Treatment Outcomes of Immune-Related Cutaneous Adverse Events

PURPOSE The aim of the current study was to report the efficacy of topical and systemic treatments for immune-related cutaneous adverse events (ircAEs) attributed to checkpoint inhibitors in an uncontrolled cohort of patients referred to oncodermatology clinics. METHODS A retrospective analysis of patients with ircAEs evaluated by dermatologists from January 1, 2014, to December 31, 2017, at three tertiary care hospitals and cancer centers were identified through electronic medical records. Clinicopathologic characteristics, dermatologic therapy outcome, and laboratory data were analyzed. RESULTS A total of 285 patients (median age, 65 years [range, 17 to 89 years]) with 427 ircAEs were included: pruritus (n = 138; 32%), maculopapular rash (n = 120; 28%), psoriasiform rash (n = 22; 5%), and others (n = 147; 34%). Immune checkpoint inhibitor class was associated with ircAE phenotype ( P = .007), where maculopapular rash was predominant in patients who received combination therapy. Severity of ircAEs was significantly reduced (mean Common Terminology Criteria for Adverse Events grade: 1.74 v 0.71; P < .001) with dermatologic interventions, including topical corticosteroids, oral antipruritics, and systemic immunomodulators. A total of 88 ircAEs (20%) were managed with systemic immunomodulators. Of these, 22 (25%) of 88 persisted or worsened. In seven patients with corticosteroid-refractory ircAEs, improvement resulted from targeted biologic immunomodulatory therapies that included rituximab and dupilumab. Serum interleukin-6 (IL-6) was elevated in 34 (52%) of 65 patients; grade 3 or greater ircAEs were associated with increased absolute eosinophils (odds ratio, 4.1; 95% CI, 1.3 to 13.4) and IL-10 (odds ratio, 23.8; 95% CI, 2.1 to 262.5); mean immunoglobulin E serum levels were greater in higher-grade ircAEs: 1,093 kU/L (grade 3), 245 kU/L (grade 2), and 112 kU/L (grade 1; P = .043). CONCLUSION Most ircAEs responded to symptom- and phenotype-directed dermatologic therapies, whereas biologic therapies were effective in patients with corticosteroid-refractory disease. Increased eosinophils, IL-6, IL-10, and immunoglobulin E were associated with ircAEs, and they may represent actionable therapeutic targets for immune-related skin toxicities.

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Improved survival among patients with malignant pleural mesotheliomas who develop immune-related adverse events on immunotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.8556 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 8556-8556

Author(s):

Michael Offin ◽

Jacklynn V. Egger ◽

Caroline G. McCarthy ◽

Vasilisa Rudneva ◽

Jason Beattie ◽

...

Keyword(s):

Adverse Events ◽

Median Time ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Progression Free Survival ◽

