Iwama Shintaro, Kobayashi Tomoko, Izuchi Tetsushi, Suzuki Koji, Murase Takanori, Ando Masahiko, Handa Tomoko, Onoue Takeshi, Miyata Takashi, Sugiyama Mariko, Hagiwara Daisuke, Suga Hidetaka, Banno Ryoichi, Hase Tetsunari, Mori Shoichiro, Sano Tomoyasu, Akamatsu Shusuke, Akiyama Masashi, Ishii Makoto, Arima Hiroshi
Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
Endocrinol Metab (Seoul). 2025 Jun;40(3):459-468. doi: 10.3803/EnM.2024.2180. Epub 2025 Feb 11.
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.
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.
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).
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.
抗细胞毒性T淋巴细胞抗原4抗体（CTLA-4-Ab）单药治疗可引发两种类型的垂体免疫相关不良事件（irAEs）：多种垂体激素缺乏（Multi-D；≥2种垂体前叶激素受损）和孤立性促肾上腺皮质激素（ACTH）缺乏（IAD）。CTLA-4-Ab与抗程序性细胞死亡1抗体（PD-1/CTLA-4-Abs）的联合治疗正逐渐取代CTLA-4-Ab单药治疗，该联合治疗频繁引发垂体irAEs；然而，其是否会增加Multi-D/IAD的发生率尚不清楚。
分别对74例和748例接受PD-1/CTLA-4-Abs和PD-1-Ab治疗的恶性肿瘤患者进行前瞻性评估，在基线时以及治疗开始后每6周检测促肾上腺皮质激素和皮质醇水平，然后观察至最后一次临床随访。通过垂体刺激试验评估垂体irAEs的特征，并与PD-1-Ab单药治疗所引发的特征进行比较。
与PD-1-Ab单药治疗相比，PD-1/CTLA-4-Abs治疗的垂体irAEs发生率更高（16/74 [21.6%] 对25/748 [3.3%]，P<0.001）、Multi-D发生率更高（9/74 [12.2%] 对2/748 [0.3%]，P<0.001）以及IAD发生率更高（7/74 [9.5%] 对23/748 [3.1%]，P=0.014）。所有病例均观察到促肾上腺皮质激素缺乏，而PD-1/CTLA-4-Abs治疗后促黄体生成素缺乏的患病率（8/16 [50.0%] 对1/25 [4.0%]）、促卵泡生成素缺乏的患病率（6/16 [37.5%] 对1/25 [4.0%]）和促甲状腺激素缺乏的患病率（4/16 [25.0%] 对0/25 [0%]）均显著高于PD-1-Ab治疗后。仅在Multi-D病例中观察到垂体增大，PD-1/CTLA-4-Abs治疗后垂体增大的频率显著高于PD-1-Ab治疗后（6/16 [37.5%] 对0/25 [0%]，P=0.002）。
这项前瞻性研究揭示了PD-1/CTLA-4-Abs治疗下Multi-D和IAD的高风险，强调了仔细评估垂体功能的必要性。
