Combined PD-1 and CTLA-4 Blockade Increases the Risks of Multiple Pituitary Hormone Deficiency and Isolated Adrenocorticotropic Deficiency: A Prospective Study

Shintaro Iwama; Tomoko Kobayashi; Tetsushi Izuchi; Koji Suzuki; Takanori Murase; Masahiko Ando; Tomoko Handa; Takeshi Onoue; Takashi Miyata; Mariko Sugiyama; Daisuke Hagiwara; Hidetaka Suga; Ryoichi Banno; Tetsunari Hase; Shoichiro Mori; Tomoyasu Sano; Shusuke Akamatsu; Masashi Akiyama; Makoto Ishii; Hiroshi Arima

doi:10.3803/EnM.2024.2180

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Original Article Combined PD-1 and CTLA-4 Blockade Increases the Risks of Multiple Pituitary Hormone Deficiency and Isolated Adrenocorticotropic Deficiency: A Prospective Study: Shintaro Iwama^1*, Tomoko Kobayashi^1*, Tetsushi Izuchi¹, Koji Suzuki¹, Takanori Murase¹, Masahiko Ando², Tomoko Handa¹, Takeshi Onoue¹, Takashi Miyata¹, Mariko Sugiyama¹, Daisuke Hagiwara¹, Hidetaka Suga¹, Ryoichi Banno³, Tetsunari Hase⁴, Shoichiro Mori⁵, Tomoyasu Sano⁶, Shusuke Akamatsu⁶, Masashi Akiyama⁵, Makoto Ishii⁴, Hiroshi Arima¹; DOI: https://doi.org/10.3803/EnM.2024.2180
Published online: February 11, 2025

¹Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan

²Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan

³Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya, Japan

⁴Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan

⁵Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan

⁶Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan

Corresponding authors: Shintaro Iwama. Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan Tel: +81-52-744-2142, Fax: +81-52-744-2206, E-mail: iwama.shintaro.m1@f.mail.nagoya-u.ac.jp

Hiroshi Arima. Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan Tel: +81-52-744-2142, Fax: +81-52-744-2206, E-mail: arima.hiroshi.t6@f.mail.nagoya-u.ac.jp

*These authors contributed equally to this work.

• Received: September 24, 2024 • Revised: November 5, 2024 • Accepted: November 18, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
Supplementary Material
Article information
References

ABSTRACT

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.
Keywords: Hypopituitarism; Adrenocorticotropic hormone deficiency; Immune checkpoint inhibitors; Immunotherapy; Immunerelated adverse event

INTRODUCTION

Cancer immunotherapy with immune checkpoint inhibitors (ICIs) can lead to immune-related adverse events (irAEs), including pituitary dysfunction. This serious irAE may result in adrenal insufficiency [1-3]. The incidence of pituitary dysfunction varies depending on the ICI class used [3-5]. Meta-analyses have shown that the incidence of pituitary dysfunction is higher with anti-cytotoxic T-lymphocyte antigen-4 antibodies (CTLA-4-Abs), ranging from 2% to 6%, compared to less than 1% with anti-programmed cell death-1 antibodies (PD-1-Abs) or anti-programmed cell death-1 ligand 1 antibodies (PD-L1-Abs) [6-11]. Conversely, in our prospective study that involved regular hormone measurements, we found a 24% incidence of pituitary dysfunction (six out of 25 cases) with CTLA-4-Ab monotherapy and 6% (10 out of 167 cases) with PD-1-Ab monotherapy [12]. Therefore, these meta-analyses, which include clinical trials [6-11], may have underestimated the occurrence of pituitary dysfunction, underscoring the importance of regular hormone monitoring during ICI therapy.

Pituitary dysfunction induced by ICIs can be endocrinologically classified into the following two types: multiple pituitary hormone deficiency (Multi-D; impairment of two or more anterior pituitary hormones) and isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) [5,13]. In our prospective study, we conducted regular hormone measurements from baseline and administered pituitary stimulation tests at the onset of pituitary dysfunction. We found that under CTLA-4-Ab monotherapy, the incidence ratio of Multi-D to IAD was 1:1, with each category accounting for 12% (3/25 cases) [12]. In contrast, under PD-1-Ab monotherapy, all cases of pituitary dysfunction were classified as IAD [12].