Clinicopathologic Characteristics ◽

Kaplan Meier ◽

Clinicopathologic Feature ◽

Thoracic Radiation ◽

Grade 3

8556 Background: While immune checkpoint inhibitors (ICI) are a standard option for patients with malignant pleural mesotheliomas (MPM), there is limited data on the rate of immune related adverse events (irAEs) and effects on clinical outcomes. Methods: 61 patients with MPM who received ICI between January 2016 and October 2020 were assessed and followed through November 2020. irAEs (CTCAE v5.0) were noted along with the time from ICI start to irAE onset. Patients were grouped into irAE ever versus never. Clinicopathologic characteristics, prior treatments, and investigator assessed clinical benefit rate (CBR; partial response [PR] + stable disease [SD]) were compared by Fisher’s Exact and Mann-Whitney Tests. Overall survival (OS) and investigator assessed progression free survival (PFS) from ICI start were compared using Kaplan Meier. In consented patients (n = 56), next generation sequencing (MSK-IMPACT) was performed with HLA genotyping analysis by POLYSOLVER software and alleles for the three major MHC class I (HLA-A, -B, -C) genes were obtained from whole exome recapture. Results: Most patients were male (72%), smokers (55%), > 70 years old (median 72, range 34-90), and had epithelioid histology (67%). No patients had baseline autoimmune disease. The median line of prior systemic therapies to ICI start was 2 (range 1-5). 17 patients (28%) developed an irAE on therapy including 7 (11%) with grade 3 to 5 events (pneumonitis, myositis, pancreatitis, nephritis, encephalitis and adrenal insufficiency). The median time from ICI start to irAE was 2.5 months (range 2 days – 5.8 months). There was no association with dual ICI (n = 6) vs single agent (n = 11) and sooner onset (2.1 vs 4.0 months; p = 0.10) nor higher grade (median grade 2 vs 3; p = 0.31) of irAEs. 1 patient developed grade 5 pneumonitis with onset 2 days after initial dose of dual-ICI. Comparing patients with irAEs to those without, there was no difference in distribution of epithelioid histology (n = 10 vs 31; p = 0.54), median age (71 vs 72 years old; p = 0.43), nor prior thoracic radiation (n = 5 vs 11; p = 0.75).There was no difference in HLA type nor the fraction of HLA alleles of individual genes amongst the groups. Patients who had an irAE were on ICI longer than those that did not (median time on ICI 5.4 vs 0.9 months, respectively; p = 0.02). OS was higher in patients with irAEs compared to those without (21.1 vs 4.7 months; p = 0.003) as was PFS (6.8 vs 1.7 months; p = 0.01). There was a significant increase in the CBR between those that had an irAE (65%; 5 PR, 6 SD) and those that did not (27%; 2 PR, 10 SD; p = 0.006). Conclusions: 28% of patients with MPM who received ICIs developed an irAE and onset tended to be early in the course of treatment. There was no clear predictive clinicopathologic feature that correlated with the occurrence of irAE. There was a significant increase in OS, PFS, and CBR in patients that had an irAE compared to those that did not.

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Systematic Review and Network Meta-Analysis of Immune Checkpoint Inhibitors in Combination with Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Carcinoma

Cancers ◽

10.3390/cancers12123629 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3629

Author(s):

Hsiao-Ling Chen ◽

Yu-Kang Tu ◽

Hsiu-Mei Chang ◽

Tai-Huang Lee ◽

Kuan-Li Wu ◽

...

Keyword(s):

Systematic Review ◽

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Small Cell ◽

Randomized Controlled ◽

Extensive Stage ◽

Grade 3

Patients with extensive-stage small cell lung cancer (ED-SCLC) have a very short survival time even if they receive standard cytotoxic chemotherapy with etoposide and platinum (EP). Several randomized controlled trials have shown that patients with ED-SCLC who received a combination of EP plus immune checkpoint inhibitors (ICIs) had superior survival compared with those who received EP alone. We conducted a systematic review and network meta-analysis to provide a ranking of ICIs for our primary endpoints in terms of overall survival (OS), progression free survival (PFS), and objective response rate (ORR), as well as our secondary endpoint in terms of adverse events. The fractional polynomial model was used to evaluate the adjusted hazard ratios for the survival indicators (OS and PFS). Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being best (Prbest) reference. EP plus nivolumab, atezolizumab or durvalumab had significant benefits compared with EP alone in terms of OS (Hazard Ratio HR = 0.67, 95% Confidence Interval CI = 0.46–0.98 for nivolumab, HR = 0.70, 95% CI = 0.54–0.91 for atezolizumab, HR = 0.73, 95% CI = 0.59–0.90 for durvalumab) but no significant differences were observed for pembrolizumab or ipilimumab. The probability of nivolumab being ranked first among all treatment arms was highest (SCURA = 78.7%, Prbest = 46.7%). All EP plus ICI combinations had a longer PFS compared with EP alone (HR = 0.65, 95% CI = 0.46–0.92 for nivolumab, HR = 0.77, 95% CI = 0.61–0.96 for atezolizumab, HR = 0.78, 95% CI = 0.65–0.94 for durvalumab, HR = 0.75, 95% CI = 0.61–0.92 for pembrolizumab), and nivolumab was ranked first in terms of PFS (SCURA = 85.0%, Prbest = 66.8%). In addition, nivolumab had the highest probability of grade 3–4 adverse events (SUCRA = 84.8%) in our study. We found that nivolumab had the best PFS and OS in all combinations of ICIs and EP, but nivolumab also had the highest probability of grade 3–4 adverse events in our network meta-analysis. Further head-to head large-scale phase III randomized controlled studies are needed to verify our conclusions.

