To our knowledge, this study represents the most recent and largest clinical description and characteristics of ICI-associated PAI using individual adverse events reports from FDA FAERS database. Although PAI is a rare adverse event, it calls for emergent reorganization and treatment for its possibility of adrenal crisis and death. Our study revealed the increasing incidence of ICI-associated PAI from 2016 to 2020. The increasing trend of incidence of ICI-PAI along with the reporting year may be explained by a more prevalent application of ICIs therapy, also a more profound understanding of the disease by clinicians.
In our study, the incidence of ICI-PAI was 1.03% (1180 to 114121) in all reported cases of ICI-related adverse events, and between 0.60% and 0.77% in individuals on mono-therapy, which was in accordance with the number of less than 1% in previous study . Our research indicated an incidence of ICI-PAI of 1.47% in patients on the combination therapy of ipilimumab and nivolumab. This was lower than the number reported in patients on combination therapy, which was raised to 4%-8% . In randomized clinical trials and meta-analysis, the incidence of ICI-PAI was up to 2.43% . Since a proportion of non-serious cases may be not reported in the real-world practice, it may result in lowered incidence of ICI-PAI in FAERS database.
Our study suggested that ICI-PAI had a distinct gender and age distribution compared with other irAE endocrinopathies or autoimmune PAI. Of all 1180 cases of ICI-PAI, 62.5% were male in our study population. Similar result was concluded in a study using data from VigiBase, the World Health Organization’s pharmacovigilance database, in which 54.4% of all 451 cases of PAI-irAE occurred in men . However, studies revealed a female predominance on ICI-induced endocrinopathies , and different endocrinologic irAEs present with diverse gender predominance. A population study using data from FAERS consistently indicated that female had significant higher reporting frequencies in both hypothyroidism and hyperthyroidism, while hypophysitis showed a male dominated disparity .
Our study found a significant higher susceptibility of ICI-PAI in patients elder than 65 year-olds, and this predominance of elder patients was seen in individuals receiving anti-PD-1 therapy or the combined therapy of anti-PD-1 and anti-CTLA-4. There was no report of patient under the age of 18 who developed ICI-induced PAI in FAERS, since the prevalence of lung cancer, renal cell carcinoma or melanoma was rare in under-age population.
Regarding the co-occurrence endocrinopathies, 24.2% of cases with ICI-PAI developed polyendocrinopathies. Ipilimumab mono-therapy or the combined therapy of anti-CTLA-4 and anti-PD-1 resulted in highest risk of polyendocrinopathies including PAI, followed by anti-PD-1 mono-therapy, which was consistent with other researchers . This could be explicated by the possible destructive potential of ipilimumab and its combination therapy to endocrine glands, including thyroid glands and pancreas β cells. More frequent surveillance on thyroid and adrenal function should be implemented in patients on CTLA-4 inhibitors or its combination therapy.
In our study, 79.4% of ICI-PAI cases were severe, and the mortality rate was 11.9% due to various causes. Previous study reported a severe adverse event rate of 91.1% and a mortality rate of 7.3% in PAI-irAE patients using VigiBase, in which the severe adverse event had a broadened definition of the outcome of death, being life-threatening, hospitalization, disability or any other medically important conditions . In both studies, ICI-PAI could lead to a high proportion of serious outcome, which could be explained by the damage to adrenal gland and acute insufficiency of serum cortisol. Our study suggested that the risk of serious events increased in subgroup of the combination therapy of anti-PD-1 and anti-CTLA-4, the risk of death or severe clinical outcome was insignificant in different mono-therapies. Some researchers concluded that patients on PD-1 inhibitors had raised mortality among ICIs mono-therapy , and combination therapy of ICIs was proved to be a positive factor of poor clinical outcome [15–16].
In our study, further analysis of prognostic factors suggested that lower body weight could lead to higher risk of death in the study population. Cancer associated weight loss indicated poor prognosis, thus higher BMI of patients with malignancy and slower weight loss during treatment suggests better survival rate . The linkage of body weight and prognosis in patients receiving ICIs therapy was first proved in our study. In subgroup of PD-1 inhibitors, the comorbidity of ICI-related thyroid dysfunction in ICI-PAI patients revealed a positive correlation with severe clinical outcomes, while no association was discovered between ICI-TD and the risk of death. A prospective study and an observational study indicated that the overall survival was significantly longer in patients on ICIs treatment after developed ICI-related thyroid dysfunction, and the prognosis was even better in patients with overt hypothyroidism [18–20]. One possible explanation was that patients who developed irAEs might also have preferable treatment response, while irAEs in itself could bring about poor clinical outcomes. Therefore, more attention should be paid for the monitor of irAEs, especially patients with lowered body mass during ICIs treatment.
No case of adrenal crisis was reported FAERS. A life-threatening disease as it is, less is known about ICI-induced adrenal crisis. Regular measurement of serum cortisol and adrenocorticotropin could be recommended for patients on ICIs treatment presented with fatigue or nausea, in the order of early diagnosis .
As a retrospective study, the limitations are associated to referral bias and the lack of follow-up. Since a proportion of non-serious cases may be not reported in FAERS database, it could result in bias to the analysis of prognosis. The incomplete data of FAERS database and the fact that adrenocorticotropic hormone (ACTH) level was not available in FAERS, which is critical in the differential diagnosis of primary and secondary adrenal insufficiency, led to inevitable bias to the incidence of ICI-PAI. Although the reaction terms including secondary or pituitary adrenal insufficiency and hypophysitis were excluded from our study population, the data of FAERS reporting is voluntary from endocrinologists as well as oncologists and general practitioners, and it was unrealistic to the confirmed diagnosis of PAI or central adrenal insufficiency for all reporters. In addition, our study focused on ICIs-mediated new-diagnosed PAI instead of other causes of PAI including bilateral adrenal metastasis or hemorrhage, which brought about bias to data analysis.