Nivolumab induced hypophysitis in an advanced RCC patient

Introduction

Immune checkpoint inhibitors (ICIs) are being commonly used to treat solid tumours. ¹ Drugs used as immunotherapy agents include cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors (ipilimumab and tremelimumab), programmed death-1 (PD-1) inhibitors (nivolumab and pembrolizumab), and programmed death ligand 1 (PD-L1) inhibitors (atezolizumab, avelumab, and durvalumab). Nivolumab is a monoclonal antibody of immunoglobulin G4 type which targets the PD-1 receptor. It was approved by the United States Food and Drug Administration (FDA) in October 2015 for patients with metastatic renal cell carcinoma (mRCC) based on the CheckMate 025 trial that showed improvement in overall survival as compared to everolimus in patients who progressed on sunitinib or pazopanib treatment. ²

The main immune-related adverse events (irAEs) associated with nivolumab include diarrhea, colitis, hepatitis, pneumonitis, skin toxicities, and endocrinopathies such as hypophysitis, diabetes mellitus, and thyroid dysfunction. Although thyroid dysfunction is a frequent adverse effect of nivolumab, hypophysitis is rare with an incidence of less than 1% and only a handful of cases of nivolumab induced hypophysitis in patients with mRCC have been described in the literature.^1,3 Usually, such cases present with fewer symptoms and radiological features as compared to other immunotherapy related hypophysitis. ³ We present a novel case of a patient with mRCC who was diagnosed with nivolumab induced hypophysitis based on clinical suspicion due to his hormonal profile and a range of symptoms that he developed during nivolumab immunotherapy.

Case report

A 67-year-old male, who was first diagnosed with clear cell carcinoma of the left kidney in July 2018, underwent left radical nephrectomy and retroperitoneal lymph node dissection. The patient was followed up with the diagnosis of stage 3 renal cell carcinoma. Multiple metastatic nodules were detected in the bilateral lung parenchyma in the routine radiological imaging performed 8 months after the surgery. He received first-line sunitinib 50 mg/day (four weeks on two weeks off treatment) for ten months as first line treatment. Hypothyroidism and pretibial edema were observed as sunitinib side effects and levothyroxine sodium 100 mcg/day was started. After the progression of the disease axitinib was initiated as second line treatment in February 2020. After the third progression of the disease, nivolumab 240 mg, every two weeks, was introduced in August 2020 and partial remission was detected. By January 2021 he had completed 12 cycles of nivolumab immunotherapy and had complaints of fatigue, increased sleepiness, and headaches during his office visits. Hemogram and other laboratory tests were normal.(Table 1) His thyroid profile showed normal thyroid stimulating hormone (TSH) and thyroid hormone (T4) levels. The patient received one more treatment with nivolumab in mid-January. On continuing with the same treatment in February 2021, he complained of frequent episodes of syncope and nausea. Brain magnetic resonance imaging (MRI) did not show any metastatic lesion. Since nivolumab is known to cause endocrine irAEs such as hypophysitis, albeit rarely, a hormonal examination was performed. (Table 2) ACTH and cortisol levels, as well as dehydroepiandrosterone sulfate levels were low. Insulin-like growth factor-1 (IGF-1) levels were also low and this may have been due to malnutrition. In contrast, prolactin levels were slightly elevated. Basal LH and FSH levels as well as testosterone levels were normal. Based on these laboratory findings, we suspected nivolumab-induced hypophysitis associated with an ACTH deficiency in this case. Sodium, potassium, glucose and hemogram were rechecked prior to initiation of steroid therapy and did not show any metabolic abnormalities.

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Table 1.

Hematological and biochemical findings on admission.

Hct	42.7% (40–52)
Hb	14.3 g/dL (13.2–17.3)
RBC	449  ×  104 /μL (402–570)
WBC	9.100 /μL (4000–9600)
Neutro	54.4% (42.2–73.2)
Lymph	36.9% (20.1–47.3)
Eosino	1.7% (0.5–7.3)
Plt	21,5 x104 /μL (16–35)
BG	88 mg/dL (80–110)
TP	6.9 g/dL (6.3–7.9)
Alb	4.3 g/dL (3.9–5.0)
T-bil	0.6 mg/dL (0.3–1.2)
AST	20 U/L (13–33)
ALT	19 U/L (8–42)
LDH	257 U/L (119–229)
ALP	174 U/L (115–359)
γGTP	24 U/L (10–47)
BUN	14 mg/dL (8–20)
Cr	0.92 mg/dL (0.65–1.07)
Na	138 mEq/L (137–145)
K	4.7 mEq/L (3.5–4.8)
Cl	106 mEq/L (100–107)

Hct, hematocrit; Hb, hemoglobin; RBC, red blood cell; WBC, white blood cell; Neutro, neutrophil; Lymph, lymphocyte; eosino, eosinophil; Plt, platelet; BG, blood glucose;TP, total protein; Alb, albumin; T-Bil, total bilirubin; D-Bil, direct bilirubin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; ALP, alkaline phosphatase; γGTP, γ-glutamyl transpeptidase; CK, creatine kinase; BUN, blood urea nitrogen; Cr, creatinine. Normal ranges are shown in parentheses.

