Pituitary immune-related adverse events induced by
programmed cell death protein 1 inhibitors in advanced
lung cancer patients: A report of 3 cases SUMMARY
Programmed cell death protein 1 (PD-1) and its
ligand 1 (PD-L1) have been widely used in
lung cancer treatment, but their immune-related adverse events (irAEs) require intensive attention. Pituitary irAEs, including
hypophysitis and
hypopituitarism, are commonly induced by
cytotoxic T lymphocyte antigen 4 inhibitors, but rarely by PD-1/
PD-L1 inhibitors. Isolated
adrenocorticotropic hormone(
ACTH) deficiency (IAD) is a special subtype of pituitary irAEs, without any other pituitary
hormone dysfunction, and with no enlargement of pituitary gland, either. Here, we described three patients with advanced
lung cancer who developed IAD and other irAEs, after
PD-1 inhibitor treatment. Case 1 was a 68-year-old male diagnosed with metastatic
lung adenocarcinoma with high expression of PD-L1. He was treated with
pembrolizumab monotherapy, and developed immune-related
hepatitis, which was cured by high-dose
methylprednisolone [0.5-1.0 mg/(kg·d)]. Eleven months later, the patient was diagnosed with primary gastric
adenocarcinoma, and was treated with
apatinib, in addition to
pembrolizumab. After 17 doses of
pembrolizumab, he developed severe
nausea and
asthenia, when
methylprednisolone had been stopped for 10 months. His blood tests showed severe
hyponatremia (121 mmol/L, reference 137-147 mmol/L, the same below), low levels of 8:00 a.m.
cortisol (< 1 μg/dL, reference 5-25 μg/dL, the same below) and
ACTH (2.2 ng/L, reference 7.2-63.3 ng/L, the same below), and normal thyroid function,
sex hormone and
prolactin. Meanwhile, both his
lung cancer and
gastric cancer remained under good control. Case 2 was a 66-year-old male with metastatic
lung adenocarcinoma, who was treated with a new
PD-1 inhibitor, HX008, combined with
chemotherapy (clinical trial number: CTR20202387). After 5 months of treatment (7 doses in total), his
cancer exhibited partial response, but his
nausea and
vomiting suddenly exacerbated, with mild
dyspnea and weakness in his lower limbs. His blood tests showed mild
hyponatremia (135 mmol/L), low levels of 8:00 a.m.
cortisol (4.3 μg/dL) and
ACTH (1.5 ng/L), and normal thyroid function. His thoracic computed tomography revealed moderate immune-related
pneumonitis simultaneously. Case 3 was a 63-year-old male with locally advanced
squamous cell carcinoma. He was treated with first-line
sintilimab combined with
chemotherapy, which resulted in partial response, with mild immune-related
rash. His
cancer progressed after 5 cycles of treatment, and
sintilimab was discontinued. Six months later, he developed asymptomatic hypoadrenocorticism, with low level of
cortisol (1.5 μg/dL) at 8:00 a.m. and unresponsive
ACTH (8.0 ng/L). After being rechallenged with another
PD-1 inhibitor, teslelizumab, combined with
chemotherapy, he had pulmonary
infection, persistent low-grade
fever, moderate
asthenia, and severe
hyponatremia (116 mmol/L). Meanwhile, his blood levels of 8:00 a.m.
cortisol and
ACTH were 3.1 μg/dL and 7.2 ng/L, respectively, with normal thyroid function,
sex hormone and
prolactin. All of the three patients had no
headache or visual disturbance. Their pituitary magnetic resonance image showed no pituitary enlargement or stalk thickening, and no dynamic changes. They were all on
hormone replacement therapy (HRT) with
prednisone (2.5-5.0 mg/d), and resumed the
PD-1 inhibitor treatment when symptoms relieved. In particular, Case 2 started with high-dose
prednisone [1 mg/(kg·d)] because of simultaneous immune-related
pneumonitis, and then tapered it to the HRT dose. His
cortisol and
ACTH levels returned to and stayed normal. However, the other two patients'
hypopituitarism did not recover. In summary, these cases demonstrated that the pituitary irAEs induced by
PD-1 inhibitors could present as IAD, with a large time span of onset, non-specific clinical presentation, and different recovery patterns. Clinicians should monitor patients' pituitary
hormone regularly, during and at least 6 months after
PD-1 inhibitor treatment, especially in patients with good oncological response to the treatment.