In this study, OS and PFS for nivolumab treatment were significantly prolonged in the irHT (+) group of patients with R/M HNC. The DCR was significantly higher in the irHT (±) group than in the irHT (−) group. These results suggest that irHT by nivolumab treatment is involved in clinical benefit in patients with R/M HNC.
The occurrence of irAEs is more frequent in organs such as the skin, gastrointestinal tract, liver, and endocrine system [7]. Endocrine dysfunction includes thyroid dysfunction, hypopituitarism, hypoadrenocorticism, hypoparathyroidism, and type 1 diabetes [13]. Furthermore, thyroid dysfunction is classified into two types, hyperthyroidism and hypothyroidism. In particular, hypothyroidism is a common irAE caused by nivolumab treatment, and the incidence of nivolumab-induced irHT is 10% in melanoma [14], 15% in NSCLC [15], and 7.6% in R/M HNC [4]. Interestingly, 45% (14/31) of patients with R/M HNC in this study experienced irHT with nivolumab treatment. Although irAEs are typically evaluated using CTCAE, we evaluated irHT in this study based on our hospital's criteria. Symptoms of thyroid dysfunction are often absent or vague. Therefore, routine surveillance of thyroid function at each visit is necessary to identify these disorders. In fact, if hormone levels are low, hormone-replacement therapy is recommended (if TSH < 0.5 times the lower limit of normal, > 2 times the upper limit of normal, or consistently out of range in 2 subsequent measurements) [16–20]. As the evaluation method using CTCAE does not use quantified objective data such as TSH, FT4, and FT3 levels, such an assessment of thyroid dysfunction may be an underestimation. For these reasons, the evaluation of thyroid dysfunction based on our hospital's criteria was considered to be more clinical in practice. Several studies have similarly assessed irHT based on their criteria, not on CTCAE, and reported the association between the onset of irHT and the clinical effect of nivolumab treatment [21]. Therefore, the high incidence of irHT in this study was attributed to the differences in evaluation methods.
It is difficult to predict the onset of irAE. However, Weber et al. [22] reported that the median time to onset of nivolumab-induced endocrine dysfunction was 73 days in melanoma. Nivolumab-induced hypothyroidism is considered to occur after a transient and asymptomatic period of hyperthyroidism [9]. Moreover, the median onset of hypothyroidism was 98 days in NSCLC [9]. Our results are supported by these results because the median onset of irHT was 76 days in this study. Seven patients (50.0%) classified as grade 2 in the irHT (+) group required treatment with levothyroxine during the observation period. In general, irHT has been reported as an irreversible adverse event [23]. These results suggest that it is important to constantly monitor the TSH and FT4 levels during the treatment period, especially in the first 3 months of treatment with nivolumab.
The relationship between the onset of irAEs and the clinical benefits of nivolumab is evaluated based on the anti-tumor effects of nivolumab on T cells to regulate and reactivate the immune response to tumor cells. However, irAEs are attributed to excessive autoimmune effects associated with the activation of normal cells. Several studies have reported an association of the onset of irAEs with clinical benefits in the treatment with immune checkpoint inhibitors (ICIs) [8] [24–26]. Freedman et al. [24] reported that cutaneous irAEs increased the prolongation of OS in melanoma. Moreover, Ricciuti et al. [25] reported that gastrointestinal tract and endocrine irAEs increased clinical benefits such as prolongation of the OS in NSCLC. In this study, clinical outcomes, such as OS and PFS, were significantly prolonged in the nivolumab-induced irHT (+) group. We also found that the DCR was significantly higher in the irHT (+) group than in the irHT (‒) group. This result suggests that suppression of tumor growth might contribute to the prolongation of OS and PFS in the irHT (+) group.
In general, except for the onset of severe irAEs, such as interstitial pneumonia, renal dysfunction, and myasthenia gravis, ICI treatment can be continued with careful management of irAEs. The incidence of multiple irAEs was significantly higher in the irHT (+) group than in the irHT (‒) group. DCR was also significantly higher in the irHT (+) group than in the irHT (‒) group. Weber et al. [22] supported our results by reporting that patients with advanced melanoma who achieved an objective response to treatment with nivolumab experienced multiple irAEs. In this study, the number of nivolumab courses was significantly higher in the irHT (+) group than in the irHT (‒) group. We speculated that the higher incidence of multiple irAEs in the irHT (+) group was related to more courses of nivolumab treatment and longer survival. However, since the frequency of serious irAEs did not differ between the irHT (+) and irHT (‒) groups, appropriate treatment of irAEs by careful management may facilitate the continuation of nivolumab treatment in patients with R/M HNC.
Our study had several limitations. First, we excluded patients with hyperthyroidism or thyroiditis. Therefore, we could not examine the relationship between irHT onset and clinical outcomes in these patients. Second, this analysis has lead-time bias. We showed that patients in the irHT (+) group after nivolumab treatment experienced better survival than those in the irHT (‒) group. Although long‐term survivors may have longer exposure to nivolumab and a higher risk of irHT onset, an extreme delay in the onset of irAEs is generally only observed in patients who respond to treatment [27]. Third, this was a single-center, retrospective study with a small number of patients with R/M HNC. Further studies with more patients and longer follow-up periods are needed to validate the findings.