There is no doubt that immunotherapy based on ICIs are the biggest breakthrough in the field of tumor treatment in recent years, which has brought a satisfactory efficacy for the patients with advanced or refractory tumors and greatly improved the prognosis of the tumor patients. However, the global increase in ICIs use not only brings a satisfactory curative effect for tumor patients but also brings a unique spectrum of fatal toxic side-effects, such as myocarditis, colitis, pneumonitis, hepatitis, and nephritis[5]. Although the risk for mortality of ICIs-related fatal ADRs is lower than common oncologic interventions, clinicians need to raise the awareness of the severity of these toxic effects.
Since human cardiomyocytes express immune checkpoint receptors, ICIs may cause fatal myocarditis while eliminating cancer cells[17]. Several studies reported that the myocarditis associated with PD-1/PD-L1 inhibitors occurred to melanoma patients, which has aroused people’s attention[18–20]. A preclinical research revealed that the left ventricle ejection fraction and global radial strain in transplantable melanoma mice treated with anti-PD-1 antibodies were reduced, compared to the control group, and the analysis of metabolites and lipids indicated dysfunctional energy metabolism, suggesting that immunotherapy based on PD-1 can disturb cardiac function and disrupt cardiomyocyte functional integrity[21]. Javid JJ et al.[7] identified 101 cases of reports submitted to WHO-Vigibase. In these 101 reports of patients with severe myocarditis after treatment with ICIs, most patients (57%) received anti-PD-1 monotherapy, while 27% of patients received anti-PD-1/PD-L1 plus anti-CTLA-4 combination therapy. The results of this study showed that 46 patients died, and the mortality rate of patients with combination therapy was higher than that of patients with monotherapy[7]. It was worth noting that there were 3 deaths in 5 patients because of ipilimumab-related myocarditis and the reporting of AEs has increased dramatically over time. Besides, Wang DY et al.[4] retrieved 3545 ADRs reports related to immunosuppressive therapy from 7 academic centers in the WHO-Vigbase database, and systematically reviewed the published researches involved in ICIs. They found that the death of patients treated with anti-PD-1 and anti-CTLA-4 antibodies was usually caused by colitis [32 (37.0%)] and myocarditis [22 (25.0%)], and the fatal toxic effects usually occurred early after therapy initiation for combination therapy. Among these fatal ADRs, the lethality rate of myocarditis was the highest [39.7% (52 of 131 reported cases)]. Furthermore, Mahmood SS et al.[10] created a multicenter registry with 8 sites after observing sporadic cases of ICIs-related myocarditis. 35 patients with ICIs-associated myocarditis were compared with a random sample of 105 patients without myocarditis treated by ICIs. All patients (29% for female patients) were 65 ± 13 years old, and 54% of patients had no other irAEs. The results showed that the prevalence of myocarditis was 1.14% and the median time of onset was 34 days (interquartile range: 21 to 75 days). Taken together, assessing the marketing safety of target drugs by mining the real-world data reported in pharmacovigilance databases is of great significance, and we can fully understand the safety profiles of target drugs by signal detection.
In this study, we analyzed spontaneous reports of five fatal ADRs related to seven ICIs submitted to EV and FAERS databases, and detect signals of ICIs-associated ADRs by data mining methods. The findings showed that a total of 7613 fatal ICIs-associated ADEs were reported to the EV database, whereas a total of 5786 fatal toxic effects related to ICIs were submitted to the FAERS database. Among these ADRs, the numbers of ICIs-associated myocarditis were 625 for the EV system, and 507 for the FAERS system, respectively. Although the prevalence rate of myocarditis was not the highest, its risk for lethality was the highest, especially the mortality rate of avelumab-related myocarditis was as high as 50%, suggesting that clinicians should take notice of these toxic effects when using immune strategies based on ICIs for tumor patients. We also noted that the most frequently reported ADR was colitis, which was consistent with the results of several systematic reviews[4, 22, 23]. Besides, we found that elderly patients (older than 65-year-old), especially those aged between 65 and 85 years old, were more likely to suffer from myocarditis compare to young patients by analyzing the characteristics of the patients developed myocarditis associated with ICIs, which can be partially explained by the fact that the immune function of elderly is low and the tumor incidence rate of elderly is higher than young people. Gender distribution of patients with ICIs-related myocarditis showed that male patients are more likely to develop myocarditis compared to female patients, suggesting that male patients have a higher risk of myocarditis caused by ICIs, which may be associated with that men play a dominant role in the development of acute myocarditis(sex ratio = 6.75)[7]. And this finding may also be related to the fact that the incidence rate and mortality rate of malignant tumors in males were higher than those in females[24]. Furthermore, the results of signal mining showed that the signal value of avelumab-related myocarditis detected by ROR and PRR methods was the highest, and the highest signal value measured by the IC method was ipilimumab-related myocarditis, suggesting that there is a high risk of myocarditis caused by avelumab or ipilimumab. The fatality cases of cemiplimab-related myocarditis were 0 and there was no signal generated, which may be related to its short time on the market, and further study needs to be explored the risk of cemiplimab-related ADRs. Among these ADEs, the signal value of ipilimumab-related colitis was the highest by using both three data mining methods, which is consistent with the conclusion that colitis is the most common ADE of treatment with CTLA‑4 inhibitors (ipilimumab)[5].
This study is mainly to analyze the post-marketing safety of ICIs and detect signals of ICIs-associated myocarditis reported in EV and FAERS databases via ROR, PRR, and BCNPP methods. The data of this study were obtained from two international pharmacovigilance databases in the real world, which could provide evidence for the safe use of ICIs to some extent. However, this study has several limitations. First of all, the ADR reports submitted to the EV database and FAERS database usually conclude missing data, duplicate data, the irregular spelling of drug and ADR names, and so on. And most ADRs reports come from America and Europe, while there are few data from Asia or Africa. Secondly, although the pharmacovigilance databases are recognized as an important tool to assess the post-marketing safety of drugs by data mining algorithm and the signal detected by data mining methods indicated that the target drug and the target ADR are statistically correlated, that does not mean the target drug and the target ADR have a biological causal relationship, which needs to be further observation and verified through several large-scale clinical trials.
Despite the limitations, the results of this study showed that the application of ICIs is associated with an increase in fatal toxic effects, especially myocarditis, which is consistent with previous studies. It is suggested that clinicians should pay attention to these fatal ICIs-associated ADRs and take preventive measures when treating tumor patients with immunotherapy based on ICIs. The findings of this study also provided objective evidence for post-marketing safety of ICIs, so as to ensure the safe use of these drugs and improve the prognosis of patients with cancer.