Discussion

Monoclonal antibodies (anti-PD-1/anti-PD-L1 and anti-CTLA-4) have brought about a significant breakthrough in the treatment of multiple cancers. Their side effects are equally fascinating as irAEs have been reported in almost all systems [13]. Endocrinopathies are most common irAEs and often irreversible [14]. Prior studies have suggested that about 5–10% of patients treated with ICIs are likely to experience endocrine irAEs of any grade [15]. Nevertheless, the detail risk of experiencing such AEs following the use of ICI regimens are not clearly quantified. To our knowledge, this is the largest and most extensive pharmacovigilance study on endocrine irAEs associated with ICIs leveraging FAERS database. Our study provided more precise data on the endocrine profiles of ICI therapy. In general, there were four main findings observed in our study.

1. Remarkably, we found male accounted for a larger proportion of ICIs-related endocrinopathies than female. It has reported that compared to male, female tend to trigger and sustain a stronger immune response against infections and have an increased propensity to experience autoimmune diseases [16]. Therefore, theoretically, female are more likely to experience ICI-related AEs [17], and consequently might with higher reporting frequencies than male. To explore the effect of gender on the reporting frequencies of endocrine complications after ICIs initiation, we further conducted disproportionality analysis.

In general, male had a slightly lower reporting frequencies compared with female but not significant (ROR = 0.98 95%CI: 0.93–1.04) (Additional file 1: Table S1;Fig. S1). Considering the most common consequences observed in the study, the reporting frequencies also varied. Male have significant lower reporting frequencies in hypothyroidism (ROR = 0.68, 95%CI:0.59–0.78) and hyperthyroidism (ROR = 0.77, 95%CI:0.63–0.93) compared with female, which was consistent with a prior retrospective study demonstrated that thyroid disorders associated with ICIs immunotherapy were more common in female [18]. Regarding hypophysitis, which has been reported at higher rates among male [5], a slightly higher but not significant reporting frequencies was observed in male compared with female (ROR = 1.15, 95%CI:0.96–1.38).

It has been reported among patients with non-small cell lung cancer, males had significantly higher odds of receiving anti-PD1 treatment compared with females [19]. Moreover, both melanoma and non-small cell lung cancer, the two most common reasons that a person would be exposed to ICI therapy, occurring at higher rates in male than in female [5, 20, 21]. Consequently, we tried to explore the gender difference of reporting frequencies in the recipients of ICIs for the therapy of melanoma and non-small cell lung cancer and the results became more complex. For patients receiving ICIs for melanoma and other reasons, the reporting frequencies of endocrinopathies in male and female were comparable, corresponding ROR = 0.91(95%CI:0.84–1.00) and ROR = 1.06(95%CI:0.97–1.15), respectively. By contrast, for individuals receiving ICIs for non-small cell lung cancer, male tended to higher reporting frequencies for endocrine diseases compared with female (ROR = 1.16, 95%CI:1.01–1.33). These results suggesting that sex was a fundamental biological variable and it appeared that gender difference for endocrine irAEs may differ for different cancer/tumor types, as well as specific organs, but the exact factors medicated this observed difference was not clear which deserves more attention in oncology.

Actually, we found studies adequately quantifying the gender difference on ICIs-related irAEs or toxicities were scarce. A systematic review concluded that patients who died of ICIs-associated toxic effects were with similar sex distribution (57% vs 60% male; χ2 = 0.09; p = 0.77) [22]. A few studies have evaluated gender disparity in specific endocrinopathies, and most results were derived from retrospective studies with limited individuals involved. Nonetheless, compared with existing studies, our research based on tremendous records in FAERS may offer some useful clinical evidence and future studies are warranted to monitor and research for these gender difference in the recipient of ICIs.

1. Importantly, our study evaluated and compared the signal strength of endocrine AEs in different immunotherapy regimens. Higher reports of endocrine AEs were observed in all ICI regimens compared with the whole database. It appears that potential endocrine irAEs were more likely to occur in patients in anti-CTLA-4 inhibitors monotherapy group than in anti-PD-1/anti-PD-L1 monotherapy groups. Prior studies [23, 24] have concluded that treatment with anti-PD-1/anti-PD-L1 antibodies therapy appears to result in fewer irAEs than with ipilimumab.

Additionally, another analysis [25] based on FAERS database also support our results suggesting anti-CTLA-4 treatment was associated with a higher reporting frequency of endocrine disorders when compared with anti-PD1/anti-PD-L1 treatment (ROR = 1.60, 95%CI 1.46–1.75). Studies from basic research suggesting that blockade of PD-1 is expected to affect a more restricted repertoire of T cells than that affected by CTLA-4 inhibition [23, 26]. This is likely the reason why immune adverse events seem less frequent with anti-PD-1 or anti-PD-L1 antibodies. Notably, our study revealed combining these agents appears to further increase the risk of ICI-related endocrinopathies. This was concordant to what is observed in prior studies [5, 13], whereas, precise mechanisms underlying these endocrine irAEs remain to be elucidated. Indeed, not only endocrine system, combination therapy was reported to associate with higher toxicity involving multiple organ systems [27]. Therefore, despite combination therapy has shown impressive activity in several common cancers [28–32], it also carried a higher risk of toxicity which should be fully and properly recognized.