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Immune-related adverse events associated with immune checkpoint inhibitors in patients with cancer

Tumori Journal ◽

10.1177/0300891620953468 ◽

2020 ◽

pp. 030089162095346

Author(s):

Nilay Sengul Samanci ◽

Duygu Ilke Cikman ◽

Kerem Oruc ◽

Sahin Bedir ◽

Emir Çelik ◽

...

Keyword(s):

Adverse Events ◽

Health Care Providers ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Early Recognition ◽

Care Providers ◽

Patients With Cancer ◽

Combination Treatments ◽

Grade 3

Introduction: With the widespread use of immune checkpoint inhibitors (ICIs), we are facing challenges in the management of immune-related adverse events (irAEs). We aimed to characterize the spectrum of toxicity, management, and outcomes for irAEs. Methods: Patients who were treated with at least one ICI in clinical trials, expanded access programs, or routine clinical practice were included. Clinical and laboratory parameters were collected retrospectively to determine the incidence of irAEs, methods of management, and treatment outcomes. Results: A total of 255 patients were screened retrospectively. Of these, 71 (27.8%) patients developed irAEs. More than 2 different types of irAEs were detected in 16 (6.2%) out of 255 patients. A total of 3177 doses were given to 255 patients. In 93 (2.9%) of the 3177 doses, 1 episode of irAEs was experienced. A total of 22 out of 93 (23.7%) episodes were reported as grade 1, 49 (52.7%) as grade 2, 19 (20.4%) as grade 3, and 3 (3.2%) as grade 4. The most frequently seen irAEs were pneumonitis, hepatitis, and hypothyroidism. With regard to treatment, 39 out of 93 episodes (42%) of any grade irAEs occurred after anti–programmed cell death-1 therapy, 47 (50.5%) occurred following administration of anti–programmed death-ligand 1, and 7 (7.5%) occurred after combination treatments. Conclusion: With the increased use of immunotherapeutic agents, increased awareness and early recognition are required for effective management of irAEs. Our experience as a single institution might be of use for health care providers in oncology.

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Comparative risk of serious and fatal treatment-related adverse events caused by 19 immune checkpoint inhibitors used in cancer treatment: a network meta-analysis

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920940927 ◽

2020 ◽

Vol 12 ◽

pp. 175883592094092 ◽

Cited By ~ 1

Author(s):

Tingting Liu ◽

Bo Jin ◽

Jun Chen ◽

Hui Wang ◽

Shuiyu Lin ◽

...

Keyword(s):

Adverse Events ◽

Cancer Treatment ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Combinatorial Therapy ◽

Grade 5 ◽

Comparative Risk ◽

Grade 3

Background: This network meta-analysis assessed the comparative risk of grade 3–5 and grade 5 treatment-related adverse events (TRAEs) for immune checkpoint inhibitors (ICIs), either alone or in combination with other modalities, for cancer treatment. Methods: PubMed, Embase, Cochrane Library, Web of Science, and recent predominant oncology congresses were searched for relevant phase II and phase III randomized controlled trials (RCTs). As outcomes, grade 3–5, and grade 5 TRAE outcomes were reported as odds ratios and 95% confidence intervals. Results: In 67 RCTs involving 36,422 patients and 19 ICIs, the incidence of grade 3–5 and grade 5 TRAEs was 17.9% and 0.8% with ICI monotherapy and 46.3% and 1.4%, respectively, with combinatorial therapy. Pneumonitis was the most common cause of grade 5 TRAEs following either monotherapy (16.3%) or combinatorial therapy (11.4%). Regarding grade 3–5 TRAEs, atezolizumab + chemotherapy (CT) and antiangiogenic therapy (AT) (atezolizumab + CAT), pembrolizumab + CT, ipilimumab + CT, and atezolizumab + CT were more toxic than any ICI monotherapy, pembrolizumab or nivolumab + radiotherapy (RT), and ICIs dual therapy (durvalumab + tremelimumab and nivolumab + ipilimumab). Tremelimumab, ipilimumab, durvalumab, and pembrolizumab were, however, associated with higher grade 5 TRAEs than combinatorial treatments. Atezolizumab + CAT was the most toxic and nivolumab + RT was the least toxic of combinatorial treatments; among monotherapies, tremelimumab and avelumab were the most and least toxic, respectively. The toxicity ranking changed with type of grade 3–5 TRAEs. Conclusions: Compared with combinatorial therapy, ICI monotherapy caused lower grade 3–5 TRAEs, but some monotherapies resulted in a higher incidence of fatal TRAEs. Atezolizumab + CAT and nivolumab + RT were the most and least toxic of combinatorial treatments, respectively, and tremelimumab and avelumab were the most and least toxic of the monotherapies, respectively.