Recently, the use of combination therapy with PD-1-Ab and CTLA-4-Ab (PD-1/CTLA-4-Abs) has rapidly increased, supplanting CTLA-4-Ab monotherapy, as it has shown superior antitumor effects [14,15]. A prospective registry study at Yale University, which did not include regular measurements of pituitary hormones, found that the incidence of pituitary dysfunction during PD-1/CTLA-4-Abs therapy was 19% (53/277 cases) [16]. This rate is as high as that observed with CTLA-4-Ab monotherapy in our study [12]. However, previous studies that analyzed the clinical features of pituitary dysfunction induced by PD-1/CTLA-4-Abs therapy measured baseline ACTH levels in only about half of the cases [16], and only a few cases received a comprehensive evaluation through pituitary function tests [13,16]. Since no study has yet assessed all pituitary hormones or conducted pituitary stimulation tests to classify the types of pituitary dysfunction induced by PD-1/CTLA-4-Abs therapy, the incidence of Multi-D and IAD under combination therapy remains unknown.

In this prospective study, we investigated the clinical characteristics of pituitary dysfunction induced by combined PD-1/CTLA-4-Abs. We measured baseline levels of all pituitary hormones—ACTH, thyroid-stimulating hormone (TSH), prolactin (PRL), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and growth hormone (GH)—conducted pituitary stimulation tests, and performed magnetic resonance imaging (MRI) at the onset of dysfunction in all affected patients. These features were then compared with those observed in pituitary dysfunction resulting from PD-1-Ab monotherapy.

Patients: Since November 2, 2015, we have been conducting prospective research to analyze irAEs in patients undergoing treatment with ICIs, specifically focusing on the clinical characteristics of endocrine irAEs (Registration No. UMIN000019024). A flow diagram illustrating the patient selection process is presented in Fig. 1. This study included all patients who commenced treatment with PD-1/CTLA-4-Abs or PD-1-Ab at Nagoya University Hospital between November 2, 2015 and November 16, 2022. We excluded patients who either declined to provide informed consent or had a pre-existing pituitary disease. Treatment with ICIs continued until the occurrence of disease progression, death, unacceptable severe adverse events, or withdrawal of consent by the patient. The follow-up period extended until the patients either died or were referred to another facility. The Ethics Committee of Nagoya University Hospital granted approval for this study (Approval No. 2015-0273), and written informed consent was obtained from all participants.
Assessments: To examine pituitary dysfunction, ACTH and cortisol levels were assessed at baseline and every 6 weeks after the first administration of ICI therapy for 24 weeks as described previously [17]. The evaluation period was then changed to 48 weeks due to a minor amendment to the study protocol. ACTH and cortisol levels were tested when pituitary dysfunction was suspected based on symptoms such as fatigue and nausea. After the initial 48 weeks, ACTH and cortisol levels were measured if clinically necessary until the visits stopped. When cortisol levels were low and ACTH levels were low to normal, pituitary MRI and pituitary stimulation tests were performed for a definitive diagnosis. Endocrine irAEs and pituitary dysfunction were defined according to the corresponding Japan Endocrine Society clinical guidelines [3,18]. ACTH deficiency was defined as low or normal ACTH, low cortisol, and decreased peak serum cortisol value (<18 µg/dL) levels and an impaired response of ACTH (<2-fold increase over baseline) in corticotropin-releasing hormone loading tests (intravenous injection of 0.25 mg tetracosactide acetate) [19]. When corticotropin-releasing hormone loading tests were unavailable in Japan (from May 2022 to October 2022), ACTH deficiency was diagnosed based on low resting morning serum cortisol and the absence of elevated plasma ACTH (n=2). TSH deficiency was defined by a low TSH level, low free thyroxine level, and/or the administration of levothyroxine for central hypothyroidism, along with an impaired TSH response (<6 µU/ mL) in TSH-releasing hormone loading tests (intravenous injection with 0.5 mg protirelin). PRL deficiency was identified by a low PRL level and an impaired PRL response (<2-fold increase over baseline) in TSH-releasing hormone loading tests. LH deficiency was characterized by low testosterone/estradiol levels, low or inappropriately normal LH levels, and an impaired LH response (<5-fold increase over baseline and <30 mIU/mL) in LH-releasing hormone (LH-RH)-loading tests (intravenous injection of 0.1 mg gonadorelin). FSH deficiency was defined similarly, with low testosterone/estradiol levels, low or normal FSH levels, and an impaired FSH response (<1.5-fold increase over baseline) in LH-RH-loading tests. Additionally, LH and FSH functions were considered normal if postmenopausal women exhibited elevated basal levels of LH and FSH with a low estradiol level, even if LH or FSH showed impaired responses in the LH-RH loading test. GH deficiency was defined by a low insulin-like growth factor 1 (IGF-1) level and an impaired GH response in GH-releasing hormone loading tests (<3 ng/mL in the GH-releasing factor test [intravenous injection with 100 µg somatrelin] or <9 ng/mL in the GH-releasing peptide-2 [GHRP-2] test [intravenous injection with 100 µg of pralmorelin]) [20]. All stimulation tests were performed in the morning.
Statistical analysis: Statistical analyses were conducted using IBM SPSS Statistics version 29 (IBM, Armonk, NY, USA). Continuous variables, such as age and days to diagnosis, are presented as either the mean±standard deviation or the median (interquartile range). The significance of differences between continuous variables was assessed using the two-sample t test for variables with normal distribution, and the Mann–Whitney U test for those without. Nominal variables were analyzed using the Fisher exact test. All statistical tests were two-sided, with statistical significance set at P<0.05.

