Ipilimumab, pembrolizumab, and nivolumab novel immune checkpoint blockade drugs are increasingly used in the treatment of metastatic melanoma and other cancers. Ipilimumab is an anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) MAB and the first drug shown to improve overall survival in metastatic melanoma. Hypophysitis is a widely described side-effect linked with both lymphocytic inflammation and a direct toxic effect on the pituitary in mouse studies, but has been shown to link with survival in some patients. Pembrolizumab is an anti-programmed death 1 (PD1) antibody active in ipilimumab-treated and naïve patients. Hypophysitis is less commonly described with pembrolizumab treatment, but glycaemic variation was noted in early clinical studies.
We describe the case of a 50-year-old female, with type 2 diabetes (initially on metformin monotherapy) who presented with stage 2a malignant melanoma. A wide local excision was performed but, two years later, she developed metastatic disease. The patient received first line immunotherapy with ipilimumab with some clinical response. She developed low cortisol and prolactin levels, i.e. drug-related hypophysitis, and was treated with prednisolone. Thyroid function and an MRI of the pituitary were normal. Disease progression led to treatment with pembrolizumab. Measurements of HbA1c indicated increasingly unstable glycaemia, peaking at 91 mmol/mol. Gliclazide was then added at which point the HbA1c began to fall.
In terms of altered glycaemia, a phase two trial of ipilimumab reports hyperglycaemia; and hypoglycaemia was mentioned in a different study. There have been two reported cases of diabetes mellitus following pembrolizumab treatment. In one, acute onset of insulin-dependent diabetes was attributed to a possible link between PD1 inhibition and autoimmune diabetes. This case is remarkable in that ipilimumab-related endocrine effects were sequentially followed by pembrolizumab-related glycaemic changes. It is not yet known whether pembrolizumab-associated glycaemic changes are linked to oncological benefit, an area that would require further study.