wang, Jun, Xinyue Han, Yingcui Chen, Hong Xie, Yuekai Zhang, Yu Cui, and Yaping Guan. "Organ-specific immune-related adverse events and survival in patients with cancer with immune checkpoint inhibitors." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): 12124. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.12124.
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12124 Background: Immunotherapy with immune checkpoint inhibitors (ICIs) can lead to immune-related adverse events (irAEs). This study was designed to assess whether the occurrence of irAEs or different irAE characteristics correlates with survival outcomes in advanced cancer patients treated with ICIs. Methods: This cohort study included a panel of patients with advanced cancer who received ICI therapy at a single institute. Kaplan‒Meier curves were generated to describe progression-free survival (PFS) and overall survival (OS) in patients with irAEs or specific irAE characteristics. Results: A total of 238 patients were enrolled, and 83 (34.9%) patients developed at least one irAE. The irAE development was associated with prolonged OS (not reached vs 17.8 months, HR: 0.48, p < 0.001), PFS (8.7 vs 4.8 months, HR: 0.63, p = 0.003), and an improved objective response rate (24.1% vs 10.3%, p = 0.005). However, irAE characteristics, including severity, number of organs or systems affected, and timing of onset, were not associated with OS. Furthermore, we observed that only skin and endocrine toxicities independently protected against OS and PFS. Based on the results from organ-specific irAEs, the first development of skin or endocrine toxicities as protective irAEs rather than other irAEs was an independent indicator for predicting OS (HR: 0.24, p < 0.001) and PFS (HR: 0.43, p< 0.001). A prognostic irAE score based on organ-specific irAEs was developed to show the effect of total protective irAEs on patient outcomes. Conclusions: Not all irAEs are associated with prolonged survival. Identification of organ-specific irAEs but not other irAE characteristics is useful for stratifying patients who actually respond to and benefit from ICIs across different cancer types.
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Reid, Pankti, Daniel Olson, and Thomas Gajewski. "Assessing the effect of immunosuppressive agents for immune-related adverse event management on tumor response." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 3066. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3066.
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3066 Background: High grade immune-related adverse events (irAEs) to cancer immune checkpoint inhibitors (ICI) require considerable immunosuppression (IS) with high-dose steroids and steroid-sparing IS (SSIS) for steroid-dependent cases. T lymphocyte-specific IS has generally been avoided or used with significant caution due to the fear that these agents may negatively impact ICI efficacy. We sought to determine whether T cell-specific IS agents, such as calcineurin inhibitors (CNIs), have an adverse effect on tumor control when compared to other immunomodulatory drugs (IMDs). Methods: We retrospectively analyzed clinical annotations of adult patients treated with ICIs for malignancy from 1/1/2000-12/31/2019, highlighting patients who were managed with SSIS, specifically those most commonly used for autoimmune disease therapy. Topical IS use was excluded. Patients were categorized as tumor responders or non-responders, and irAEs were graded according to National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE). Progression-free survival (PFS) was assessed via Kaplan-Meier curve. Results: 1331 unique individuals were prescribed ≥1 ICIs, with 526 prescribed systemic steroids (39.5%) and 90 (6.8%) patients prescribed SSIS agents, 25 patients with >1 SSIS: mycophenolate (39), methotrexate (26), leflunomide (5), azathioprine (3), rituximab (24), tocilizumab (3), infliximab (8), etanercept (1), adalimumab (1), golimumab (1) and CNIs (18): cyclosporine, tacrolimus. IMDs hydroxychloroquine (6) and sulfasalazine (5) were also prescribed. The objective response rate was 50.0% in the CNI group compared to 45.5% in the IMD cohort and 45.4% in the irAE group (CTCAE grade matched) with steroids alone without any SSIS. Median PFS were compared between CNI cohort (5.4 months, range 1.3-34 months) to IMD (1.1 months, range 0.4-6.4, p=0.02) and steroid alone (2.4 months, range 0.69-17.7, p=0.48). Multiple regression analysis identified irAE presence as an independent correlates to tumor response (p=0.02). Conclusions: T cell-specific IS should not be excluded from irAE treatment algorithm as we observed that PFS was comparable to immunomodulators and similar efficacy was observed compared to steroids alone. Rapid identification and management of irAEs can help mitigate morbidity but there are virtually no reliable clinical trials to guide irAE management with SSIS. These findings support the need for larger, prospective evaluation of immunosuppression use for high grade irAE therapy.
