Pituitary dysfunction induced by immune checkpoint inhibitors is associated with better overall survival in both malignant melanoma and non-small cell lung carcinoma: a prospective study

Abstract

BackgroundSeveral immune-related adverse events (irAEs) are reported to be associated with therapeutic efficacy of immune checkpoint inhibitors, yet whether pituitary dysfunction, a life-threatening irAE, affects overall survival (OS) in patients with malignancies is unclear. This prospective study examined the association of pituitary dysfunction (pituitary-irAE) with OS of patients with non-small cell lung carcinoma (NSCLC) or malignant melanoma (MM).MethodsA total of 174 patients (NSCLC, 108; MM, 66) treated with ipilimumab, nivolumab, pembrolizumab, or atezolizumab at Nagoya University Hospital were evaluated for OS and the development of pituitary-irAE. Kaplan-Meier curves of OS as a function of the development of pituitary-irAE were produced with the log-rank test as a primary endpoint.ResultsPituitary-irAE was observed in 16 patients (4 (3.7%) with NSCLC, 12 (18.2%) with MM) having two different disease types: hypophysitis with deficiency of multiple anterior pituitary hormones accompanied by pituitary enlargement, and isolated adrenocorticotropic hormone (ACTH) deficiency without pituitary enlargement. Among these patients, 6 developed pituitary-irAE while being treated with ipilimumab (6/25 patients (24.0%) treated with ipilimumab) and 10 developed pituitary-irAE during treatment with nivolumab or pembrolizumab (10/167 (6.0%)). All 16 patients had ACTH deficiency and were treated with physiological doses of hydrocortisone. The development of pituitary-irAE was associated with better OS in patients with NSCLC (not reached vs 441 (95% CI not calculated) days, p<0.05) and MM (885 (95% CI 434 to 1336) vs 298 (95% CI 84 to 512) days, p<0.05).ConclusionsIn our study cohort, the incidence of pituitary-irAE was higher than previously reported and the development of pituitary-irAE predicted better prognosis for both NSCLC and MM when patients were treated with physiological doses of hydrocortisone.Clinical trials registrationUMIN000019024.

Clinical Characteristics, Management, and Potential Biomarkers of Endocrine Dysfunction Induced by Immune Checkpoint Inhibitors

“…Endocrine irAEs include dysfunction of the pituitary, adrenal gland, thyroid, parathyroid, and pancreatic β cells [ 3 - 6 ] and can cause life-threatening consequences, such as adrenal crisis and diabetic ketoacidosis. On the other hand, it has been reported that the development of pituitary [ 7 , 8 ] or thyroid [ 8 - 10 ] dysfunction is associated with better outcomes after ICI treatment. Therefore, endocrine irAEs should be diagnosed promptly and managed appropriately.…”

Treatment of Advanced Melanoma: Past, Present and Future

“…Since absolute serum levels of sCD163 were significantly increased in patients who developed AEs [74], and serum levels of sCD163 were also significantly increased in melanoma patients who responded to nivolumab monotherapy [64], irAEs caused by ICIs might correlate with the efficacy of nivolumab. Indeed, serum levels of sCD163 in a patient with isolated ACTH deficiency caused by nivolumab were increased with good response to nivolumab monotherapy [72]. These reports suggest that several subtypes of irAEs caused by ICIs might correlate with better response in melanoma patients.…”

“…Among these, the incidence of treatment-related colitis, hepatitis and skin rash was 5 to 10 times much higher with N + I combination therapy than with nivolumab monotherapy [8]. Moreover, several reports have suggested that AEs caused by ICIs correlate with better response among melanoma patients [64,[72][73][74]. For example, Kobayashi et al reported that melanoma patients who developed pituitary dysfunction induced by ICIs display better OS than patients without this irAE [72].…”

“…Moreover, several reports have suggested that AEs caused by ICIs correlate with better response among melanoma patients [64,[72][73][74]. For example, Kobayashi et al reported that melanoma patients who developed pituitary dysfunction induced by ICIs display better OS than patients without this irAE [72]. Schadendorf et al reported that the ORR to N + I combination therapy was higher in patients who discontinued because of irAEs during the induction phase than in patients who did not discontinue [73].…”

Endocrine toxicity of cancer immunotherapy: clinical challenges

“…• Development of endocrinopathy is associated with longer overall survival versus those patients without and therefore, lifelong hormonal treatment with specialist care from both endocrinologists and oncologists is required. D L Morganstein Endocrine toxicity of immunotheraphy R121 10:3 better cancer outcomes and longer overall survival than controls without endocrinopathy (78,79,80). Therefore the cohort of long term survivors is likely to include many with endocrinopathy, with the associated need for hormone replacement, impact on quality of life and need for specialist follow up.…”