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.

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.

Informations de copyright

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: SI receives personal fees from Ono Pharmaceutical Company, Bristol-Myers Squibb, MSD K.K., and Chugai Pharmaceutical Co., Ltd. TO receives personal fees from MSD K.K. HT receives grants from MSD K.K. YI receives grants from Sanwa Kagaku Kenkyusho, Kowa Pharmaceutical, MSD K.K., Dainippon Sumitomo, Kyowa Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., Boehringer Ingelheim, Nihon Medi-Physics Co., Ltd., and personal fees from Astellas Pharma, Daiichi Sankyo, and Ono Pharmaceutical Company. KY receives personal fees from Ono Pharmaceutical Company, MSD K.K., and Bristol-Myers Squibb. TH received personal fees from Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Company, and Bristol-Myers Squibb while the study was being conducted. TH also received grants from Boehringer Ingelheim, Taiho Pharmaceutical Co., Ltd., and personal fees from Boehringer Ingelheim outside the submitted work. MMS receives personal fees from Ono Pharmaceutical Company, Bristol-Myers Squibb, MSD K.K., and Chugai Pharmaceutical Co., Ltd. MA receives grants from Kyowa Kirin Co., Ltd. YA receives grants and personal fees from Ono Pharmaceutical Company, Chugai Pharmaceutical Co., Ltd., and Taiho Pharmaceutical Co. Ltd. as well as personal fees from Bristol-Myers Squibb. MA receives grants and personal fees from Ono Pharmaceutical Company, MSD K.K., and personal fees from Bristol-Myers Squibb. YH receives grants and personal fees from Ono Pharmaceutical Company, Chugai Pharmaceutical Co., Ltd., Eli Lilly, Boehringer Ingelheim, Bristol-Myers Squibb, MSD K.K., and Pfizer; grants from Novartis and Taiho Pharmaceutical Co., Ltd., and personal fees from Astra Zeneca. HA receives grants from Ono Pharmaceutical Company, MSD K.K., Chugai Pharmaceutical Co. Ltd., and personal fees from Ono Pharmaceutical Company, Bristol-Myers Squibb, and MSD K.K.