1. Notably, our study observed the endocrine adverse event profiles of PD-1, PD-L1 and CTLA-4 targeting medications differed and anti-PD-1 drugs appeared to associate with more endocrine toxicities.

Actually, an adequate comparison between toxicity profiles of anti-PD-1 and anti-PD-L1 agents is difficult [33]. PD-L1 blocking antibodies are much less frequently used than PD-1 blocking antibodies, because these medications are approved later. Additionally, they are also differed in FDA-approved indications and tumor types. A study through meta-analysis and systematic review of the literature confirmed that the incidence of irAEs is higher in patients treated with CTLA-4 medications than in those treated with PD-1 and is lowest in patients receiving PD-L1 drugs [34]. Moreover, in another systematic review, Khoja et al. shown that CTLA-4 and PD-1 monoclonal antibodies have different irAE profiles, which may also differ according to tumor types. They were unable to discriminate the adverse event profiles of the anti-PD-L1 antibodies from those of anti-PD-1 antibodies. However, the authors advanced the hypothesis that anti-PD-L1 antibodies, theoretically, might be less toxic owing to PD-L2 sparing which preserves normal immune homeostasis [35]. needed to be further investigated in future research. Our research might provide some new clues for future research but the exact mechanism behind these observations needed to be further investigated.

1. In addition, our study also provides more precise data on the frequency, spectrum of endocrine irAEs induced by different ICI regimens. Pituitary, thyroid, and adrenal glands are endocrine organs typically affected by ICIs treatment [36]. Accordingly, our analysis demonstrated that hypothyroidism, adrenal insufficiency, hypophysitis and hyperthyroidism were the most frequently occurring endocrine irAEs following the ICIs use. Data from clinical trials focusing on ICIs also present similar results [37]. What’s more, a prior meta-analysis [38] also demonstrated that ICIs are associated with increased risk of these four specific AEs compared with placebo or chemotherapy.

Thyroid dysfunction is one of the most common endocrine-related irAEs associated with ICI treatment, which often presented as hyperthyroidism or hypothyroidism. It is thought to mainly associated with anti-PD-1 therapy as well as combination therapy of anti-PD-1 and anti-CTLA-4 [5]. Evidence from our study also favors this point. Our study demonstrated a higher association of hypothyroidism/ hypothyroidism among patients who received nivolumab or pembrolizumab compared with ipilimumab monotherapy. A prior pharmacovigilance study [39] also showed similar result. A meta-analysis [40] also reported that several types of thyroid dysfunction seem to be more strongly associated with anti-PD-1 treatment or ipilimumab plus nivolumab therapy than ipilimumab alone. Additionally, in our study, hypothyroidism was observed to have a much higher reporting frequency than hyperthyroidism (885 vs 472), and this in accord with results from clinical trials that hypothyroidism occurs more frequently than hyperthyroidism [15].

Adrenal insufficiency is an endocrine disorder usually characterized by the adrenal cortex not producing enough hormone cortisol. ICI-associated adrenal insufficiency can be life-threatening if not early recognized and promptly managed [13]. Our research showed that adrenal insufficiency was with secondary reporting frequency among all endocrine AEs after ICIs. Additionally, a stronger association with adrenal insufficiency emerged for ipilimumab alone or combined with nivolumab. More attention should be focused on it for the potential dehydration, hypotension, and electrolyte imbalances events it may trigger. Individuals on ICI therapy should also be informed about the potential danger of this complication, and prompt diagnosis and treatment are essential.

Hypophysitis is more frequently occurred in patients on anti-CTLA-4 therapy and can affect up to 10% of patients [15]. It is reported that hypophysitis is particularly associated with anti-CTLA-4 therapy [5]. In this study, we noticed that ipilimumab alone as well as combined with nivolumab showing higher risk of developing hypophysitis compared with other regimens and this trend has also been revealed in another study [41]. It is reported that adrenal insufficiency can be triggered by ICI-related hypophysitis [5], which could be life-threating. Thus, special care should be given to individuals (especially on ipilimumab/ ipilimumab+ nivolumab therapy) with this symptom.

Several limitations in our study should also be recognized. Firstly, detail information on clinical data which might contribute to a better comprehensive evaluation of the response rate of the patients associated with these irAEs and durability of the response was missing a lot in FAERS database. Secondly, when a report involves several drugs and/or several adverse events, we took combination of drug–adverse event pair as the basic unit rather than report, so results from this pharmacovigilance analysis may subject bias. Nonetheless, compared with existing studies, strength of enormous records at a national level supports our study quantify the potential risk but truly risk of these events should be ascertained in prospective studies.