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Kaszycki, Margaret A., and Jonathan Leventhal. "Review of Immune Checkpoint Inhibitors and Radiotherapy Related Skin Toxicities." Journal of Dermatology and Skin Science 3, no. 3 (October 20, 2021): 10–19. http://dx.doi.org/10.29245/2767-5092/2021/3.1140.
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Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, and their use in combination with radiation therapy (RT) has become increasingly utilized to optimize positive outcomes. The cutaneous adverse reactions from RT as well as ICIs are both well documented; however, in combination these cutaneous toxicities can be exacerbated. ICIs and RT may work synergistically to create an enhanced immune response against the tumor cells. This synergistic effect has been reported to occur both locally at the site of RT, as well as systemically via an abscopal effect. Fortunately, this combination of treatment does not increase the incidence of cutaneous reactions, although several cases have reported enhanced skin toxicity at the site of RT. RT is thought to create an ‘immunocompromised skin district’ or localized immune dysregulation in irradiated skin. This review summarizes previously published case reports and discusses the cutaneous adverse reactions from ICI and RT combination therapy. Properly identifying ICI and RT induced skin reactions depends on several factors including patient history, sequence of therapies, timing of reaction, and histological findings. Skin reactions from combination therapy can range in severity and include ICI-induced radiation recall dermatitis, as well as uncommon presentations of Stevens-Johnson syndrome, lichen planus, and bullous pemphigoid which are localized to or enhanced within areas of prior radiation exposure. It is important for oncologists and dermatologists alike to be aware of the spectrum of reactions associated with ICI and RT.
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Wanchoo, Rimda, Sabine Karam, Nupur N. Uppal, Valerie S. Barta, Gilbert Deray, Craig Devoe, Vincent Launay-Vacher, and Kenar D. Jhaveri. "Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review." American Journal of Nephrology 45, no. 2 (2017): 160–69. http://dx.doi.org/10.1159/000455014.
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Background: Cancer immunotherapy, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death 1 (PD-1), has revolutionized the treatment of malignancies by engaging the patient's own immune system against the tumor rather than targeting the cancer directly. These therapies have demonstrated a significant benefit in the treatment of melanomas and other cancers. Summary: In order to provide an extensive overview of the renal toxicities induced by these agents, a Medline search was conducted of published literature related to ipilimumab-, pembrolizumab-, and nivolumab-induced kidney toxicity. In addition, primary data from the initial clinical trials of these agents and the FDA adverse reporting system database were also reviewed to determine renal adverse events. Acute interstitial nephritis (AIN), podocytopathy, and hyponatremia were toxicities caused by ipilimumab. The main adverse effect associated with both the PD-1 inhibitors was AIN. The onset of kidney injury seen with PD-1 inhibitors is usually late (3-10 months) compared to CTLA-4 antagonists related renal injury, which happens earlier (2-3 months). PD-1 as opposed to CTLA-4 inhibitors has been associated with kidney rejection in transplantation. Steroids appear to be effective in treating the immune-related adverse effects noted with these agents. Key Message: Although initially thought to be rare, the incidence rates of renal toxicities might be higher (9.9-29%) as identified by recent studies. As a result, obtaining knowledge about renal toxicities of immune checkpoint inhibitors is extremely important.
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Jamal, Shahin, Marie Hudson, Aurore Fifi-Mah, and Carrie Ye. "Immune-related Adverse Events Associated with Cancer Immunotherapy: A Review for the Practicing Rheumatologist." Journal of Rheumatology 47, no. 2 (July 15, 2019): 166–75. http://dx.doi.org/10.3899/jrheum.190084.