The incidence of pituitary dysfunction: During the study period, 831 patients at Nagoya University Hospital began treatment regimens with PD-1/CTLA-4-Abs or PD-1-Ab (Fig. 1). After excluding three patients who declined to provide informed consent and six who had a history of pituitary disease at enrollment, a total of 822 patients were enrolled in the study (PD-1/CTLA-4-Abs: n=74; PD-1-Ab: n=748).; After the initiation of PD-1/CTLA-4-Abs and PD-1-Ab treatments, pituitary dysfunction developed in 16 out of 74 (21.6%) and 25 out of 748 (3.3%) patients, respectively (Table 1). MRI was conducted at the onset of pituitary dysfunction in all 41 affected patients, and 38 (92.7%) of these underwent pituitary stimulation tests. Among these patients, nine treated with PD-1/CTLA-4-Abs and two treated with PD-1-Ab exhibited Multi-D, including ACTH deficiency. Conversely, seven and 23 patients in the respective treatment groups presented with IAD. Both Multi-D (9/74 [12.2%] vs. 2/748 [0.3%], P<0.001) (Table 1) and IAD (7/74 [9.5%] vs. 23/748 [3.1%], P=0.014) (Table 1) occurred significantly more frequently in the PD-1/CTLA-4-Abs group than in the PD-1-Ab group.
The clinical characteristics of pituitary dysfunction: The clinical characteristics of the patients who developed pituitary dysfunction are shown in Table 2. Of the 16 patients who developed pituitary dysfunction after PD-1/CTLA-4-Abs treatment, six exhibited pituitary enlargement, all of whom had Multi-D (Table 2, Fig. 2A). Conversely, 10 patients showed normal pituitary MRI results (Fig. 2B); of these, seven had IAD and three had Multi-D. In contrast, none of the 25 patients who developed pituitary dysfunction after PD-1-Ab treatment presented with pituitary enlargement (Fig. 2C). The prevalence of pituitary enlargement (37.5% vs. 0%, P=0.002) and Multi-D (56.3% vs. 8.0%, P=0.001) was significantly higher in patients treated with PD-1/CTLA-4-Abs than in those treated with PD-1-Ab (Table 2). ACTH secretion was impaired in all 41 patients. Additionally, impairments in LH (8/16), FSH (6/16), and TSH (4/16) were more common in patients treated with PD-1/CTLA-4-Abs. The incidence rates of LH, FSH, and TSH deficiencies were significantly higher in this group than in those treated with PD-1-Ab, while there were no significant differences in PRL or GH deficiencies between the two groups (Table 2). Two patients treated with PD-1-Ab monotherapy presented with Multi-D. One had a low IGF-1 level, with a peak GH level of 8.4 ng/mL (<9 ng/mL) in the GHRP-2 test. The other had a low estradiol level, a 3.8-fold increase in LH level compared to baseline (<5-fold), and a 1.2-fold increase in FSH level compared to baseline (<1.5-fold) in the LH-RH test. The time to diagnosis of pituitary dysfunction after starting ICIs was significantly shorter with PD-1/CTLA-4-Abs treatment than with PD-1-Ab treatment (88 days vs. 168 days, P=0.012) (Table 2). There were no significant differences in sex, tumor type, or prior ICI treatment usage between the two groups (Table 2).
Comparison of clinical characteristics of patients with IAD receiving PD-1/CTLA-4-Abs vs. PD-1-Ab treatment: The clinical characteristics of patients who developed IAD are presented in Table 3. There were no significant differences in the examined parameters between the two groups, with the exception of tumor type (Table 3).
Comparison of the clinical characteristics of patients with Multi-D vs. IAD under PD-1/CTLA-4-Abs treatment: Next, we examined the differences in clinical characteristics between patients treated with PD-1/CTLA-4-Abs who developed Multi-D versus those with IAD. The prevalence of pituitary enlargement was significantly higher in the Multi-D group than in the IAD group (6/9 [66.7%] vs. 0/7 [0%], P=0.011) (Table 4). Additionally, there was a notable difference in the type of malignancy between the two groups. Specifically, the prevalence of malignant melanoma (MM) was significantly higher in the Multi-D group than in the IAD group (5/9 [55.6%] vs. 0/7 [0%], P=0.034). The proportion of patients receiving a high-dose ipilimumab (3 mg/kg) regimen was also significantly higher in the Multi-D group than in the IAD group (5/9 [55.6%] vs. 0/7 [0%], P=0.034). This is because the 3 mg/kg ipilimumab regimen is only approved for MM in Japan. Furthermore, the cumulative dose of ipilimumab administered was significantly higher in the Multi-D group than in the IAD group (5.8±3.5 mg/kg vs. 2.4±1.0 mg/kg, P=0.021). There was no significant difference in the number of treatment cycles for each drug or in the time to diagnosis of pituitary dysfunction following the initiation of ICI therapy.; The clinical characteristics of patients experiencing pituitary dysfunction while undergoing PD-1/CTLA-4-Abs treatment are shown in Supplemental Table S1, categorized by whether they had pituitary enlargement. The prevalence of Multi-D was significantly higher among patients with pituitary enlargement than among those without (100.0% [6/6] vs. 30.0% [3/10], P=0.011). Additionally, the time to diagnose pituitary dysfunction after initiating ICI treatment was significantly shorter for patients with pituitary enlargement than for those without (67.5 days vs. 136 days, P=0.030).

