Immune-related adverse events associated with immune-checkpoint inhibitors therapy in Mexican patients: Experience at a single center.

e14580 Background: The use of immune-checkpoint inhibitors (ICIs) for solid malignancies is rapidly rising, and many new agents and treatment combinations are in development. However, ICIs have a unique side-effect profile of immune-related adverse events (irAEs) compared with chemotherapeutic agents or targeted therapies. The aim of this work was to describe the irAEs in diverse types of malignant tumors using real-world data. Methods: This is a retrospective and descriptive study of patients with diverse types of advanced malignancies treated with immunotherapy at Centro Oncológico Integral of the Hospital Ángeles in Puebla, México; during the period 2016-2020. Data about the primary neoplasm, ICIs, irAEs, organ system affected, grade and treatment was collected. Clinical and laboratory parameters were obtained by reviewing medical records. Results: A total of 117 patients were included, median age of 65 years, of which 63.2% were male and 36.8% were female. The most frequent neoplasms treated with ICIs were: lung (27.4%), kidney (16.2%), melanoma (12.8%), hepatocellular (9.4%), breast (8.5%), non-melanoma skin cancer (6.0%), mesothelioma (4.3%) and other tumors (15.3%). 39.3% of the patients had no metastases, 41.9% had metastases to at least 1 or 2 sites, and 18.8% to 3 or more sites. The types of ICIs were: nivolumab (35.0%), pembrolizumab (28.2%), atezolizumab (23.9%), ipilimumab + nivolumab (12.0%) and durvalumab (0.9%). The most frequent irAEs were: gastrointestinal (61.5%), neurologic (46.2%), pulmonary (38.5%), metabolic (32.5%) and hematologic (29.1%). 39.3% of the irAEs were reported as grade 1, 31.6% as grade 2, 14.5% as grade 3 and 2.6% as grade 4. Conclusions: Our work shows the incidence of irAEs in a poorly studied population and provides new data that complement that reported by other works, however, further prospective studies are necessary.[Table: see text]

Download Full-text

Gastrointestinal Adverse Events Induced by Immune-Checkpoint Inhibitors

Digestion ◽

10.1159/000518543 ◽

2021 ◽

pp. 1-9

Author(s):

Shunichi Yanai ◽

Yosuke Toya ◽

Tamotsu Sugai ◽

Takayuki Matsumoto

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Malignant Tumors ◽

Checkpoint Inhibitors ◽

Architectural Distortion ◽

Management Guidelines ◽

Crypt Abscess ◽

Gastrointestinal Adverse Events ◽

Histopathologic Findings

Background: As immune-checkpoint inhibitors (ICI) are becoming standard therapies for malignant tumors, increasing attention has been paid to their associated immune-related adverse events (irAEs). The gastrointestinal tract is the major site of irAEs, and it has recently become evident that the large bowel is the most frequently affected region. The aim of this narrative review was to clarify the endoscopic and histopathologic findings of and treatments for ICI-induced colitis. Summary: Endoscopic findings of ICI-induced colitis include a reddish, edematous mucosa with increased mucous exudate, loss of normal vascularity, and a granular mucosa with or without mucosal breaks. Histopathologic findings of ICI-induced colitis are expansion of the lamina propria, intraepithelial infiltration of neutrophils, crypt architectural distortion, neutrophilic crypt abscess, and prominent apoptosis. The clinical, endoscopic, and histopathologic severity of ICI-induced colitis is diverse, but colonoscopy together with biopsy is necessary for diagnosis. While a certain proportion of patients with ICI-induced colitis have an intractable clinical course, management guidelines are based on retrospective analyses. Prospective studies are needed to assess the efficacy of various medications, including immunosuppressive regimens. Key Messages: Colonoscopy with biopsy is the gold standard for the diagnosis of ICI-induced colitis. Endoscopists should be aware of the clinical features and pathophysiology of ICI-induced colitis for prompt diagnosis and treatment planning.