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Immune checkpoint inhibitors have revolutionized cancer therapy by blocking inhibitory pathways of the immune system to fight cancer cells. Their use is often limited by the development of autoimmune toxicities, which can affect multiple organ systems and are referred to as immune-related adverse events (irAE). Among these are rheumatologic irAE, including inflammatory arthritis, myositis, vasculitis, and others. Rheumatologic irAE seem to be different from irAE in other organs and from traditional autoimmune diseases in that they can occur early or have delayed onset, and can persist chronically, even after cancer therapy is terminated. Because immune checkpoint inhibitors are increasingly used for many types of cancer, it is important for oncologists and rheumatologists to recognize and manage toxicities early. In this review, we discuss currently approved immune checkpoint inhibitors and their mechanisms of action and systemic toxicities, with a focus on the management and effect on further cancer therapy of rheumatic irAE.
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Nardi Agmon, Inbar, Osnat Itzhaki Ben Zadok, and Ran Kornowski. "The Potential Cardiotoxicity of Immune Checkpoint Inhibitors." Journal of Clinical Medicine 11, no. 3 (February 7, 2022): 865. http://dx.doi.org/10.3390/jcm11030865.
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The use of immune checkpoint inhibitors (ICIs) as a mono- or adjuvant oncologic treatment is rapidly expanding to most fields of cancer. Alongside their efficacy, ICIs carry the risk of immune-related adverse events (irAEs) arising from misguided immune-mediated response to normal tissues. In the cardiovascular system, the cardiac toxicity of ICIs has been primarily related to the development of an acute, immune-mediated myocarditis; beyond this potentially fatal complication, evidence of an increased risk of cardiovascular events and accelerated atherosclerosis is emerging, as well as reports of other cardiovascular adverse events such as arrythmias, Takotsubo-like syndrome and vascular events. The absence of identified risk factors for cardiotoxic complications, specific monitoring strategies or diagnostic tests, pose challenges to the timely recognition and optimal management of such events. The rising numbers of patients being treated with ICIs make this potential cardiotoxic effect one of paramount importance for further investigation and understanding. This review will discuss the most recent data on different cardiotoxic effects of ICIs treatment.
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Shivaji, Uday N., Louisa Jeffery, Xianyong Gui, Samuel C. L. Smith, Omer F. Ahmad, Ayesha Akbar, Subrata Ghosh, and Marietta Iacucci. "Immune checkpoint inhibitor-associated gastrointestinal and hepatic adverse events and their management." Therapeutic Advances in Gastroenterology 12 (January 2019): 175628481988419. http://dx.doi.org/10.1177/1756284819884196.
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Background: Drug-induced colitis is a known complication of therapies that alter the immune balance, damage the intestinal barrier or disturb intestinal microbiota. Immune checkpoint inhibitors (ICI) directed against cancer cells may result in activated T lymphocyte-induced immune-related adverse events (AEs), including immune-related colitis and hepatitis. The aim of this review article is to summarize the incidence of gastrointestinal (GI) and hepatic AEs related to ICI therapy. We have also looked at the pathogenesis of immune-mediated AEs and propose management strategies based on current available evidence. Methods: A literature search using PubMed and Medline databases was undertaken using relevant search terms pertaining to names of individual drugs, mechanism of action, related AEs and their management. Results: ICI-related GI AEs are common, and colitis appears to be the most common side effect, with some studies reporting incidence as high as 30%. The incidence of both all-grade colitis and hepatitis were highest with combination therapy with anti-CTLA-4/PD-1; severity of colitis was dose-dependent (anti-CTLA-4). Early intervention is associated with better outcomes. Conclusion: ICI-related GI and hepatic AEs are common and clinicians need to be aware. Patients with GI AEs benefit from early diagnosis using endoscopy and computed tomography. Early intervention with oral steroids is effective in the majority of patients, and in steroid-refractory colitis infliximab and vedolizumab have been reported to be useful; mycophenolate has been used for steroid-refractory hepatitis.
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Tanimura, Keiko, Tadaaki Yamada, Yusuke Chihara, Yutaka Kubota, Shinsuke Shiotsu, Takayuki Takeda, Takahiro Yamada, Osamu Hiranuma, Junji Uchino, and Koichi Takayama. "The Impact of Immune-related Adverse Events on the Effect of Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer." Haigan 59, no. 2 (April 20, 2019): 128–36. http://dx.doi.org/10.2482/haigan.59.128.