DISCUSSION

This prospective study examined in detail the clinical characteristics of pituitary dysfunction induced by PD-1/CTLA-4-Abs through regular measurements of ACTH and cortisol following the initiation of PD-1/CTLA-4-Abs treatment. It also included assessments of all anterior pituitary hormones, along with pituitary function tests and MRI at the onset of pituitary dysfunction. The findings indicated that the clinical characteristics differed from those resulting from PD-1-Ab treatment in terms of incidence, time to onset, and patterns of hormone impairment.

The reported incidence of pituitary dysfunction induced by combination therapy with CTLA-4-Ab and PD-1-Ab or PD-L1-Ab varies widely among meta-analyses [6-10], ranging from 0.52% [8] to 10.5% [7]. This discrepancy is likely due to variations in the frequency and type of the hormone tests performed. In this prospective study, which included regular measurements of ACTH and cortisol, the exact incidence of pituitary dysfunction was determined to be 21.6% when using PD-1/CTLA-4-Abs therapy. This study also corroborated previous findings that pituitary dysfunction tends to occur earlier during PD-1/CTLA-4-Abs therapy than with PD-1-Ab monotherapy [16].

Pituitary dysfunction induced by ICIs can be classified into two types: Multi-D and IAD [5,13]. However, no studies have evaluated all pituitary hormones or performed pituitary MRI at the time of onset in all cases of PD-1/CTLA-4-Abs-induced pituitary dysfunction [13,16,21,22]. Furthermore, pituitary function tests have been performed only in a limited number of cases [23]. In our previous study, where we performed pituitary function tests on all patients, CTLA-4-Ab monotherapy frequently led to pituitary dysfunction (six of 25 [24.0%] cases), which included Multi-D with pituitary enlargement (12.0%) and IAD (12.0%). In contrast, PD-1-Ab monotherapy resulted in only IAD, occurring at a lower rate (10 of 167 [6.0%] cases)] [12]. This study is the first to report the incidences of Multi-D and IAD induced by PD-1/CTLA-4-Abs (12.2% and 9.5%, respectively), similar to those seen with CTLA-4-Ab monotherapy. The risk of pituitary dysfunction induced by PD-1/CTLA-4-Abs did not demonstrate an additive or synergistic effect compared to the risk associated with each drug individually, suggesting a common mechanism underlying the pituitary dysfunction caused by each drug. In contrast, PD-1/CTLA-4-Abs treatment had a synergistic effect on the risk of ICI-induced thyroid dysfunction [24]. Specifically, ICI-induced thyroid dysfunction was more likely with PD-1-Ab or PD-L1-Ab therapy [17,25-28], while it rarely occurred with CTLA-4-Ab monotherapy (0%) [24]. However, the risk was higher with PD-1/CTLA-4-Abs combination therapy (37.0%) than with PD-1-Ab monotherapy (9.9%) [24]. In future research, we hope to elucidate the differences in mechanism between irAEs that show a synergistic increase in risk induced by PD-1/CTLA-4-Abs and those that do not.

