scholarly journals Immunotherapy-related adverse events (irAEs): extraction from FDA drug labels and comparative analysis

JAMIA Open ◽  
2018 ◽  
Vol 2 (1) ◽  
pp. 173-178 ◽  
Author(s):  
QuanQiu Wang ◽  
Rong Xu
Keyword(s):  
Adverse Events ◽  
Broad Spectrum ◽  
Checkpoint Inhibitors ◽  
Endocrine System ◽  
Biological Mechanisms ◽  
Fold Enrichment ◽  
Improved Outcomes ◽  
Organ Systems ◽  
Treatment Research ◽  
Target Effects

Abstract Objectives Immune checkpoint inhibitors (ICIs) have dramatically improved outcomes in cancer patients. However, ICIs are associated with significant immune-related adverse events (irAEs) and the underlying biological mechanisms are not well-understood. To ensure safe cancer treatment, research efforts are needed to comprehensively detect and understand irAEs. Materials and methods We manually extracted and standardized irAEs from The U.S Food and Drug Administration (FDA) drug labels for six FDA-approved ICIs. We compared irAE profile similarities among ICIs and 1507 FDA-approved non-ICI drugs. We investigated how irAEs have differential effects on human organs by classifying irAEs based on their targeted organ systems. Finally, we identified broad-spectrum (nontarget-specific) and narrow-spectrum (target-specific) irAEs. Results A total of 893 irAEs were extracted. 31.4% irAEs were shared among ICIs as compared to the 8.0% between ICIs and non-ICI drugs. irAEs were resulted from both on- and off-target effects: irAE profiles were more similar for ICIs with same target than different targets, demonstrating the on-target effects; irAE profile similarity for ICIs with the same target is less than 50%, demonstrating unknown off-target effects. ICIs significantly target many organ systems, including endocrine system (3.4-fold enrichment), metabolism (3.7-fold enrichment), immune system (3.6-fold enrichment), and autoimmune system (4.8-fold enrichment). We identified 21 broad-spectrum irAEs shared among all ICIs, 20 irAEs specific for PD-L1/PD-1 inhibition, and 28 irAEs specific for CTLA-4 inhibition. Discussion and conclusion Our study presents the first effort toward building a standardized database of irAEs. The extracted irAEs can serve as the gold standard for automatic irAE extractions from other data resources and set a foundation to understand biological mechanisms of irAEs.

scholarly journals Immune-related adverse events of immune checkpoint inhibitors: a brief review

2018 ◽  
Vol 25 (5) ◽  
Author(s):  
G. Myers
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Health Care Professionals ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Hematologic Malignancies ◽  
T Cell Response ◽  
Proactive Management ◽  
Organ Systems

Immune checkpoint inhibitors (icis) such as inhibitors of ctla-4, PD-1, and PD-L1, given as monotherapy or combination therapy have emerged as effective treatment options for immune-sensitive solid tumours and hematologic malignancies. The benefits of icis can be offset by immune-related adverse events (iraes) that leave all organ systems vulnerable and subsequently increase the risk for morbidity and mortality.Because of fluctuating onset and prolonged duration, the toxicities associated with iraes represent a shift from the understanding of conventional anticancer toxicities. The ctla-4 and PD-1/PD-L1 inhibitors modulate T-cell response differently, resulting in distinct toxicity patterns, toxicity kinetics, and dose–toxicity relationships. Using individualized patient education, screening, and assessment for the early identification of iraes is key to proactive management and is therefore key to improving outcomes and prolonging therapy.Management of iraes is guided by appropriate grading, which sets the stage for the treatment setting (outpatient vs. inpatient), ici treatment course (delay vs. discontinuation), supportive care, corticosteroid use, organ specialist consultation, and additional immunosuppression. Health care professionals in oncology must work collaboratively with emergency and community colleagues to facilitate an understanding of iraes in an effort to optimize seamless care.