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Abdel-Wahab, Noha, Teresa Kus, Salah-Eddine Bentebibel, Jennifer Leigh McQuade, Isabella Claudia Glitza, Rodabe Navroze Amaria, Sapna Pradyuman Patel, et al. "Immune-related adverse events and symptom burden in patients with melanoma receiving adjuvant immune checkpoint inhibitor." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): TPS12147. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.tps12147.
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TPS12147 Background: Adjuvant therapy with immune checkpoint inhibitors (ICIs) is approved for melanoma, but immune-related adverse events (irAEs) remain a challenge. Although acute toxicities are well defined, long-term AEs and impact on quality of life (QOL) are undetermined. Available data derived from clinical trials involve highly selected populations and do not reflect real world experience. Additionally, trials measure outcomes only at predetermined endpoints, and symptoms may vary throughout the course of therapy. Moreover, the pathogenesis of irAEs and symptoms remains poorly understood. We hypothesize that AEs and sustained inflammation induced by adjuvant ICIs increase symptom burden and negatively impact function and QOL in a subset of patients (pts), and elevated expression of pro-inflammatory cytokines and T cell signatures during therapy correlate with toxicity and symptom burden. Our preliminary data identified i) interleukin-6/Th-17 pathway as a possible mediator of irAEs, ii) immune reactivity and increases in inflammatory cytokines are associated with symptom burden in cancer survivors, and iii) prioritized 30 genetic markers conferring risk for irAEs in ICI-treated melanoma pts. Methods: This is a prospective longitudinal cohort study to evaluate potential toxicity/symptom burden and immune correlates in melanoma pts receiving adjuvant ICIs (NCT04990726). A total of 240 pts will be enrolled. Eligibility criteria: age ≥18 years (yrs), surgically resected stage II, III, or IV melanoma, initiating adjuvant nivolumab or pembrolizumab, no prior systemic therapy for melanoma, and no prior autoimmune diseases. Patients will be assessed at baseline (before ICI infusion) and every 3 months (mos) up to 2 yrs or until attrition or death. The primary endpoint is the incidence rate of any irAEs at 12 mos. Demographics, personal/family history, comorbidities, tumor history/stage, prior therapies, performance status, concurrent medications, and other factors that play a role in pts perceptions of disease are collected. At each visit, pts undergo a clinical evaluation to assess potential irAEs, new comorbidities, and tumor recurrence. Patient-reported outcomes of fatigue, depression, sleep disturbance, and QOL are collected at each visit to assess changes from baseline up to 2 yrs. In addition to standard methods of data collection at pre-specified times, we leverage mobile technology to capture symptoms and AEs in real time. Longitudinal blood samples will characterize pts immune signatures from baseline up to 2 yrs to evaluate their association with irAEs, symptom burden, and QOL, and to compare the genotype of pts with and without irAEs. To characterize the effect of adjuvant ICI on bone health, eligible pts are evaluated by whole body dual-energy X-ray absorptiometry at baseline and at 12 mos as an exploratory aim. The study is currently active, and 27 pts are enrolled. Clinical trial information: NCT04990726.
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Sharma, Nitika, Prashanti Atluri, Chipman Robert Geoffrey Stroud, Paul R. Walker, Sulochana Devi Cherukuri, Cynthia R. Cherry, Paul Gibbs, Teresa Parent, and Jessica Hardin. "Immune related adverse events (irAEs): A unique profile based on tumor type." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e14606-e14606. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e14606.