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Neurological adverse events from checkpoint inhibition: A comprehensive review of literature.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.7_suppl.62 ◽

2017 ◽

Vol 35 (7_suppl) ◽

pp. 62-62

Author(s):

Ahmad Daher ◽

Tummala Sudhakar

Keyword(s):

Adverse Events ◽

Time Course ◽

Checkpoint Inhibitors ◽

Laboratory Data ◽

Neuromuscular Disorder ◽

Drug Dose ◽

Checkpoint Inhibition ◽

Comprehensive Review ◽

Ovid Medline ◽

Initiation Of Therapy

62 Background: Checkpoint (CTLA-4 & PD-1) inhibitors are the most commonly used anti-cancer immunotherapeutics. Their use is associated with well-documented immune-related adverse events (iAEs), but among those, neurological adverse events (nAEs) are rare. They have been described in multiple reports but detailed analysis of the spectrum of neurotoxicities, their relationship to the drug dose, and their time course is lacking. We provide a comprehensive review of all published checkpoint inhibitors-induced nAEs. Methods: PubMed and Ovid-MEDLINE databases were queried for all nAEs from checkpoint inhibition published cases. Three additional cases from our institution were included. Clinical, radiologic, and laboratory data was reviewed and analyzed. Results: 63 cases were identified, 57 of which were analyzed in Table 1. The remaining 6 cases included nAEs occurring > 6 months after initiation of therapy and were analyzed separately. Neurotoxicity occurred after a median of 3 doses with a range of 1 to 6. Neuropathy was the most common nAE from overall checkpoint inhibition (32%) or CTLA-4 inhibition (43%) but in PD-1 blockade cases, Myasthenia Gravis (44%) was more common than neuropathy (11%). CNS demyelination (11%), encephalopathy (10%), and meningitis (6%) were also reported. Peripheral nAEs outweighed central ones by about 2:1. Improvement was seen in 77% of the cases while systemic iAEs were seen in 25% only. The 6 cases with delayed nAEs analyzed occurred 31-76 weeks after therapy initiation. Conclusions: nAEs from checkpoint inhibition typically affect PNS > CNS, occur after a few doses of therapy, and are not commonly associated with systemic iAEs. Their profile varies by type of blockade (PD-1 vs. CTLA-4). Immunotherapy may unmask a subclinical previously undiagnosed neuromuscular disorder (ex: MG). Prompt recognition and relevant testing before and during therapy is of utmost importance as a majority of cases improve with discontinuation of the drug +/- immunosuppressive therapy. [Table: see text]

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Pilot study of NKTR214 and nivolumab in patients with sarcomas.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.11010 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 11010-11010

Author(s):

Sandra P. D'Angelo ◽

Anthony Paul Conley ◽

Ciara Marie Kelly ◽

Mark Andrew Dickson ◽

Mrinal M. Gounder ◽

...

Keyword(s):