In this study, we determined the types of impaired pituitary hormones for the first time by using results from pituitary stimulation tests. A previous study that reviewed 128 cases of pituitary dysfunction induced by CTLA-4-Ab (ipilimumab or tremelimumab) found the following incidences of impaired function: ACTH at 91% (85/93), TSH at 84% (80/95), gonadotropin at 83% (65/78), PRL at 9% (5/53), and GH at 42% (13/31) [21]. It has been reported that TSH-producing and gonadotropin-producing cells express CTLA-4 protein [21], and that complement activation, which leads to pituitary inflammation, is induced by the direct action of administered CTLA-4-Ab [29]. Therefore, the expression of CTLA-4 in TSH-producing and gonadotropin-producing cells might explain the high incidence of dysfunction in these hormones. However, it remains unclear why ACTH deficiency is the most frequent despite the absence of CTLA-4 expression in ACTH-producing cells [21,29]. Given that ACTH deficiency is also common in lymphocytic hypophysitis, an autoimmune disease of the anterior pituitary gland [30], it is possible that autoantigens recognized by the immune system are present within corticotrophs. Another study reported a high incidence of impaired TSH (60.0% [12/20]) and gonadotropin (55.6% [5/9]) under PD-1/CTLA-4-Abs treatment [13]. A prospective study analyzing the clinical characteristics of 69 patients with pituitary dysfunction found incidences of ACTH deficiency, TSH deficiency, low testosterone, and low LH/FSH at 100%, 36%, 71%, and 45% respectively in patients treated with PD-1/CTLA-4-Abs, and 100%, 17%, 22%, and 50% respectively in patients treated with PD-1-Ab [16]. However, that prospective study did not measure baseline levels of every pituitary hormone in all cases; for example, ACTH and testosterone were measured at the onset of pituitary dysfunction in only 51% (35/69) and 43% (20/47) of cases, respectively [16]. This study confirmed that ACTH deficiency was observed in all cases and clarified that the incidences of other anterior pituitary dysfunctions were not as frequent as previously reported. This suggests that hormone replacement therapies, except for hydrocortisone replacement, should be initiated based on careful evaluations, including pituitary stimulation tests.

We also demonstrated that treatment with PD-1/CTLA-4-Abs can induce Multi-D without causing pituitary enlargement. Although the underlying pathologies of Multi-D with and without pituitary enlargement may differ, the absence of observed enlargement could be due to either mild enlargement or delayed MRI timing. Additionally, two cases of Multi-D were induced by PD-1-Ab monotherapy. In these instances, each case showed a certain level of response in the GHRP-2 and LH-RH tests, respectively. Considering that aging attenuates the response to gonadotropin-releasing hormone [31] and GH-releasing hormone [32], the Multi-D observed in the two patients (a 74-year-old woman and 73-year-old man) could potentially be redefined under future diagnostic criteria that take age into account.

Among patients with pituitary dysfunction induced by PD-1/CTLA-4-Abs, the prevalence of MM and the administration of high-dose (3 mg/kg) ipilimumab were significantly higher in the Multi-D group than in the IAD group, respectively. However, in Japan, a high-dose (3 mg/kg) regimen of ipilimumab is approved only for MM [33], while a low-dose (1 mg/kg) regimen is approved for non-small cell lung carcinoma [34], renal cell carcinoma [35], and mesothelioma [36]. Given that the incidence of irAEs was reported to increase in a dose-dependent manner under ipilimumab treatment [37], the impairment of pituitary function induced by ipilimumab may also be dose-dependent. If this is the case, robust complement activation may be induced in the pituitary following direct binding of injected CTLA-4-Ab [21,29,38]. As relates to possible associations between the cancer type and pituitary dysfunction, it has been reported that the incidence of pituitary dysfunction under PD-1/CTLA-4-Abs treatment was higher in patients with MM (25% [46/187]) than in those with renal cell carcinoma (9% [7/77]) [16], suggesting that shared antigens between melanoma and pituitary tissue are recognized by the immune system after CTLA-4 blockade. In addition, the time to diagnosis of pituitary dysfunction after ICI initiation and the prevalence of Multi-D showed significant associations with pituitary enlargement, suggesting that the pathogenesis varies between cases with and those without pituitary enlargement.

This study has some limitations. First, the number of patients treated with PD-1/CTLA-4-Abs was not large. In particular, further research with a larger cohort is needed to clarify the association between the cancer type or ipilimumab dose and the clinical characteristics of pituitary dysfunction. Second, it was not possible to determine the differences in the clinical characteristics of pituitary dysfunction between the PD-1/CTLA-4-Abs and CTLA-4-Ab monotherapy cases. This study did not include patients treated with CTLA-4-Ab monotherapy due to the small sample size, as ipilimumab monotherapy is rarely used at present. Third, the interpretation of pituitary stimulation tests did not take into account the patient’s age or general condition.

In conclusion, this prospective study involving pituitary stimulation tests and MRI demonstrated a high risk of both Multi-D and IAD under PD-1/CTLA-4-Abs treatment, indicating the importance of careful monitoring and evaluation of pituitary hormone impairment.

Supplementary Material

Supplemental Table S1.