Download Full-text

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

Liver injury by immune checkpoint inhibitors in patients with hepatocellular carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.341 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 341-341 ◽

Cited By ~ 1

Author(s):

Nicola Personeni ◽

Tiziana Pressiani ◽

Antonio Capogreco ◽

Arianna Dal Buono ◽

Antonio D'Alessio ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Injury ◽

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Subsequent Treatment ◽

Drug Induced ◽

Increased Risk ◽

Grade 3

341 Background: In patients with hepatocellular carcinoma (HCC) and baseline liver dysfunction, hepatic immune-related adverse events (HIRAEs) during immunotherapy have not been adequately characterized and their impact on subsequent treatment outcomes is not known. Methods: 40 patients with advanced/unresectable HCC and Child Pugh score A have been enrolled in first and second-line clinical trials of anti-programmed cell death protein 1 (PD-1) monoclonal antibodies (mAbs). HCC etiologies were: hepatitis C (32.5%), hepatitis B (7.5%), alcohol abuse (27.5%), other (32.5%). 7 received anti-PD-1 mAbs alone and 33 received combined regimens that included anti-PD-1 mAbs plus either anti-cytotoxic T lymphocyte antigen 4 (30.4%) or tyrosine kinase inhibitors (TKIs) (54.5%), or both (15.1%). We reviewed their liver function tests and HIRAEs onset was related to time to treatment failure (TTF). Results: Overall, 12 patients (30%) developed grade ≥ 3 hepatitis according to Common Toxicity Criteria for Adverse Events v. 4.03, resulting in 4 cases of grade 2 drug-induced liver injury per DILI Working Group criteria. Time between therapy initiation and hepatitis onset was 1.4 months (0.4-2.8) and median peak aminotransferase (AT) level was 258 IU/L (85-869). Out of 6 permanent treatment discontinuations due to adverse events (AEs), 4 were linked to hepatitis. Higher AT median levels at baseline were significantly linked to grade ≥ 3 hepatitis compared with lower grades (95 IU/L vs. 36 IU/L, respectively; p = 0.008). Etiology, age, treatment did not predict HIRAEs onset. TTF in patients in patients with grade ≥ 3 hepatitis was shorter than in the whole cohort (1.4 vs. 3.8 months, p = 0.041), while overall survival did not differ (p = 0.125). Conclusions: We observed a 30% incidence of clinically significant HIRAEs. HIRAEs represent the most frequent AEs leading to treatment discontinuation in patients with HCC undergoing treatments with immune checkpoint inhibitors. Baseline AT levels may identify patients at increased risk of grade ≥ 3 hepatitis.

Download Full-text

Emergency Department Utilization for Patients Receiving Immune Checkpoint Inhibitors: A Retrospective Analysis of Identification and Outcomes for Those Presenting for Immune-Related Adverse Events

Current Oncology ◽

10.3390/curroncol28010007 ◽

2020 ◽

Vol 28 (1) ◽

pp. 52-59

Author(s):

Ryan Holstead ◽

Adi Kartolo ◽

Tara Baetz

Keyword(s):

Emergency Department ◽

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Significant Risk ◽

Emergency Department Utilization ◽

Presenting Symptoms ◽

Grade 3 ◽

Time Of Presentation

Background: Immune-related adverse events (iRAEs) are known complications of immune checkpoint inhibitors (ICIs). Early identification and management leads to improved morbidity and mortality. This study seeks to address our center’s experience with iRAEs in the emergency department (ED). Methods: We performed a retrospective review of patients treated with ICIs in 2018 and 2019 for any indication. All diagnoses of iRAEs were recorded. For all patients who presented to the ED following administration of an ICI, we assessed whether the presenting symptoms were eventually diagnosed as an iRAE. We assessed disposition, time to initiation of corticosteroids and outcomes in these patients. Results: 351 evaluable patients were treated with an ICI, 129 patients (37%) had at least one presentation to the ED, 17 of whom presented with symptoms due to a new iRAE. New iRAE diagnoses were broad, occurred after median 2 cycles, majority irAEs were grade 3 or higher (70.6%), and two patients died due to toxicity. Twelve patients were admitted to the hospital during initial presentation or at follow-up, four required ICU care. All patients required immunosuppressive therapy, and only three were later re-challenged with an ICI. Of the patients who were admitted to the hospital, median time to first dose of corticosteroid was 30.5 h (range 1–269 h). Conclusions: Patients on ICI have a significant risk of requiring an ED visit. A notable proportion of iRAEs have their first presentation at the ED and often can present in a very nonspecific manner. A standardized approach in the ED at the time of presentation may lead to improved identification and management of these patients.