Behcet’s-like syndrome following pembrolizumab: An immune-related adverse event associated with programmed death receptor-1 inhibitor therapy

2019 ◽  
Vol 26 (4) ◽  
pp. 995-999 ◽  
Author(s):  
Steffi Thomas ◽  
Chay Bae ◽  
Tabanor Joy-Ann ◽  
William Traverse
Keyword(s):  
Adverse Events ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Death Receptor ◽  
Programmed Death ◽  
Organ Systems ◽  
Wide Range ◽  
The Right

Introduction The landscape for the treatment of metastatic melanoma has been revolutionized with the introduction immune checkpoint inhibitors. Immune checkpoint inhibitors have now become the standard of care for the treatment of cancers. These immune agents including programmed death receptor-1 inhibitors, programmed death-ligand 1 inhibitors and cytotoxic T-lymphocyte antigen-4 inhibitors have shown promising results but have been associated with numerous immune-related complications. Pembrolizumab, a programmed death receptor-1 inhibitor, has been associated with a number of immune-related adverse events affecting multiple organ systems including integument, ocular, endocrine, cardiovascular, pulmonary, renal, gastrointestinal, and musculoskeletal system. Case report We present a case of an 88-year-old Caucasian male with metastatic melanoma of the face with metastasis to the right fifth cranial nerve and into the right cavernous sinus. He underwent resection of the melanoma and was placed on pembrolizumab at 2 mg/kg every three weeks. Interestingly, 24 months on pembrolizumab therapy, he developed corneal erosions, oral and genital ulcerations. Management and outcome Patient completed his 24 months of pembrolizumab and was started on prednisone and colchicine with improvement in his symptoms. At his follow-up eight months, he had recurrence of an oral ulcer. Discussion Here we present a rare case of an elderly male on pembrolizumab who suffered from corneal erosions, oral and genital ulcers, a syndrome similar to Behcet’s disease. Given that pembrolizumab and other immune checkpoint inhibitors are being utilized in the treatment of cancers, physicians should be aware of the wide range immune-related adverse events including the possible Behcet’s-like syndrome presentation.

Implementation of a pharmacy consult service for evaluation of immune checkpoint inhibitor related adverse events at a large community hospital

2020 ◽  
pp. 107815522097026
Author(s):  
Jeff Kamta ◽  
Bren Magruder ◽  
Lisa Hymel
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Primary Outcome ◽  
Checkpoint Inhibitors ◽  
Delayed Presentation ◽  
Consult Service ◽  
Organ Systems ◽  
History Of ◽  
Secondary Outcomes

Introduction Immune checkpoint inhibitors (ICI) are novel oncolytic therapies associated with various immune related adverse events (irAEs) affecting multiple organ systems, which may have a delayed presentation. Identification of irAEs and prompt initiation of appropriate treatment represents a challenge to clinicians. The purpose of this study was to evaluate the effectiveness of a pharmacy consult service in identification and management of irAEs. Methodology: This was a single center, retrospective study. Patients included were: ≥18 years old, admitted as inpatients, and reported a history of cancer treatment within the last year. A pharmacy consult was developed and implemented for patients who reported a history of ICI therapy within the last year. Education regarding the consult service was provided to select physicians, nurses, and all pharmacists. Primary outcome: percent of admitted patients reporting ICI therapy within the last year, who required pharmacist intervention for an irAE. Secondary outcomes: types of interventions performed, percentage of recommendation acceptance, pharmacist time spent. Results Fifty-one patients received a pharmacy immunotherapy consult. Seventeen patients (33%) met the primary outcome. Thirty-three separate recommendations were made by pharmacists for these 17 patients. The secondary outcomes of interventions made and percentage accepted (n; % accepted): Initiation/adjustment of steroid therapy (20; 40%), placement of a consult for oncology or other specialist (10; 70%), other therapeutic interventions (3; 67%). Average time spent by pharmacist on initial consultations (SD): 29 minutes (15). Conclusion A pharmacy consult service may help to increase identification of patients receiving immune checkpoint inhibitors and initiate timely interventions.