Pilot Study ◽

Adverse Events ◽

Checkpoint Inhibitors ◽

Soft Part ◽

Objective Response ◽

Multiple Tumor ◽

Pleomorphic Sarcoma ◽

Treatment Naïve ◽

Grade 3 ◽

Tumor Types

11010 Background: Monotherapy checkpoint inhibitors have minimal efficacy in most patients with metastatic sarcoma. NKTR-214 is a CD122-preferential IL-2 pathway agonist that activates and expands natural killer and CD8+ T cells. Phase I/II data demonstrated the safety and efficacy of nivolumab plus NKTR-214 in multiple tumor types. A trial of NKTR-214 plus nivolumab was initiated in patients with selected sarcomas. Methods: This is a multi-center pilot study enrolling patients (pts) failing prior regimens within 9 cohorts: leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (DDLPS), chondrosarcoma (CS), osteosarcoma (OS), angiosarcoma (AS), alveolar soft part sarcoma (ASPS), synovial sarcoma/small blue round cell and other. Pts received NKTR 0.006mg/kg with nivolumab 360 mg every 3 weeks. Primary endpoint was objective response rate (ORR), secondary endpoints were adverse events (AEs), progression-free, overall survival (PFS,OS) and clinical benefit rate (CBR.) Pre/on treatment biopsies performed on patients for correlative studies including PD-L1 expression and TIL characterization by immunohistochemistry, whole exome sequencing and RNAseq. Results: Enrollment completed with 10 patients in cohorts below. 50 pts enrolled (median age 58, range 14-80), 54% female. Median follow-up time is 13m. 50% of patients were refractory ≥3 lines of therapy. Grade 3/4 treatment related adverse events occurred in 26% of patients. 2% of patients stopped due to AEs. Median time to response was 3.6m. Responses seen in LMS, UPS, dedifferentiated CS; on-going in UPS/CS. Prolonged disease stability in DDLPS. 6 patients remain on treatment. Conclusions: Nivolumab plus NKTR-214 was safe and tolerable in heavily pre-treated and refractory sarcoma patients. Responses were protracted overtime; on-going in UPS and dedifferentiated CS. Prolonged disease stability seen in DDLPS in patients. All correlative analyses are in progress and will be presented. Enrollment continues with plans to add a treatment naïve cohort. Clinical trial information: NCT03282344. [Table: see text]

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Impact of immune-related adverse events on survival in patients with metastastic urothelial carcinoma treated with immune-checkpoint inhibitors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.4531 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 4531-4531 ◽

Cited By ~ 2

Author(s):

Rafael Morales-Barrera ◽

Cristina Suarez Rodriguez ◽

Macarena Gonzalez ◽

Javier Ros ◽

Maria Eugenia Semidey ◽

...

Keyword(s):

Adverse Events ◽

Urothelial Carcinoma ◽

T Cell Activation ◽

Checkpoint Inhibitors ◽

Strong Predictor ◽

Immune Checkpoints ◽

Rank Test ◽

Platinum Based Chemotherapy ◽

Previously Treated ◽

Grade 3

4531 Background: Immune-checkpoints inhibitors (ICIs) represents the standard of care for platinum-pretreated advanced urothelial cancer patients (pts). By enhancing T-cell activation, a unique spectrum of inflammatory side effects has emerged, also known as immune-related adverse events (irAEs). Data regarding the association between irAEs and pts outcomes are conflicting. Here we conducted a retrospective analysis to investigate the association between irAEs profile and disease outcome in metastastic urothelial carcinoma (mUC) pts. Methods: Medical records from pts with mUC included in clinical trials between July 2013 and June 2018 and treated with ICIs were reviewed. Pts previously treated with platinum-based chemotherapy or cisplatin ineligible pts who had not been previously treated with chemotherapy were included. Clinical responses were assessed as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) according to RECIST v1.1. Adverse events were graded based CTCAE v4.03. Overall survival (OS) was calculated from the date of initiation of ICI to the date of death. X2 test was used to determine differences in rates. OS was estimated using Kaplan-Method and long rank test was used to assess differences between groups. All analyses were performed using SPSS v21. Results: From a total of 52 pts, 44 (84.6%) were treated with ICI monotherapy and 8 (15.3%) in combination (anti-CTLA4 or targeted therapy). Median age was 65 years, 42 pts (80.8%) were male, 44 patients (84.6%) had ECOG PS 0-1, 14 pts (26.9%) had liver metastasis. Overall irAEs were observed in 30 pts (57.7%) and 10 pts (19.2%) developed grade 3/4 irAES. Most common grade 3/4 irAEs were diarrhea (6.6%), rash (6.6%) and hepatitis (6.6%). Disease control rate (CR [26%]+PR[33%]+SD[20%]) was higher for patients with irAEs compared to those patients who did not developed irAEs (CR [13.6%]+PR[0%]+SD[22.7%], this difference was statically significant (P = 0.002). Median OS was 11.23 mo (CI 95%, 3.76-18.70) for the overall cohort, while median OS was 21.91 mo for those patients with irAEs compared to 6.47 mo in patients who did not developed irAEs (P = 0.004). Conclusions: In this analysis we found that the development of irAEs was a strong predictor of improved OS in mUC patients treated with ICI.

