Renal adverse effects following the use of different immune checkpoint inhibitor regimens: A real-world pharmacoepidemiology study of post-marketing surveillance data.

Although kidney impairments have been reported following immune checkpoint inhibitors (ICIs) in clinical studies, there are few pharmacoepidemiology studies to compare the occurrences, clinical features, and prognosis of renal adverse effects. Disproportionality and Bayesian analysis were used in data mining to screen the suspected renal adverse effects after the administration of different ICIs, based on FDA's Adverse Event Reporting System (FAERS) from January 2004 to September 2019. The time to onset, fatality and hospitalization rates of renal adverse effects were also investigated. We identified 1444 reports of renal adverse effects. Affected patients tended to be older than 65 years (52.7%). Renal effects were most commonly reported in nivolumab monotherapy (33.24%). Atezolizumab appeared the strongest association among six ICI monotherapies, based on the highest reporting odds ratio (ROR = 144.38, two-sided 95% CI = 123.08 -169.37), proportional reporting ratio (PRR = 139.13, χ2  = 21 425.38), and empirical Bayes geometric mean (EBGM = 131.75, one-sided 95% CI = 115.28). The combination treatments showed higher RORs, PRRs, and EBGMs, compared with either nivolumab or pembrolizumab monotherapy. The median onset time of renal adverse effects was 48 (interquartile range [IQR] 18.75-121.25) days after the monotherapies of ICI regimens. Patients treated with the combination of nivolumab plus ipilimumab were younger than receivers in nivolumab monotherapy (63.81 ± 12.03 vs 66.39 ± 11.53, P = .004); The fatality rate of renal adverse effects appeared lower in the combination group, compared to nivolumab monotherapy (18.53% vs 27.50%, P = .004). The top hospitalization rates due to renal effects occurred in patients with combination therapies. Based on the FAERS database, we profiled renal adverse effects after various ICIs with real-world data in occurrences, clinical characteristics, and prognosis. Renal effects should be tightly monitored, especially within the first several months after ICIs administration. Particular concern should be paid for patients with a tendency for kidney impairments, such as old age.

Chen G ，Qin Y ，Fan QQ ，Zhao B ，Mei D ，Li XM ... -  《Cancer Medicine》

Myocarditis following the use of different immune checkpoint inhibitor regimens: A real-world analysis of post-marketing surveillance data.

Although myocarditis has been reported in patients treated with immune checkpoint inhibitors (ICIs), there are few real-world studies to compare the occurrences and characteristics of myocarditis after different ICI regimens. Disproportionality analysis and Bayesian analysis were utilized for data mining of the suspected adverse events of myocarditis after ICIs use based on the Food and Drug Administration's Adverse Event Reporting System (FAERS) from January 2004 to June 2018. The times to onset and fatality rates of myocarditis following different ICI regimens were also compared. A total of 315 reports of myocarditis adverse events were identified with ICIs. Among 6 ICI monotherapies, avelumab had the highest association with myocarditis based on the highest reporting odds ratio (ROR = 42.65, 95% two-sided CI = 15.86-114.72), proportional reporting ratio (PRR = 42.61, χ2 = 159.63) and empirical Bayes geometric mean (EBGM = 41.87, 95% one-sided CI = 15.57). The combination therapies of ipilimumab plus pembrolizumab or nivolumab had higher RORs, PRRs and EBGMs than did pembrolizumab or nivolumab monotherapy. Myocarditis associated with the ipilimumab plus nivolumab treatment appeared to have earlier onset (16.5 [IQR 14-29.75] days vs 32 [IQR 16-77] days, p<0.01) and higher fatality rate (65.75% vs 50.40%, p<0.05) than that associated with nivolumab monotherapy. Analysis of FAERS data provides more precise profile on the occurrences and characteristics of myocarditis after different ICI regimens. The findings support continued surveillance, risk factor identification, and comparative studies.