Experience of immune-related adverse events associated with ipilimumab and nivolumab in a single center.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 91-91 ◽  
Author(s):  
Bernardo Leon Rapoport ◽  
Teresa Smit ◽  
Ronwyn van Eeden
Keyword(s):  
Adverse Events ◽  
Metastatic Melanoma ◽  
Performance Status ◽  
Death Receptor ◽  
Endocrine System ◽  
Organ Systems ◽  
Anti Cancer ◽  
Life Threatening ◽  
Prompt Diagnosis ◽  
Cell Death Receptor

91 Background: Anti-programmed cell death receptor-1 (PD-1) and anti-CTLA4 antibodies represent an effective anti-cancer. Ipilimumab and nivolumab can induce immune-related adverse events (IrAEs). These IrAEs affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Life-threatening and fatal irAEs have been reported; adequate diagnosis and management are essential. Methods: A retrospective review of data from 40 patients (pts) records were used to describe the IrAE’s associated with 15 pts treated with ipilimumab and 25 pts treated with nivolumab. Results: A total of 40 pts (25 males and 15 females) were included in the analysis. The median age was 63 years (range 30 - 85 years). The performance status (PS) ranged from 0 to 2, with a median PS of 1. In total, 3 pts with metastatic melanoma, 18 with non small cell lung cancer (NSCLC), 2 with renal cell carcinoma and 2 with Hodgkin’s disease were treated with nivolumab and 15 with metastatic melanoma received ipilimumab. A total of 167 cycles of nivolumab (median = 4, range 1-16) and 60 cycles of ipilimumab (median = 4 cycles, range 1-4 cycles) were administered. Seven IrAEs are described in 19 pts treated with ipilimumab. These include endocrinopathy in 3 pts (hypophysitis in pt and hyphothyroidsm in 2 pts), colitis in 3 pts (1 required infliximab) and hepatitis in 1 pt. Among the pts treated with nivolumab 7 IrAEs were documented. These included pneumonitis in 2 pts, skin rash in 3 pts, mild diarrhea in 1 pt and mild uveitis in 1 pt. Additionally, 3 chest infections were documented including a case of pulmonary tuberculosis in a pt with NSCLC. Conclusions: Anti-PD1 and anti-CTLA4 antibodies can induce a plethora of irAEs. Colitis was more common with ipilimumab while pneumonitis more common with nivolumab. The knowledge of IrAE’s will allow prompt diagnosis and improve the management resulting in decreased morbidity.

Multisystem immune-related adverse events from anti-PD-1/PD-L1 in patients with lung cancer: Incidence, clinical patterns, management, and outcomes.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 84-84
Author(s):  
Bairavi Shankar ◽  
Jiajia Zhang ◽  
Durrant Barasa ◽  
Patrick M. Forde ◽  
Josephine Louella Feliciano ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Checkpoint Inhibitors ◽  
Retrospective Chart Review ◽  
Outcome Data ◽  
Multiple Organ ◽  
Johns Hopkins Hospital ◽  
Lung Cancer Patients ◽  
Organ Systems ◽  
Clinical Patterns

84 Background: Anti-PD-1/PD-L1 immune checkpoint inhibitors (ICIs) for cancer may cause immune-related adverse events (irAEs). Large clinical trials and meta-analyses have identified the spectrum of single organ-specific irAEs that may occur with these agents. However, patients treated with these agents may develop irAEs involving multiple organ systems. The prevalence and clinical patterns of multi-system irAEs and their management have yet to be elucidated. Methods: Patients with lung cancer treated with either PD-1/PD-L1 monotherapy or PD-1/PD-L1-based combinations at Johns Hopkins Hospital were identified. Clinical, radiologic and pathologic data were stored in an IRB-approved database. irAEs were identified through retrospective chart review and confirmed by a multidisciplinary team. Multi-system irAEs were defined as irAEs in +1 organ system. Patients with multi-system irAEs, their clinical patterns, management and outcomes were identified. Results: 319 patients were identified (NSCLC: 299, 93.7%; SCLC: 20, 6.3%) and received treatment with either PD-1/PD-L1 monotherapy (197, 61.8%) or combinations (122, 38.2%: + chemotherapy = 42; +immunotherapy = 41; +other = 39). Of these patients, 77 (24.1%) developed 1 irAE, and 16 (5%) developed multi-system irAEs (2 irAEs: 14; 3 irAEs: 2). The most common irAEs were pneumonitis (42, 13.2%), dermatitis (11, 3.4%), and hypothyroidism (9, 2.8%). The most common multi-system irAEs was pneumonitis/dermatitis (3, 3.9%). Patients who developed dermatitis, colitis, or hypothyroidism were most likely to develop multi-system irAEs (all p < 0.05). Management and outcome data for individual and multi-system irAEs will be presented. Conclusions: Patients treated with ICIs may develop multi-system irAEs. In the first report of this clinical entity, we identified that 5% of lung cancer patients treated with PD-1/PD-L1 developed multi-system irAEs, and that those who developed dermatitis, colitis, or hypothyroidism were most likely to develop multi-system events. These data have important implications for interdisciplinary patient management in the era of cancer immunotherapy.