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Predictors of immune-related adverse events associated with checkpoint inhibitors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15159 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15159-e15159

Author(s):

Alhareth Alsayed ◽

Ashish Manne ◽

Daisy E Escobar ◽

Gaurav Sharma ◽

Pranitha Prodduturvar ◽

...

Keyword(s):

Lung Cancer ◽

Adverse Events ◽

Lymphocyte Count ◽

Checkpoint Inhibitors ◽

Hematological Parameters ◽

White Blood Count ◽

Categorical Variables ◽

Fisher Exact Test ◽

Continuous Variables ◽

Grade 3

e15159 Background: Immune-related adverse events (irAE) remain a significant challenge with the expansion of checkpoint inhibitors (ICI) indications. Unlike previous studies published, we investigated risk factors for irAE development, including lymphocytes and neutrophils counts in lung cancer and melanoma treated with all available ICIs in current clinical practice. Methods: This is a retrospective study conducted at the University of South Alabama Mitchell Cancer Institute. Between 2015-2019. A total of 160 patients with a diagnosis of melanoma (N = 54) or lung cancer (N = 106) who received at least two doses of ICI including ipilimumab (15%), nivolumab (32%), pembrolizumab (35%), dual nivolumab/ipilimumab (5%), durvalumab (9%) and atezolizumab (4%). The patient's baseline characteristics were extracted with irAE (grade 3/4) details and survival outcomes. Descriptive statistics were used, Fisher exact test to compare categorical variables, and Wilcoxon rank sum test for continuous variables using JMP software. Results: The median age at diagnosis was 64 years (range 17-93), with 51% females. Race distribution with 76% Caucasians and 26% African Americans. Around 30% of the cohort was treated for recurrence, and 39% did receive prior systemic chemotherapy. Median overall survival (OS) was 13.5 months (m) for melanoma and 16 m for lung cancer with CI 95% [16-24] and [15-23], respectively. Twenty-nine (29%) percent of the cohort (N = 46) had grade 3/4 irAEs. Median of baseline hematological parameters including total white blood count (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), ANC to ALC ratio, and platelet to ALC ratio of these patients were not statistically different from the cohort without grade 3/4 irAEs. Interestingly, if a patient has baseline ALC < 1K/μL, the risk of irAE recurrence is low when ICI is re-initiated, p = .0143 (after symptomatic recovery from irAEs). Conclusions: Irrespective of ICI used, baseline lymphocyte count, and its relation to other blood counts have no clear impact on irAE. Larger cohorts or prospective studies are needed to make stronger conclusions about the relationship between the immune system and the occurrence of irAEs

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Common Immune-Related Adverse Events of Immune Checkpoint Inhibitors in the Gastrointestinal System: A Study Based on the US Food and Drug Administration Adverse Event Reporting System

Frontiers in Pharmacology ◽

10.3389/fphar.2021.720776 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiaoyin Bai ◽

Shiyu Jiang ◽

Yangzhong Zhou ◽

Hongnan Zhen ◽

Junyi Ji ◽

...

Keyword(s):