Clinical Characteristics of Patients Who Developed Pituitary Dysfunction under PD-1/CTLA-4-Abs Treatment with Pituitary Enlargement and Those without It

enm-2024-2180-Supplemental-Table-S1.pdf

Article information

CONFLICTS OF INTEREST

Shintaro Iwama received personal fees from Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., and MSD K.K. outside of this study. Tomoko Handa received personal fees from AstraZeneca K.K., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., MSD K.K., Merck Biopharma Co. Ltd., Pfizer Inc., and Eli Lilly Japan K.K., and grants from Novartis Pharma K.K., AstraZeneca K.K., BeiGene Inc., AbbVie Inc., Amgen Co. Ltd., and Chugai Pharmaceutical Co. Ltd., outside of this study. Shoichiro Mori received research funding from MSD K.K. for a clinical trial outside of this study. Makoto Ishii reports research funding from Nippon Boehringer Ingelheim Co., Ltd. outside of this study and lecture fees from Shionogi & Co., Ltd. and AstraZeneca K.K. outside of this study. Hiroshi Arima received grants from Ono Pharmaceutical Co., Ltd., MSD K.K., and Chugai Pharmaceutical Co., Ltd., and personal fees from Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb, and MSD K.K. outside of this study. The remaining authors have nothing to disclose.

AUTHOR CONTRIBUTIONS

Conception or design: S.I. Acquisition, analysis, or interpretation of data: S.I., T.K., T.I., K.S., T.M., M.A., T.H., T.O., T.M., M.S., D. H., H.S., R.B., T.H., S.M., T.S., S.A., M.A., M.I., H.A. Drafting the work or revising: S.I., T.K., H.A. Final approval of the manuscript: S.I., T.K., T.I., K.S., T.M., M.A., T.H., T.O., M.S., D. H., H.S., R.B., T.H., S.M., T.S., S.A., M.A., M.I., H.A.

Acknowledgements

This work was supported in part by JSPS KAKENHI Grant Number JP 23K24386 Shintaro Iwama.

Fig. 1.

Enrollment of the study subjects. PD-1/CTLA-4-Abs, PD-1- Ab plus CTLA-4-Ab combination therapy; PD-1-Ab, anti-programmed cell death-1 antibody; CTLA-4-Ab, anti-cytotoxic T-lymphocyte antigen-4 antibody.

Fig. 2.

Magnetic resonance imaging (MRI) of the pituitary gland in patients with pituitary dysfunction. Representative MRI from a patient who developed multiple pituitary hormone deficiencies after anti-programmed cell death-1 antibody (PD-1-Ab) plus anti-cytotoxic T-lymphocyte antigen-4 antibody (CTLA-4-Ab) combination therapy (PD-1/CTLA-4-Abs) show that the pituitary gland was enlarged and enhanced heterogeneously (A, left: plain, right: contrast). Representative MRI scans from a patient who developed isolated adrenocorticotropic hormone deficiency (IAD) after PD-1/CTLA-4-Abs show a normal-sized pituitary gland enhanced homogeneously (B, left: plain, right: contrast). Representative MRI images from a patient who developed IAD after PD-1-Ab show a normal- sized pituitary gland enhanced homogeneously (C, left: plain, right: contrast).

Table 1.

The Frequency of Pituitary Dysfunction in Patients Treated with PD-1/CTLA-4-Abs and PD-1-Ab

	PD-1/CTLA-4-Abs (n=74)	PD-1-Ab (n=748)	P value
Pituitary dysfunction	16 (21.6)	25 (3.3)	<0.001
Multi-D	9 (12.2)	2 (0.3)	<0.001
IAD	7 (9.5)	23 (3.1)	0.014

Values are expressed as number (%).

PD-1/CTLA-4-Abs, PD-1-Ab plus CTLA-4-Ab combination therapy; PD-1-Ab, anti-programmed cell death-1 antibody; CTLA-4-Ab, anticytotoxic T-lymphocyte antigen-4 antibody; Multi-D, multiple pituitary hormone deficiency; IAD, isolated adrenocorticotropic hormone deficiency.

Table 2.

Clinical Characteristics of Patients Who Developed Pituitary Dysfunction under PD-1/CTLA-4-Abs or PD-1-Ab Treatment

Characteristic	PD-1/CTLA-4-Abs (n=16)	PD-1-Ab (n=25)	P value
Sex, male/female	12/4	15/10	0.501
Malignancy			0.133
MM	5 (31.2)	7 (28.0)
NSCLC	4 (25.0)	10 (40.0)
RCC	4 (25.0)	2 (8.0)
Mesothelioma	3 (18.8)	0
Esophageal cancer	0	2 (8.0)
Uterine cancer	0	1 (4.0)
Head and neck cancer	0	2 (8.0)
Breast cancer	0	1 (4.0)
Age, yr	71 (64–76)	68 (63–74)	0.375
Prior ICI treatment	2 (12.5)	3 (12.0)	>0.999
Pituitary enlargement	6 (37.5)	0	0.002
Multiple pituitary hormone deficiency	9 (56.3)	2 (8.0)	0.001
Hormone deficiency
ACTH	16 (100)	25 (100)	>0.999
TSH	4 (25.0)	0	0.018
LH	8 (50.0)	1 (4.0)	0.001
FSH	6 (37.5)	1 (4.0)	0.009
PRL	1 (6.3)	0	0.390
GH	1 (6.3)	1 (4.0)	>0.999
Onset, day	88 (69–155)	168 (116–239)	0.012

Values are expressed as median (interquartile range) or number (%).

