TY - JOUR
T1 - Combined PD-1 and CTLA-4 Blockade Increases the Risks of Multiple Pituitary Hormone Deficiency and Isolated Adrenocorticotropic Deficiency
T2 - A Prospective Study
AU - Iwama, Shintaro
AU - Kobayashi, Tomoko
AU - Izuchi, Tetsushi
AU - Suzuki, Koji
AU - Murase, Takanori
AU - Ando, Masahiko
AU - Handa, Tomoko
AU - Onoue, Takeshi
AU - Miyata, Takashi
AU - Sugiyama, Mariko
AU - Hagiwara, Daisuke
AU - Suga, Hidetaka
AU - Banno, Ryoichi
AU - Hase, Tetsunari
AU - Mori, Shoichiro
AU - Sano, Tomoyasu
AU - Akamatsu, Shusuke
AU - Akiyama, Masashi
AU - Ishii, Makoto
AU - Arima, Hiroshi
N1 - Publisher Copyright:
© 2025 Korean Endocrine Society.
PY - 2025/6
Y1 - 2025/6
N2 - Background: Anti-cytotoxic T-lymphocyte antigen-4 antibody (CTLA-4-Ab) monotherapy induces two types of pituitary immunerelated adverse events (irAEs): multiple pituitary hormone deficiency (Multi-D; impairment of ≥2 anterior pituitary hormones) and isolated adrenocorticotropic hormone (ACTH) deficiency (IAD). Combination therapy with CTLA-4-Ab and anti-programmed cell death-1 antibody (PD-1/CTLA-4-Abs), which is increasingly replacing CTLA-4-Ab monotherapy, frequently causes pituitary irAEs; however, whether it increases Multi-D/IAD incidence is unknown. Methods: In total, 74 and 748 patients with malignancies treated with PD-1/CTLA-4-Abs and PD-1-Ab, respectively, were prospectively evaluated for ACTH and cortisol levels at baseline and every 6 weeks after treatment initiation, and then observed until the last clinical visit. The characteristics of pituitary irAEs were evaluated by pituitary stimulation tests and compared with those induced by PD-1-Ab monotherapy. Results: PD-1/CTLA-4-Abs therapy showed higher incidence rates of pituitary irAEs (16/74 [21.6%] vs. 25/748 [3.3%], P<0.001), Multi-D (9/74 [12.2%] vs. 2/748 [0.3%], P<0.001), and IAD (7/74 [9.5%] vs. 23/748 [3.1%], P=0.014) than PD-1-Ab monotherapy. ACTH deficiency was observed in all cases, whereas the prevalence rates of luteinizing hormone deficiency (8/16 [50.0%] vs. 1/25 [4.0%]), follicle-stimulating hormone deficiency (6/16 [37.5%] vs. 1/25 [4.0%]), and thyrotropin deficiency (4/16 [25.0%] vs. 0/25 [0%]) were significantly higher after PD-1/CTLA-4-Abs than after PD-1-Ab treatment. Pituitary enlargement, which was observed only in the Multi-D cases, was significantly more frequent after PD-1/CTLA-4-Abs than after PD-1-Ab treatment (6/16 [37.5%] vs. 0/25 [0%], P=0.002). Conclusion: This prospective study revealed high risks of both Multi-D and IAD under PD-1/CTLA-4-Abs treatment, emphasizing the need for careful evaluation of pituitary function.
AB - Background: Anti-cytotoxic T-lymphocyte antigen-4 antibody (CTLA-4-Ab) monotherapy induces two types of pituitary immunerelated adverse events (irAEs): multiple pituitary hormone deficiency (Multi-D; impairment of ≥2 anterior pituitary hormones) and isolated adrenocorticotropic hormone (ACTH) deficiency (IAD). Combination therapy with CTLA-4-Ab and anti-programmed cell death-1 antibody (PD-1/CTLA-4-Abs), which is increasingly replacing CTLA-4-Ab monotherapy, frequently causes pituitary irAEs; however, whether it increases Multi-D/IAD incidence is unknown. Methods: In total, 74 and 748 patients with malignancies treated with PD-1/CTLA-4-Abs and PD-1-Ab, respectively, were prospectively evaluated for ACTH and cortisol levels at baseline and every 6 weeks after treatment initiation, and then observed until the last clinical visit. The characteristics of pituitary irAEs were evaluated by pituitary stimulation tests and compared with those induced by PD-1-Ab monotherapy. Results: PD-1/CTLA-4-Abs therapy showed higher incidence rates of pituitary irAEs (16/74 [21.6%] vs. 25/748 [3.3%], P<0.001), Multi-D (9/74 [12.2%] vs. 2/748 [0.3%], P<0.001), and IAD (7/74 [9.5%] vs. 23/748 [3.1%], P=0.014) than PD-1-Ab monotherapy. ACTH deficiency was observed in all cases, whereas the prevalence rates of luteinizing hormone deficiency (8/16 [50.0%] vs. 1/25 [4.0%]), follicle-stimulating hormone deficiency (6/16 [37.5%] vs. 1/25 [4.0%]), and thyrotropin deficiency (4/16 [25.0%] vs. 0/25 [0%]) were significantly higher after PD-1/CTLA-4-Abs than after PD-1-Ab treatment. Pituitary enlargement, which was observed only in the Multi-D cases, was significantly more frequent after PD-1/CTLA-4-Abs than after PD-1-Ab treatment (6/16 [37.5%] vs. 0/25 [0%], P=0.002). Conclusion: This prospective study revealed high risks of both Multi-D and IAD under PD-1/CTLA-4-Abs treatment, emphasizing the need for careful evaluation of pituitary function.
KW - Adrenocorticotropic hormone deficiency
KW - Hypopituitarism
KW - Immune checkpoint inhibitors
KW - Immune-related adverse event
KW - Immunotherapy
UR - https://www.scopus.com/pages/publications/105012139125
UR - https://www.scopus.com/inward/citedby.url?scp=105012139125&partnerID=8YFLogxK
U2 - 10.3803/EnM.2024.2180
DO - 10.3803/EnM.2024.2180
M3 - Article
C2 - 39933435
AN - SCOPUS:105012139125
SN - 2093-596X
VL - 40
SP - 459
EP - 468
JO - Endocrinology and Metabolism
JF - Endocrinology and Metabolism
IS - 3
ER -