Adverse Events ◽

Odds Ratio ◽

Adjusted Odds Ratio ◽

Reporting System ◽

Checkpoint Inhibitors ◽

Adverse Event Reporting System ◽

Adverse Event Reporting ◽

Event Reporting ◽

Logistic Analysis ◽

The Us

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, immune-related adverse events (irAEs) in the gastrointestinal (GI) system commonly occur. In this study, data were obtained from the US Food and Drug Administration adverse event reporting system between July 2014 and December 2020. Colitis, hepatobiliary disorders, and pancreatitis were identified as irAEs in our study. Reporting odds ratio (ROR) with information components (IC) was adopted for disproportionate analysis. A total of 70,330 adverse events were reported during the selected period, 4,075 records of which were associated with ICIs. GI toxicities have been reportedly increased with ICI, with ROR025 of 17.2, 6.7, and 2.3 for colitis, hepatobiliary disorders, and pancreatitis, respectively. The risks of colitis, hepatobiliary disorders, and pancreatitis were higher with anti-CTLA-4 treatment than that with anti-PD-1 (ROR025 2.6, 1.3, and 1.1, respectively) or anti-PD-L1 treatment (ROR025 4.8, 1.3, and 1.3, respectively). Logistic analysis indicated that hepatobiliary disorders and pancreatitis more frequently occurred in female patients (adjusted odds ratio, 1.16 and 1.52; both p < 0.05). Consistently, polytherapy was a strong risk factor for colitis (adjusted odds ratio 2.52, p < 0.001), hepatobiliary disorders (adjusted odds ratio 2.50, p < 0.001), and pancreatitis (adjusted odds ratio 2.29, p < 0.001) according to multivariate logistic analysis. This pharmacovigilance analysis demonstrated an increased risk of all three GI irAEs associated with ICI therapies. The comparative analysis offered supportive insights on selecting GI irAEs for patients treated with ICIs.

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SAINT: Results of a phase 1/2 study of safety/efficacy using safe amounts of ipilimumab, nivolumab, and trabectedin as first-line treatment of advanced soft tissue sarcoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.11016 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 11016-11016 ◽

Cited By ~ 1

Author(s):

Erlinda Maria Gordon ◽

Victoria S. Chua-Alcala ◽

Katherine Kim ◽

Seiya Liu ◽

Nicole Angel ◽

...

Keyword(s):

Adverse Events ◽

Checkpoint Inhibitors ◽

Phase 1 ◽

Safety Analysis ◽

Phase 2 ◽

First Line ◽

Efficacy Analysis ◽

First Line Therapy ◽

Pre Treatment ◽

Grade 3

11016 Background: Sarcoma cells are most immunogenic earlier in the disease course and prior to treatment when the immune system can recognize and destroy them. Hypothesis: Immune checkpoint inhibitors would be most effective when given as first line therapy. Methods: This is an IRB-approved dose-seeking Phase 1/2 protocol using defined doses of I (1 mg/kg i.v. q 12 weeks), N (3 mg/kg i.v. q 2 weeks) and escalating doses of T (1.0, 1.2, 1.5 mg/m2 i.v. q 3 weeks), employing the “Cohort of Three” design, followed by a Phase 2 using the MTD of trabectedin. Results: Nine subjects were treated in Phase 1 of the study, and 31 subjects in Phase 2. Safety analysis: at Dose 1: Grade 3 treatment-related adverse events (TRAEs) included fatigue (n = 1), increased TSH (n = 1). At Dose 2, Grade 4 TRAEs included thrombocytopenia with bleeding, DLT (n = 1), increased CK (n = 1); Grade 3 TRAEs included anemia (n = 1), myalgia (n = 1), increased TSH (n = 1), decreased TSH (n = 1), increased AST (n = 1). Efficacy analysis (evaluable patients): At Dose 1: Disease Control Rate (DCR = CR, PR, SD) was 67%, median PFS, 18 weeks; median OS, 50 weeks; At Dose 2: PR (n-1), DCR 60%, median PFS, 24 weeks; median OS, > 46 weeks. At Phase 2, MTD Dose 2 (PUPs): Safety analysis (n = 31): Grade 3 TRAEs included fatigue (n = 2), increased ALT (n = 6), increased AST (n = 4), hypernatremia (n = 1), hyponatremia (n = 1), dehydration (n = 1), rash (n = 1), port cellulitis (n = 1), psoriasis exacerbation (n = 1), increased TSH (n = 1), decreased hemoglobin (n = 2), neutropenia (n = 1). Efficacy analysis (N = 23 evaluable): PR (n-5; 2 UPS, 1 synovial sarcoma, 1 liposarcoma, 1 leiomyosarcoma,), BORR 22%, DCR 96%. Median PFS and OS not yet reached. After 4 treatment cycles, one resected tumor showed 80% necrosis and a greater number (30%) of CD8+ killer T cells, in the TME compared to archived pre-treatment tumor. Conclusions: These data suggest that the SAINT protocol (1) is safe with manageable adverse events, with no additive toxicity, and (2) may control tumor growth. Phase 2 of the study is on-going. Clinical trial information: NCT03138161.

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