Download Full-text

Real-world safety experience with immune checkpoint inhibitors in Saudi Arabia

Science Progress ◽

10.1177/0036850421997302 ◽

2021 ◽

Vol 104 (1) ◽

pp. 003685042199730

Author(s):

Mohammed Al Nuhait ◽

Eshtyag Bajnaid ◽

Abdulmalik Al Otaibi ◽

Abdullah Al Shammari ◽

Yousef Al Awlah

Keyword(s):

Saudi Arabia ◽

Adverse Events ◽

Emergency Room ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Immunosuppressive Agents ◽

Treatment Discontinuation ◽

Emergency Room Visits ◽

Grade 3

Lay abstract Real-world safety experience with immune checkpoint inhibitors in Saudi Arabia: Immune Checkpoint Inhibitors (ICIs) are rapidly growing and changing cancer care. With introduction of ICIs the landscape for cancer treatment has changed significantly. ICIs are known to induce immune-related adverse effects. This research is intended to shed light on ICIs and describe our safety experience with these agents. This study is a retrospective cohort study aimed to determine the safety of ICIs and its related adverse events at a tertiary hospital in Saudi Arabia. The study was conducted in the oncology center at King Abdulaziz Medical City, Riyadh. We identified study participants by using electronic health care system (BestCare)® to involve patients who received ICIs treatment during the study period from January 2016 up to December 2018, to include a total of 53 patients. Most of our patients were on nivolumab (37 patients) followed by atezolizumab (10 patients), and pembrolizumab (6 patients). The average number of emergency room visits after receiving treatment was three visits per patient. Renal adverse events occurred following ICIs use in nine patients, and none of the reported cases experienced a grade ≥3 event. Moreover, 13 patients experienced a hepatic adverse event, of whom only 1 patient experienced a grade ≥3 event leading to treatment discontinuation. As for diarrhea, among all patients who received ICIs, 14 patients experienced diarrhea, and 5 of them had grade ≥3 events. Also, thyroxine abnormalities occurred in seven patients. While, Pneumonitis occurred in four patients following ICIs use. In addition, we noticed other adverse events with ICIs including (skin reaction, nausea, vomiting, thrombocytopenia, neutropenia, and neurological adverse events). Furthermore, 17 patients required steroids to manage ICIs adverse events. And, no patients in our study required additional management with other immunosuppressive agents. Immunotherapies are rapidly growing and changing cancer care. Immune Checkpoint Inhibitors (ICIs) have the ability to block inhibitory checkpoints and restore the functions of the immune system. ICIs are used for the treatment of several types of cancer, and nowadays, many studies are ongoing in order to get approvals for newer indications. ICIs are known to induce immune-related adverse effects. The safety of ICIs and the most common immune-related adverse events are not yet well recognized for our population since this class of medications is lately introduced in our region, where only limited studies in our population are available in the literature. This research is intended to shed light on ICIs and describe our safety experience with these agents. This study is a retrospective cohort study aimed to determine the safety of ICIs and its related adverse events at a tertiary hospital in Saudi Arabia. The study was conducted in the oncology center at King Abdulaziz Medical City, Riyadh. Study participants were identified by using the electronic health care system (BestCare)® to include patients who were treated with ICIs during the study period from January 2016 up to December 2018. A total of 53 patients were included. Most of our patients were on nivolumab (37 patients) followed by atezolizumab (10 patients), and pembrolizumab (6 patients). The average number of emergency room visits after receiving ICIs was three visits per patient. Renal adverse events occurred following ICIs use in nine patients, and none of the reported cases experienced a grade ≥3 event. Moreover, 13 patients experienced a hepatic adverse event, of whom only 1 patient experienced a grade ≥3 event leading to treatment discontinuation. As for diarrhea, among all patients who received ICIs, 14 patients experienced diarrhea, and 5 of them had grade ≥3 events. Also, thyroxine abnormalities occurred in seven patients. While, pneumonitis occurred in four patients following ICIs use. In addition, we noticed other adverse events with ICIs, including (skin reaction, nausea, vomiting, thrombocytopenia, neutropenia, and neurological adverse events). Furthermore, 17 patients required steroids to manage ICIs adverse events. And, no patients in our study required additional management with other immunosuppressive agents. Patients treated with immune checkpoint inhibitors could have a variety of adverse drug events that might lead to treatment discontinuation and increase overall emergency room visits. This study highlights the most common adverse drug events associated with ICIs use at a tertiary care center in Saudi Arabia.