PD-1/CTLA-4-Abs, PD-1-Ab plus CTLA-4-Ab combination therapy; PD-1-Ab, anti-programmed cell death-1 antibody; CTLA-4-Ab, anti-cytotoxic T-lymphocyte antigen-4 antibody; MM, malignant melanoma; NSCLC, non-small cell lung carcinoma; RCC, renal cell carcinoma; ICI, immune checkpoint inhibitor; ACTH, adrenocorticotropic hormone; TSH, thyroid-stimulating hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; PRL, prolactin; GH, growth hormone.

Table 3.

Clinical Characteristics of Patients Who Developed IAD under PD-1/CTLA-4-Abs or PD-1 Ab Treatment

Characteristic	PD-1/CTLA-4-Abs (n=7)	PD-1-Ab (n=23)	P value
Sex, male/female	7/0	14/9	0.071
Malignancy			0.033
MM	0	7 (30.4)
NSCLC	2 (28.6)	9 (39.1)
RCC	2 (28.6)	2 (8.7)
Mesothelioma	3 (42.9)	0
Esophageal cancer	0	1 (4.3)
Uterine cancer	0	1 (4.3)
Head and neck cancer	0	2 (8.7)
Breast cancer	0	1 (4.3)
Age, yr	66 (61–75)	67 (62–74)	>0.999
Prior ICI treatment	0	3 (13.0)	>0.999
Onset, day	133 (74–158)	149 (114–231)	0.207

Values are expressed as median (interquartile range) or number (%).

IAD, isolated adrenocorticotropic hormone deficiency; PD-1/CTLA-4-Abs, PD-1-Ab plus CTLA-4-Ab combination therapy; PD-1-Ab, antiprogrammed cell death-1 antibody; CTLA-4-Ab, anti-cytotoxic T-lymphocyte antigen-4 antibody; MM, malignant melanoma; NSCLC, nonsmall cell lung carcinoma; RCC, renal cell carcinoma; ICI, immune checkpoint inhibitor.

Table 4.

Clinical Characteristics of Patients Who Developed Pituitary Dysfunction under PD-1/CTLA-4-Abs Treatment

Hormone deficiency	Multi-D (n=9)	IAD (n=7)	P value
Pituitary enlargement	6 (66.7)	0	0.011
Malignancy			0.049
MM	5 (55.6)	0
NSCLC	2 (22.2)	2 (28.6)
RCC	2 (22.2)	2 (28.6)
Mesothelioma	0	3 (42.9)
Ipilimumab			0.034
3 mg/kg	5 (55.6)	0
1 mg/kg	4 (44.4)	7 (100)
Ipilimumab cumulative dose, mg/kg	5.8±3.5	2.4±1.0	0.021
No. of cycles, times
Ipilimumab	2.8±1.2	2.9±0.9	0.886
Nivolumab	3.0 (2.0–6.0)	4.0 (3.0–7.0)	0.408
Onset, day	81 (55–154)	133 (74–158)	0.470

Values are expressed as number (%), mean±standard deviation, or median (interquartile range).

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Combined PD-1 and CTLA-4 Blockade Increases the Risks of Multiple Pituitary Hormone Deficiency and Isolated Adrenocorticotropic Deficiency: A Prospective Study

Fig. 1. Enrollment of the study subjects. PD-1/CTLA-4-Abs, PD-1- Ab plus CTLA-4-Ab combination therapy; PD-1-Ab, anti-programmed cell death-1 antibody; CTLA-4-Ab, anti-cytotoxic T-lymphocyte antigen-4 antibody.

Fig. 2. Magnetic resonance imaging (MRI) of the pituitary gland in patients with pituitary dysfunction. Representative MRI from a patient who developed multiple pituitary hormone deficiencies after anti-programmed cell death-1 antibody (PD-1-Ab) plus anti-cytotoxic T-lymphocyte antigen-4 antibody (CTLA-4-Ab) combination therapy (PD-1/CTLA-4-Abs) show that the pituitary gland was enlarged and enhanced heterogeneously (A, left: plain, right: contrast). Representative MRI scans from a patient who developed isolated adrenocorticotropic hormone deficiency (IAD) after PD-1/CTLA-4-Abs show a normal-sized pituitary gland enhanced homogeneously (B, left: plain, right: contrast). Representative MRI images from a patient who developed IAD after PD-1-Ab show a normal- sized pituitary gland enhanced homogeneously (C, left: plain, right: contrast).