Erdafitinib (ERDA; JNJ-42756493), a pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRa): Phase 2 continuous versus intermittent dosing.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 411-411 ◽  
Author(s):  
Yohann Loriot ◽  
Andrea Necchi ◽  
Se Hoon Park ◽  
Jesús García-Donas ◽  
Robert A Huddart ◽  
...  
Keyword(s):  
Adverse Events ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Growth Factor Receptor ◽  
Phase 2 ◽  
Open Label ◽  
Significant Treatment ◽  
Improved Outcomes ◽  
Phase 2 Study ◽  
Open Label Phase

411 Background: Although immune checkpoint inhibitors (ICI) have improved outcomes in some pts with platinum-resistant mUC, many pts (eg, pts with TCGA luminal 1 tumors, many of whom are FGFRa) may not benefit. ERDA, a pan-FGFR (1-4) inhibitor, demonstrated promising phase 1 activity: 11 partial responses among 24 FGFRa mUC pts. We report efficacy and safety of ERDA in the ongoing global open-label phase 2 study BLC2001 (NCT02365597). Methods: Pts had measurable mUC with specific FGFR2/ FGFR3 mutations or translocations per central lab Janssen assay, ECOG 0-2, and were chemorefractory (progressed during/following ≥ 1 line of prior systemic chemo or ≤ 12 mos of [neo]adjuvant chemo). Cisplatin-ineligible, chemo-naïve pts, and prior ICI treatment were allowed. Pts were randomized 1:1 to 28-d cycles of oral 6 mg/d continuous dosing (6 C) or 10 mg/d intermittent 7 d on/7 d off dosing (10 I) ERDA; the dose was further uptitrated if no significant treatment-related adverse events (TRAEs) were observed. The primary end point was ORR. Results: 78 pts received 6 C and 33 pts received 10 I (10 I cohort stopped early) ERDA. 31 pts in 6 C arm were further uptitrated. Across arms, 50% had ≥ 2 prior lines of therapy; 93% were chemorefractory. Confirmed ORRs (RECIST 1.1) were 35% and 24%, and disease control rates (CR+PR+SD) were 74% and 73% in the 6 C and 10 I arms, respectively. Adverse events (AEs) were manageable, and there were no treatment-related deaths (Table). Treatment is ongoing in 10 pts. Conclusions: ERDA (6 C or 10 I) has promising efficacy and tolerability in pts with FGFRa mUC. Based on these results and ERDA pharmacometric modeling, dosing was optimized at 8 mg/d (continuous), and this cohort is ongoing. Phase 3 study is planned. Clinical trial information: NCT02365597. [Table: see text]

scholarly journals The biomarkers related to immune related adverse events caused by immune checkpoint inhibitors

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Xiao-Hui Jia ◽  
Lu-Ying Geng ◽  
Pan-Pan Jiang ◽  
Hong Xu ◽  
Ke-Jun Nan ◽  
...  
Keyword(s):  
Immune System ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Endocrine System ◽  
Normal Tissues ◽  
Organ Specific ◽  
Common Antigens ◽  
Almost All

AbstractThe enthusiasm for immune checkpoint inhibitors (ICIs), an efficient tumor treatment model different from traditional treatment, is based on their unprecedented antitumor effect, but the occurrence of immune-related adverse events (irAEs) is an obstacle to the prospect of ICI treatment. IrAEs are a discrete toxicity caused by the nonspecific activation of the immune system and can affect almost all tissues and organs. Currently, research on biomarkers mainly focuses on the gastrointestinal tract, endocrine system, skin and lung. Several potential hypotheses concentrate on the overactivation of the immune system, excessive release of inflammatory cytokines, elevated levels of pre-existing autoantibodies, and presence of common antigens between tumors and normal tissues. This review lists the current biomarkers that might predict irAEs and their possible mechanisms for both nonspecific and organ-specific biomarkers. However, the prediction of irAEs remains a major clinical challenge to screen and identify patients who are susceptible to irAEs and likely to benefit from ICIs.