Fan Q ，Hu Y ，Yang C ，Zhao B ... -  《-》

Colitis following the use of immune checkpoint inhibitors: A real-world analysis of spontaneous reports submitted to the FDA adverse event reporting system.

Although colitis has been reported in patients treated with immune checkpoint inhibitors (ICIs), associations between colitis and ICIs had not been thoroughly assessed in real-world studies. Here, we identified and characterized significant colitis-associated with ICIs. Based on the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2004 to December 2019, the disproportionality analysis and Bayesian analysis, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN) and the multi-item gamma Poisson shrinker (MGPS) algorithms were adopted to data mining of the suspected adverse events of colitis after ICIs administrating. Clinical characteristics of patients with ICIs-associated colitis and the time to onset of colitis following different ICI regimens were collected. A total of 3786 reports of colitis adverse events were identified with ICIs. Seven ICI monotherapies were associated with the reporting of colitis. Statistically significant ROR, PRR, information component (IC), and empirical Bayesian geometric mean (EBGM) emerged for all ICI monotherapies and combination therapies. ICIs-associated colitis affected mostly male (53.51%), with a wide mean age range (60.65 to 72 years). Colitis adverse events were commonly reported in patients with melanoma and lung cancer. Adverse outcomes of colitis concerning ICI were mainly outcomes of hospitalization-initiated or prolonged and other serious. Among colitis cases, 17.43% cases of colitis concerning ICI lead to death. The adverse event ofcolitis occurred earliest in ipilimumab monotherapy with a median time to onset of 64.21 days (IQR: 27-69 days) among all monotherapies. ICI may lead to severe and disabling ICIs-associated colitis during therapy. Analysis of FAERS data identified signals for adverse events of colitis with ICI regimens. Practitioners should consider the factors that may increase the likelihood of colitis. The findings support a continued surveillance and risk factor identification studies.

Hu Y ，Gong J ，Zhang L ，Li X ，Li X ，Zhao B ，Hai X ... -  《-》

Evaluation of uveitis events in real-world patients receiving immune checkpoint inhibitors based on the FAERS database.

Fan Q ，Chen H ，Hu Y ，Zhao B ... -  《-》

Immune-related adverse events associated with immune checkpoint inhibitors: An updated comprehensive disproportionality analysis of the FDA adverse event reporting system.

Immune-related adverse events were reported in patients treated with immune checkpoint inhibitors (ICIs). However, with the increasing number of immune-related adverse events (irAEs), the differences of each immune checkpoint inhibitor regimen had not been fully assessed. Disproportionality analysis was used in data mining of the suspected adverse events after ICIs administration based on the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2004 to December 2019. The onset time and fatality proportion of ICI-associated irAEs were further evaluated. A total of 32,441 reports of ICI-associated irAEs were gathered. This study showed that all ICI regimens generated lung toxicity and endocrine toxicity signals. Colitis, pneumonitis and interstitial lung disease were the most common ICI-associated irAEs. Five regimens including durvalumab monotherapy, ipilimumab monotherapy, ipilimumab plus nivolumab, ipilimumab plus pembrolizumab, durvalumab plus tremelimumab were associated with irAEs. Anti-PD-1 agents generated more signals of ocular toxicities than anti-PD-L1 agents, while anti-PD-L1 agents reported more signals of hematologic toxicities. Anti-CTLA-4 agents showed more signals of gastrointestinal toxicities compared with anti-PD-1 or anti-PD-L1 agents. The highest fatality proportion of lung toxicities with durvalumab monotherapy, hematological toxicities with avelumab monotherapy, renal and skin toxicities with cemiplimab monotherapy were found. Our results demonstrated that each ICI regimen had different characteristics of irAEs. Pembrolizumab had the highest fatality proportion. Ipilimumab plus pembrolizumab had the shortest median time to onset irAEs. Further studies were expected to assess whether there were clinically relevant differences exist among ICIs.

Chen C ，Wu B ，Zhang C ，Xu T ... -  《-》