Fig. 1.

Fig. 2.

Combined PD-1 and CTLA-4 Blockade Increases the Risks of Multiple Pituitary Hormone Deficiency and Isolated Adrenocorticotropic Deficiency: A Prospective Study

	PD-1/CTLA-4-Abs (n=74)	PD-1-Ab (n=748)	P value
Pituitary dysfunction	16 (21.6)	25 (3.3)	<0.001
Multi-D	9 (12.2)	2 (0.3)	<0.001
IAD	7 (9.5)	23 (3.1)	0.014

Characteristic	PD-1/CTLA-4-Abs (n=16)	PD-1-Ab (n=25)	P value
Sex, male/female	12/4	15/10	0.501
Malignancy			0.133
MM	5 (31.2)	7 (28.0)
NSCLC	4 (25.0)	10 (40.0)
RCC	4 (25.0)	2 (8.0)
Mesothelioma	3 (18.8)	0
Esophageal cancer	0	2 (8.0)
Uterine cancer	0	1 (4.0)
Head and neck cancer	0	2 (8.0)
Breast cancer	0	1 (4.0)
Age, yr	71 (64–76)	68 (63–74)	0.375
Prior ICI treatment	2 (12.5)	3 (12.0)	>0.999
Pituitary enlargement	6 (37.5)	0	0.002
Multiple pituitary hormone deficiency	9 (56.3)	2 (8.0)	0.001
Hormone deficiency
ACTH	16 (100)	25 (100)	>0.999
TSH	4 (25.0)	0	0.018
LH	8 (50.0)	1 (4.0)	0.001
FSH	6 (37.5)	1 (4.0)	0.009
PRL	1 (6.3)	0	0.390
GH	1 (6.3)	1 (4.0)	>0.999
Onset, day	88 (69–155)	168 (116–239)	0.012

Characteristic	PD-1/CTLA-4-Abs (n=7)	PD-1-Ab (n=23)	P value
Sex, male/female	7/0	14/9	0.071
Malignancy			0.033
MM	0	7 (30.4)
NSCLC	2 (28.6)	9 (39.1)
RCC	2 (28.6)	2 (8.7)
Mesothelioma	3 (42.9)	0
Esophageal cancer	0	1 (4.3)
Uterine cancer	0	1 (4.3)
Head and neck cancer	0	2 (8.7)
Breast cancer	0	1 (4.3)
Age, yr	66 (61–75)	67 (62–74)	>0.999
Prior ICI treatment	0	3 (13.0)	>0.999
Onset, day	133 (74–158)	149 (114–231)	0.207

Hormone deficiency	Multi-D (n=9)	IAD (n=7)	P value
Pituitary enlargement	6 (66.7)	0	0.011
Malignancy			0.049
MM	5 (55.6)	0
NSCLC	2 (22.2)	2 (28.6)
RCC	2 (22.2)	2 (28.6)
Mesothelioma	0	3 (42.9)
Ipilimumab			0.034
3 mg/kg	5 (55.6)	0
1 mg/kg	4 (44.4)	7 (100)
Ipilimumab cumulative dose, mg/kg	5.8±3.5	2.4±1.0	0.021
No. of cycles, times
Ipilimumab	2.8±1.2	2.9±0.9	0.886
Nivolumab	3.0 (2.0–6.0)	4.0 (3.0–7.0)	0.408
Onset, day	81 (55–154)	133 (74–158)	0.470

Table 1. The Frequency of Pituitary Dysfunction in Patients Treated with PD-1/CTLA-4-Abs and PD-1-Ab

Values are expressed as number (%).

Table 2. Clinical Characteristics of Patients Who Developed Pituitary Dysfunction under PD-1/CTLA-4-Abs or PD-1-Ab Treatment

Values are expressed as median (interquartile range) or number (%).

Table 3. Clinical Characteristics of Patients Who Developed IAD under PD-1/CTLA-4-Abs or PD-1 Ab Treatment

Values are expressed as median (interquartile range) or number (%).

Table 4. Clinical Characteristics of Patients Who Developed Pituitary Dysfunction under PD-1/CTLA-4-Abs Treatment

Values are expressed as number (%), mean±standard deviation, or median (interquartile range).

Articles

ABSTRACT

INTRODUCTION

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DISCUSSION

Supplementary Material

Supplemental Table S1.

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Figure & Data

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Fig. 1.

Fig. 2.

Table 1.

Table 2.

Table 3.

Table 4.