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Table 2.

Endocrinological Findings on admission.

ACTH	4 pg/mL (7.2–63.3)
Cortisol	0.05 μg/dL (2.3–19.4)
GH	0.1 ng/mL (< 2.1)
IGF-1	32 ng/mL (70–219)
PRL	17.9 ng/mL (3.58–12.78)
TSH	3.39 μU/mL (0.35–4.94)
FT4	1.01 ng/dL (0.7–1.48)
FT3	3.35 pg/mL (1.71–3.71)
LH	7.7 mIU/mL (0.79–5.72)
FSH	10.3 mIU/mL (2.3–22.1)
DHEAS	96.7 ng/mL (240–2440)
Testosterone	3.47 ng/mL (1.31–8.71)

DHEAS, dehydroepiandrosterone sulfate; GH, growth hormone; IGF-1, insulin-like growth factor-1; PRL, prolactin.

A high dose of hydrocortisone (60 mg/d) was promptly administered intravenously. His general condition improved during the next few days, and the i.v. administration of hydrocortisone was changed to the oral route (20 mg/d) on d5, and was subsequently reduced to 10 mg/d on d10. Pituitary MRI indicated diffuse enlargement of the pituitary gland with loss of normal posterior pituitary signal intensity which were compatible with nivolumab induced hypophysitis and excluded pituitary metastasis of mRCC or pituitary adenoma (Figure 1A–B). Nivolumab was continued in the patient who received a replacement dose of hydrocortisone and he still maintains partial response. Informed consent was obtained from the patient.

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Figure 1.

(a) Precontrast T1-weighted MR image shows diffuse enlargement of the pituitary gland with loss of normal posterior pituitary signal intensity. (b) Postcontrast T1-weighted MR image of the brain reveals diffuse enlargement of the infundibulum and minimal heterogeneous enhancement of the pituitary gland.

Discussion

ICIs have revolutionized the treatment of cancers including mRCC. With increasing experience and ongoing studies assessing the efficacy and safety of agents such as ipilimumab, nivolumab, avelumab, and pembrolizumab, the initiation of such treatments can be confidently made. Growing awareness of the potential side effects has also led to the development of adverse event treatment guidelines.^1,3

Hypophysitis is an acute or chronic inflammation of the pituitary gland and it is a rare condition in the general population. ICI associated hypophysitis is commonly presented with headache and anterior hypopituitarism. Anterior hypopituitarism presents with a characteristic but atypical pattern of deficiency of ACTH followed by TSH, gonadotrophins, and prolactin deficiency or hyperprolactinemia. Pituitary enlargement is generally mild and compression of the optic apparatus is extremely rare. ⁴

Before nivolumab, hypophysitis was relatively common in patients prescribed ipilimumab, a human monoclonal antibody against the CTLA-4. A review summarizing large cohorts of ipilimumab-treated malignant melanoma patients suggested that the incidence of ipilimumab-induced hypophysitis was approximately 10–15%. ⁵ In contrast to its stronger relationship with hypophysitis in patients treated with ipilimumab, the incidence of nivolumab or pembrolizumab induced hypophysitis is markedly lower (< 1%). Nivolumab induced hypophysitis is diagnosed late (median of 6 months) and is less commonly associated with any symptoms like headache or any pituitary changes detected on MRI. Our patient presented with a range of symptoms (fatigue, headache, sleepiness, nausea, syncope) as well as laboratory confirmation of central adrenal deficiency in the sixth month of nivolumab treatment. ⁵

We also assessed causality between nivolumab and hypophysitis using the Naranjo adverse drug reaction probability scale. ⁶ We obtained a score of 7 for nivolumab with a probable adverse drug reaction score of 5 to 8.

Patients with immunotherapy related hypophysitis have been managed with physiologic to high-dose glucocorticoids resulting in improvement of symptoms and pituitary function. In most patients, the steroids and other hormone replacements, like for thyroid, need to be maintained till the end of immunotherapy or even after the end of immunotherapy as the recovery rate is variable.

Nivolumab induced hypophysitis is an uncommon condition that usually presents with fewer symptoms. A normal MRI of the brain does not eliminate hypophysitis. Hence, a high degree of clinical suspicion and a multidisciplinary team involving medical oncologists, clinical pharmacologists, endocrinologists, and radiologists is required to diagnose and treat such cases.