Background: Immune checkpoint inhibitors have revolutionized the treatment of metastatic melanoma, demonstrating durable responses, but can result in immune-related adverse events (irAEs). Endocrinopathies are amongst the more common adverse events, and thyroid dysfunction and hypophysitis being the most frequent; the latter of these has been positively correlated with oncological outcome. This study compared overall survival (OS), progression-free survival (PFS) and disease control rate in patients with and without endocrinopathy following treatment with ipilimumab, PD-1 inhibitors and combination treatment.
Patients and methods: The study was a retrospective review of 338 patients with metastatic melanoma treated with ipilimumab, nivolumab, pembrolizumab or combination of ipilimumab and nivolumab at the Royal Marsden Hospital between 1/1/2010 and 31/12/2016. Thyroid dysfunction was defined as any abnormal thyroid dysfunction following treatment (with the exception of secondary hypothyroidism without evidence of other pituitary involvement). Hypophysitis was defined as deficiency in more than one pituitary axes or deficiency in one pituitary axis plus enlargement of the pituitary gland on MRI. Follow up imaging results were evaluated to assess response to treatment and date of progression.
Results: Hypophysitis was diagnosed in 22 patients and thyroid dysfunction in 116 patients. OS was significantly prolonged in hypophysitis compared to no endocrinopathy patients (HR, 0.22; 95% CI, 0.100.46; P<0.001) and in patients with thyroid dysfunction compared to no endocrinopathy (HR, 0.49; 95% CI, 0.360.66; P<0.001). PFS following first-line treatment was also significantly higher in both hypophysitis and thyroid dysfunction groups compared to patients without endocrinopathy (respective HR, 0.42; 95% CI, 0.250.70; P<0.001 and HR, 0.71; 95% CI, 0.560.91; P<0.001), as was the disease control rate (P≤0.001 and P=0.01 respectively).
Conclusions: The development of endocrinopathy in this cohort was associated with improved oncological outcome. We hypothesise that development of endocrinopathy in response to treatment with checkpoint inhibitors may be a marker of activation of the immune system and hence of the anti-tumour response.