Download Full-text

Management of adverse events in cancer treatment with immune checkpoint inhibitors

Journal of Korean Medical Association ◽

10.5124/jkma.2021.64.5.358 ◽

2021 ◽

Vol 64 (5) ◽

pp. 358-365

Author(s):

Myoung Joo Kang

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Organ Transplant ◽

Chemotherapeutic Agents ◽

Careful Consideration ◽

The Body ◽

Close Monitoring ◽

Multiple Organs

The use of immune checkpoint inhibitors is associated with a spectrum of immune-related adverse events related to the mechanism of action which is quite different from that of cytotoxic chemotherapy. Adverse effects can affect multiple organs of the body and are most common in the skin, gastrointestinal tract, lungs, and endocrine tissues, including the thyroid, adrenal gland, pituitary gland, as well as musculoskeletal, renal, nervous, hematologic, cardiovascular, and ocular systems. Any changes should be considered as being related to treatment with immune checkpoint inhibitors. Adverse events are very infrequent, but may be very serious and, even lethal, such as neurological disorders and myocarditis. When compared with standard chemotherapeutic agents, programmed death 1/programmed deathligand 1inhibitors are associated with a lower incidence of bone marrow suppression, anorexia, nausea, vomiting, and diarrhea. Immune checkpoint inhibitor therapy can usually continue in the presence of mild immune-related adverse events with close monitoring. However, moderate to severe immune-related adverse events may be associated with a severe decline in organ function and quality of life, and may result in fatal outcomes. Hence, these toxicities require early detection and proper management. The management of immune-related adverse events usually involves corticosteroid therapy or the use of immunomodulators. The use of immune checkpoint inhibitors in patients with preexisting autoimmune disease or a history of prior organ transplant should include careful consideration and a robust discussion of potential risks and benefits.

Download Full-text

Risk factors for immune mediated adverse events with immune checkpoint inhibitors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2622 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2622-2622

Author(s):

Ari Pelcovits ◽

Hetal Mistry ◽

Rani Chudasama ◽

Sarah Andrea ◽

Humera Khurshid

Keyword(s):

Risk Factors ◽

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Multinomial Logistic Regression ◽