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e14606 Background: Immune checkpoint blockade(ICB) has revolutionized the treatment of a growing number of malignancies. Real world administration of oncolytics is often associated with increased adverse event rates versus what is demonstrated in clinical trials. Whether the tumor biology, site of disease burden or underlying organ dysfunction dictates the differing immune side effect profile in various malignancies remains to be understood. Methods: The incidence of grade 2-4 irAE was abstracted from medical records of all patients (pts) treated with ICB (ipilimumab and/or nivolumab) from 2011 to 2016 at a single institution. Results: Of the 126 pts reviewed, 82 pts had metastatic lung cancer, 31 pts had unresectable or metastatic melanoma, 13 pts had metastatic renal cancer(RCC). In the melanoma cohort, concurrent or sequential PD-1 and CTLA4 blockade was used in 10/31 pts. All of the lung cancer and RCC patients received anti-PD-1 alone. In the patients with lung cancer: pneumonitis was identified in 24%, SIRS in 16%, thrombosis in 11%, cerebritis in 9%, colitis in 4%, hepatitis in 4%, thyroiditis in 5%. In RCC, 8% pts experienced pneumonitis and 8% had thyroiditis. In the melanoma population, colitis was identified in 19%, SIRS in 10%, pneumonitis in 3%, thrombosis in 6%, adrenalitis in 6%, hepatitis in 3%. Colitis was seen in 2/13(15%) pts who got ipilimumab alone and 4/10(40%) pts who got both ipilimumab and nivolumab. Conclusions: Pneumonitis, SIRS and cerebritisappear to be the most prevalent irAEs in lung cancer as compared to melanoma or RCC. The incidence of pneumonitis was higher in RCC compared to melanoma. Colitis appears to have a higher incidence in melanoma, the incidence of which further increases when CTLA4 inhibitors are used in conjunction with anti-PD-1. The majority of the RCC patients tolerated ICB with no major irAEs. With the expanding use of ICB in advanced malignancies, increased awareness of these clinically significant and potentially serious irAEs is indispensable. Future trials designed to distinguish the incidence of irAEs in relation to specific tumor types would be informative. [Table: see text]
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Nasca, Vincenzo, Francesco Barretta, Francesca Corti, Sara Lonardi, Monica Niger, Maria Elena Elez, Marwan Fakih, et al. "Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer." Journal for ImmunoTherapy of Cancer 11, no. 1 (January 2023): e005493. http://dx.doi.org/10.1136/jitc-2022-005493.
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BackgroundImmune checkpoint inhibitors (ICIs) show a tremendous activity in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), but a consistent fraction of patients does not respond. Prognostic/predictive markers are needed. Despite previous investigations in other tumor types, immune-related adverse events (irAEs) have not been well evaluated in patients with MSI-H cancers treated with ICIs.MethodsWe conducted an international cohort study at tertiary cancer centers collecting clinic-pathological features from 331 patients with MSI-H mCRC treated with ICIs. Of note, the irAEs were summarized using a ‘burden score’ constructed in a way that the same score value could be obtained by cumulating many low-grade irAEs or few high-grade irAEs; as a result, the lower the burden the better. Clearly, the irAE burden is not a baseline information, thus it was modeled as a time-dependent variable in univariable and multivariable Cox models.ResultsAmong 331 patients, irAEs were reported in 144 (43.5%) patients. After a median follow-up time of 29.7 months, patients with higher burden of skin, endocrine and musculoskeletal irAEs (the latter two’s effect was confirmed at multivariable analysis) had longer overall survival (OS), as opposed to gastrointestinal, pneumonitis, neurological, liver, renal and other irAEs, which showed an harmful effect. Similar results were observed for progression-free survival (PFS). Based on the results retrieved from organ-specific irAEs, ‘aggregated’ burden scores were developed to distinguish ‘protective’ (endocrine and musculoskeletal) and ‘harmful’ (gastrointestinal, pneumonitis, neurological, hepatic) irAEs showing prognostic effects on OS and PFS.ConclusionsOur results demonstrate that not all irAEs could exert a protective effect on oncologic outcome. An easy-to-use model for ICIs toxicity (burden score of protective and harmful irAEs) may be used as surrogate marker of response.
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Mooradian, Meghan, Justine Vanessa Cohen, Anita Giobbie-Hurder, Riley Fadden, Krista M. Rubin, Keith Flaherty, Don P. Lawrence, and Ryan J. Sullivan. "Inflammatory arthritis: An under-recognized immune-relate adverse effect." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e14565-e14565. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e14565.