scholarly journals Problem-based review: Immune-mediated complications of ‘Checkpoint Inhibitors’ for the Acute Physician

2017 ◽  
Vol 16 (1) ◽  
pp. 21-24
Author(s):  
Philip Webb ◽  
◽  
Terry W Rice ◽  
Timothy Cooksley ◽  
◽  
...  
Keyword(s):  
Adverse Effects ◽  
Checkpoint Inhibitors ◽  
Early Recognition ◽  
Optimal Strategies ◽  
Organ System ◽  
Supportive Treatment ◽  
Immune Mediated ◽  
Improved Outcomes ◽  
Organ Systems ◽  
Timing Of Onset

Immunotherapy with ’checkpoint-inhibitors‘ has significantly improved outcomes for patients with a range of malignancies. However, significant immune-mediated toxicities of these therapies are well-described. These immune-mediated toxicities can affect virtually all organ systems and are potentially fatal. The timing of onset of the adverse effects is dependent on the organ system affected and can occur after completion of the treatment. The increasing utilisation of ‘checkpoint-inhibitors’ means that Acute Physicians are likely to see a number of immune-mediated complications presenting to the AMU. The fundamental principles of management of immune-mediated toxicities are early recognition, supportive treatment, escalating steroid therapy (dependent on the severity of the toxicity), close liaison with Oncology and specialist organ team input. Research into the optimal strategies and pathways for the management of immune-mediated toxicity, as well as increased collaboration between Acute Physicians and Oncologists, will be necessary.

scholarly journals Immune-related Adverse Events Associated with Cancer Immunotherapy: A Review for the Practicing Rheumatologist

2019 ◽  
Vol 47 (2) ◽  
pp. 166-175 ◽  
Author(s):  
Shahin Jamal ◽  
Marie Hudson ◽  
Aurore Fifi-Mah ◽  
Carrie Ye
Keyword(s):  
Cancer Therapy ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Multiple Organ ◽  
Delayed Onset ◽  
Inhibitory Pathways ◽  
Organ Systems ◽  
After Cancer

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.

scholarly journals Gastrointestinal adverse events associated with immune checkpoint inhibitor therapy

2019 ◽  
Vol 8 (1) ◽  
pp. 25-30 ◽  
Author(s):  
Eva Rajha ◽  
Patrick Chaftari ◽  
Mona Kamal ◽  
Julian Maamari ◽  
Christopher Chaftari ◽  
...  
Keyword(s):  
Adverse Events ◽  
Health Care Providers ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Care Providers ◽  
Organ Systems ◽  
Checkpoint Inhibitor Therapy ◽  
Recent Addition ◽  
Gastrointestinal Adverse Events

Abstract Immunotherapy with checkpoint inhibitors has revolutionized cancer therapy and is now the standard treatment for several different types of cancer, supported by favorable outcomes and good tolerance. However, it is linked to multiple immune manifestations, referred to as immune-related adverse events (irAEs). These adverse events frequently affect the skin, colon, endocrine glands, lungs, and liver. The gastrointestinal system is one of the most commonly affected organ systems and is responsible for the most frequent emergency visits resulting from irAEs. However, because immune checkpoint inhibitors are a recent addition to our arsenal of cancer drugs, many health-care providers remain unfamiliar with the management of irAEs. Gastroenterologists involved in the treatment of oncology patients who have received checkpoint inhibitors are currently encountering cases of abdominal pain, diarrhea, and other nonspecific symptoms that may be challenging to manage. This article reviews the gastrointestinal, hepatic, and pancreatic toxicities of checkpoint inhibitors and provides an approach to their diagnosis and recommended workup. It also highlights the management of irAEs according to their toxicity grading and specifically discusses the instances in which corticosteroids should be administered and/or the immune checkpoint inhibitors should be withheld.

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