Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Fall in TSH by ≥80% is associated with development of ipilimumab-induced hypophysitis (#262)

Nisa Sheriff 1 2 , Sunita MC De Sousa 1 3 , Alexander M Menzies 4 , Venessa HM Tsang 5 , Georgina V Long 4 , Katherine T Tonks 2
  1. Hormones and cancer group, Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. St Vincent's Hospital, Darlinghurst, NSW , Australia
  3. Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide
  4. Melanoma Institute Australia, Sydney
  5. Department of Endocrinology, Royal North Shore Hospital, Sydney

Objective: Hypophysitis occurs in up to 25% of patients with melanoma treated with ipilimumab1,2. We aimed to determine if serial routine cortisol measurements could predict hypophysitis. 

Methods: We performed a retrospective audit of metastatic melanoma patients with pituitary function tests performed during ipilimumab treatment (3mg/kg IV 3 weekly for 4 doses) at the Melanoma Institute Australia for 16 months to December 2014. Patients were included if they had two or more cortisol measurements prior to sequential doses of ipilimumab.

Results: 46 of 78 treated patients were included, receiving a total of 163 ipilimumab cycles (median 4 per patient, range 2-4). Nine (20%) developed hypophysitis, a mean of 12.3±1.6 weeks (median 13, range 7.7-18) from the first ipilimumab dose. There was no difference in cortisol levels between those who did and did not develop hypophysitis, after excluding measurements after 11 am, or on glucocorticoid therapy, prior to cycles 1, 2, 3, 4 and after cycle 4 (p=0.88, 0.98, 0.64, 0.91 and 0.23 respectively). Interestingly, TSH prior to cycle 4 was significantly lower in those who developed hypophysitis (0.31 vs 1.44 mIU/L, p=0.002), but not cycles 1, 2 and 3 (p=0.12, 0.88, and 0.11). If TSH fell by ≥80% from baseline at mean 9.1+/-0.26 weeks from first ipilimumab, prior to cycle 4, odds for developing hypophysitis were 136 (95% CI 6.2-2947, p<0.0001) compared to TSH fall <80%. The fall in TSH occurred a mean of 3.4±1.4 weeks (range -1.4-9.7) prior to hypophysitis diagnosis.

Conclusions: Pre-infusion cortisol levels did not differentiate those at risk of hypophysitis. TSH is less affected by external factors and a ≥80% fall in TSH level during ipilimumab therapy is a strong risk factor for concurrent or future development of hypophysitis. Whether TSH levels measured in the weeks between cycles 3 and 4 could predict hypophysitis earlier is unknown

  1. Ryder M, Callahan M, Postow MA, Wolchok J, Fagin JA. Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. Endocr Relat Cancer. BioScientifica; 2014 Apr;21(2):371–81.
  2. van den Eertwegh AJM, Versluis J, van den Berg HP, Santegoets SJAM, van Moorselaar RJA, van der Sluis TM, et al. Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2012 May;13(5):509–17.