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e14565 Background: Checkpoint inhibition (CPI) has significant and durable effectiveness against a broadening range of cancers and currently is FDA approved for more than 10 different malignancies. With increasing use of CPI, there is a need to understand the range and extent of immune-related adverse effects (irAE). Though certain irAEs, such as colitis and pneumonitis have been well studied, CPI- induced arthritis (CA) has not been widely recognized nor well characterized with data on the subject largely comprised of case reports and small case series. Methods: We retrospectively reviewed 125 patients (pts) with advanced melanoma treated with CPI to define the incidence and clinical features of CA. We identified 20 pts who developed CA during the course of CPI treatment. Cases were included only if active rheumatic signs or symptoms developed after receiving therapy. Demographic data (gender, age), type of CPI, number of CPI cycles, treatment of CA and other irAE manifestations were extracted from the medical chart. Results: 16% of patients treated with CPI developed CA. Among the 20 pts, the average age at CA onset was 70.3 (43, 84) with 75% of pts male. 80% had received anti-PD-1 monotherapy, 15% combination anti-PD-1 + anti-CTLA-4 and 5% monotherapy with CTLA-4 inhibition. The average number of infusions prior to symptom onset was 13.5 (1-48) after a median time point of 6.6mths on therapy. Basic rheumatologic testing (RF, CCP, ANA) was only positive in 10% of cases. 20% of pts were treated with non-steroidal anti-inflammatory drugs alone, whereas 40% required corticosteroids (systemic or injection). The remaining 40% necessitated treatment with disease modifying anti-rheumatic drugs. Conclusions: CA is a debilitating irAE with a higher incidence (16%) than most other irAEs and a negative impact on the quality of life of pts affected. Based on our retrospective review, this irAE tends to delayed in onset and often requires systemic immune suppressants for effective treatment. We posit that this is an under recognized and undertreated irAE. Further work is needed to better define the clinical factors that may affect or predict its development.
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Oren, Ohad, and Julian R. Molina. "The effect of cardiovascular disease on the association between immune-related adverse events and overall survival." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 7059. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.7059.
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7059 Background: Preliminary data suggests that immune-related adverse events (irAEs) are associated with lower all-cause mortality, presumably due to improved anti-tumor responses. Investigations of large cohorts are needed to establish better understanding of that association. Methods: We reviewed the Mayo Clinic database for all patients who received an immune checkpoint inhibitor (ICI). The primary outcome was all-cause mortality. Descriptive and uni-variate analyses were generated. Results: Between March, 2010 and July, 2019, 3,326 patients received an ICI. The most common irAEs were colitis (287, 8.6%), pneumonitis (238, 7.2%) and hepatitis (227, 6.9%). A total of 933 (28.1%) patients developed at least 1 irAE and 176 (5.3%) patients experienced 2 or more irAEs. Survival analysis demonstrated an association between the number of irAEs and all-cause mortality (log-rank, P < 0.0001), a relationship which was maintained for the 3 most common cancer types (lung, melanoma, renal) and for the individual ICI agents. In patients with lung cancer, colitis (P = 0.04) but not pneumonitis (P = 0.83) was associated with improved overall survival. No association between irEA and all-cause mortality was demonstrated in patients with history of stroke (log-rank, P = 0.12), peripheral artery disease (PAD) (log-rank, P = 0.68) and obesity (log-rank, P = 0.18). In an analysis of pre-ICI body-mass index (BMI), an association between irAE and lower overall mortality was shown in patients with BMI < 30 (log-rank, P < 0.001) and not in those with higher BMIs (log-rank, P = 0.09). The presence of stroke, PAD and obesity were associated with higher all-cause mortality in a survival analysis (P < 0.001). The irAE-mortality association was not modulated by the presence hypertension (log-rank, P < 0.0001), diabetes mellitus (log-rank, P < 0.0001), or heart failure (log-rank, P = 0.006). Conclusions: The development of any irAE is associated with higher overall survival. The presence of numerous cardiovascular disease states neutralizes that association, likely a result of competing causes of mortality although interaction with immune or inflammatory pathways is possible. In addition, pneumonitis is not associated with better overall survival in patients with lung cancer presumably due to compromise of already-tenuous respiratory status.