Concurrent Chemotherapy ◽

Historical Cohort ◽

Weighted Estimates ◽

Grade 3

2622 Background: Immune checkpoint inhibitors (ICIs) are associated with unique toxicity - immune-related adverse events (irAEs). irAEs are common, occurring in nearly 30 % of patients (pts) in clinical trials. Risk factors for irAEs remain largely unknown, with limited evidence to guide risk stratification for these pts. Methods: In this historical cohort study, we identified 400 pts receiving ICIs at our institution between 1/1/2015 - 12/31/2019 and followed them until progression, death, or study end date. Using modified Poisson and multinomial logistic regression we assessed irAEs (yes/no; none/grade 1-2/grade 3-4) as a function of independent risk factors in separate models. These included age, PDL-1%, steroid use in the 2 weeks (S2wks) prior to ICI, concurrent chemotherapy, combination ICI use, and pre-ICI creatinine (Cr) and absolute lymphocyte count. We constructed sample weights using sociodemographic and clinical factors to account for confounding by indication and mortality-related censoring. Results: 367 pts (median age: 68 yrs) had complete data for analysis comprising 55% men and 89% white. 111 (31%) experienced an irAE during the study period (median time to first event: 81 days). Risk was greatest for the youngest and oldest pts on ICI. In weighted models, Pts ≤59 yrs were 3 times as likely to experience an irAE relative to those aged 60-68 (95% CI: 1.18,7.41; Table). Additionally, for each 1 unit increase in Cr, risk of irAE increased by 19% (95% CI: 1.08,1.28). Precision of weighted estimates was impacted by limited pt comparability across factors of interest and overall sample size. While not statistically significant (RR: 2.04;95% CI:0.92,4.53) 70.6% of pts on combination ICIs experienced an irAE compared with 20.3% on one ICI. Similarly, while not statistically significant, 15.4% of pts with PDL-1 >49% experienced a grade 3/4 irAE compared with 7.7% of pts with PDL-1<1%. Conclusions: In this real-world analysis of irAEs, younger age and elevated creatinine were risk factors for development of irAEs. Further research leveraging larger data sources is needed to examine PDL-1% as a potential risk factor of irAE.[Table: see text]

Download Full-text

Treatment-related adverse events of combination immune checkpoint inhibitors: Systematic review and meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15060 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15060-e15060

Author(s):

Robin Park ◽

Laércio Lopes da Silva ◽

Ivy Riano ◽

Cagney Cristancho ◽

Anwaar Saeed

Keyword(s):

Adverse Event ◽

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Related Adverse Event ◽

Adverse Event Data ◽

Cancer Types ◽

Grade 3

e15060 Background: Despite increasing clinical experience with immune checkpoint inhibitors and the recent publication of clinical practice guidelines for managing treatment-related adverse events, precise and nuanced checkpoint inhibitor data in the setting of combination therapy is lacking. Herein we have conducted a systematic review and meta-analysis of treatment-related adverse event data from clinical trials evaluating combination immune checkpoint inhibitors. Methods: Studies published in PubMed, Embase, and Cochrane Database from conception to September 28, 2019 were included in the meta-analysis. Studies were eligible for inclusion if combination immune checkpoint inhibitor therapy was evaluated in advanced unresectable cancer and treatment-related adverse event data were available. For comparison of severity of adverse events in combination versus monotherapy, only the studies containing monotherapy arms as a control population were included, while all were included for calculation of pooled incidence of selected adverse events. Pooled risk ratio (RR) was used for the comparison of combination versus monotherapy and the logit transformed proportion for calculation of pooled incidence. Between-study risk of bias was evaluated using the Begg's funnel plot and Egger's regression test. Subgroup analysis was conducted by combination regimen, cancer type, and dosing regimen. Results: A total of 18 studies comprising 2767 patients across 10 cancer types were included in the final analysis. Combination ICI was associated with a slightly higher risk of all-grade adverse events (RR 1.07 [95% CI 1.03-1.11]) and markedly greater risk of grade 3 or higher adverse events (RR 2.21 [95% CI 1.57-3.10]) compared to monotherapy ICI. Subgroup analyses showed significant differences in risk of grade 3 or higher adverse events between treatment type (PD-1+CTLA-4 and PD-L1+CTLA-4), among cancer types, and among dosing regimens (N1I3, N3I1 and D20T1). Incidence of all-grade adverse events was 0.905 [95% CI 0.842-0.945] and grade 3 or higher events/all-grade adverse events was 0.396 [95% CI 0.315-0.483]. The most common all-grade TRAEs were diarrhea/colitis, fatigue/asthenia, nausea/vomiting, rash, and pruritis. Conclusions: Combination ICI therapy has a significantly different treatment-related adverse event profile compared to monotherapy.

Download Full-text