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

Background: Several 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).

Methods: A 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.

Results: Pituitary-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).

Conclusions: In 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 registration: UMIN000019024.

Keywords: immunotherapy; lung neoplasms; melanoma.

Figure 1

Enrollment of study subjects. ICI, immune checkpoint inhibitor; MM, malignant melanoma; NSCLC, non-small cell lung carcinoma; OS, overall survival.

Figure 2

MRI of the pituitary gland in a patient with pituitary immune-related adverse event (pituitary-irAE). Representative MRI for a patient (Ipi001) who developed hypophysitis shows that the pituitary gland was enlarged at pituitary-irAE onset (A) but had returned to normal size 6 months after the onset (B). Representative MRI for a patient (Niv096) who developed isolated adrenocorticotropic hormone deficiency show a normal-sized pituitary gland at pituitary-irAE onset (C) and absence of changes at 6 months after onset (D).

Figure 3

Overall survival (OS) after initiation of immune checkpoint inhibitor treatment in patients with and without immune-related adverse events (irAEs). OS of patients with non-small cell lung carcinoma (NSCLC) (A, C, E, G) or malignant melanoma (MM) (B, D, F, H). Solid and dashed lines indicate OS of patients who did and did not develop each irAE, respectively. The OS was significantly prolonged for patients who developed any irAEs than those who did not for both patients with NSCLC and MM (A, B). The OS was significantly prolonged for patients who developed endocrine-irAEs than those who did not for patients with NSCLC (C) but not patients with MM (D). Among patients with NSCLC and those with MM, the OS was significantly prolonged for patients who developed pituitary-irAE than those who did not (E, F). The OS was significantly prolonged for patients who developed thyroid-irAE than those who did not for patients with NSCLC (G) but not patients with MM (H).