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De Bock, Marlies, Eva Hulstaert, Vibeke Kruse, and Lieve Brochez. "Psoriasis Vulgaris Exacerbation during Treatment with a PD-1 Checkpoint Inhibitor: Case Report and Literature Review." Case Reports in Dermatology 10, no. 2 (August 9, 2018): 190–97. http://dx.doi.org/10.1159/000491572.
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Objective: The incidence of immune-related adverse events is growing as the use of checkpoint inhibitors is exponentially increasing. Cutaneous adverse events are among the most frequent immune-related adverse events. The purpose of this case report and literature review is to highlight psoriasis as a potential adverse event with need for early recognition. Case Report and Literature Review: We describe the case of a 65-year-old woman with psoriasis exacerbation while treated with nivolumab (anti-PD-1) for a stage IV melanoma. She had a history of scalp psoriasis but she presented with psoriatic lesions on both lower and upper limbs. Our patient was treated with topical steroids. So far, 34 other cases with an exacerbation of psoriasis during treatment with anti-PDL-1 or PD-1 therapy have been reported in the literature. A broad range of therapies are described, without any available guidelines for this particular condition. Conclusion: Psoriasis exacerbation is an established side effect of PD-1/PDL-1 checkpoint inhibitors with 35 reported cases. Early recognition and management are challenging as there are no clear guidelines available. A close collaboration between oncologist and dermatologist is mandatory to manage this immune-related adverse event.
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Higashiyama, Ryoko Inaba, Hidehito Horinouchi, Katsutoshi Sekine, Yuji Matsumoto, Shuji Murakami, Yasushi Goto, Shintaro Kanda, Yutaka Fujiwara, Noboru Yamamoto, and Yuichiro Ohe. "Efficacy of nivolumab in patients treated by corticosteroid due to immune-related adverse events." Journal of Clinical Oncology 36, no. 5_suppl (February 10, 2018): 163. http://dx.doi.org/10.1200/jco.2018.36.5_suppl.163.
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163 Background: Nivolumab is a standard treatment for metastatic or refractory non-small cell lung cancer (NSCLC). Because immune-related adverse events (irAEs) are common and can be severe, a number of these patients require systemic corticosteroids. irAEs are reportedly associated with improved survival in melanoma patients treated with nivolumab. To date, little information is available regarding the effect of corticosteroid on the efficacy of nivolumab in terms of progression-free survival (PFS) and overall survival (OS). Methods: We reviewed consecutive patients who received nivolumab for metastatic or refractory NSCLC between December 2015 and August 2017. Nivolumab was administered at the standard dose of 3 mg/kg every two weeks. We recorded the patient demographics, efficacy and safety of nivolumab, previous and subsequent treatments, information about irAEs, corticosteroid usage, and survival. PFS and OS were calculated from the start of nivolumab treatment. A Cox proportional hazards regression model was applied using variables with the potential to influence the PFS: sex, age, performance status (PS), smoking history, driver gene alterations, histology, line of nivolumab treatment, and irAEs. Results: A total of 184 patients received nivolumab. Among them, 117 (64%) were male, the median age was 64 years (range, 34-83 years), 23 (13%) had a PS of 2 or more, 125 (68%) were ex-smokers, 37 (20%) had squamous NSCLC, and 37 (20%) had some kind of driver gene alteration, mainly EGFR mutation. Fifty patients (27%) experienced some grade of irAEs, and 37 (20%) patients required corticosteroid treatment. A multivariate analysis identified the occurrence of irAEs (hazard ratio [HR], 0.55; 95% confidence interval [CI] 0.33-0.91) and smoking (HR, 0.60;95% CI, 0.36-0.99) as independent predictors of a favorable PFS. There were no apparent differences in the proportions of patients who survived with or without the use of corticosteroid for irAEs: 73% vs. 71% at 6 months and 46% vs. 45% at 18 months. Conclusions: The occurrence of irAEs was positively associated with the PFS, and corticosteroid treatment did not have an adverse effect on OS in patients with NSCLC who were treated with nivolumab.