Predicting development of ipilimumab-induced hypophysitis: utility of T4 and TSH index but not TSH

M S Siddiqui,J Larkin,V Greener,S Turajlic,D L Morganstein,Z M Lai,L Spain

doi:10.1007/s40618-020-01297-3

M S Siddiqui, J Larkin + Show 5 more

Open Access

https://doi.org/10.1007/s40618-020-01297-3

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Abstract

PurposeIpilimumab, a monoclonal antibody inhibiting CLTA-4, is an established treatment in metastatic melanoma, either alone or in combination with nivolumab, and results in immune mediated adverse events, including endocrinopathy. Hypophysitis is one of the most common endocrine abnormalities. An early recognition of hypophysitis may prevent life threatening consequences of hypopituitarism; therefore, biomarkers to predict which patients will develop hypophysitis would have clinical utility. Recent studies suggested that a decline in TSH may serve as an early marker of IH. This study was aimed at assessing the utility of thyroid function tests in predicting development of hypophysitis.MethodsA retrospective cohort study was performed for all patients (n = 308) treated with ipilimumab either as a monotherapy or in combination with nivolumab for advanced melanoma at the Royal Marsden Hospital from 2010 to 2016. Thyroid function tests, other pituitary function tests and Pituitary MRIs were used to identify those with hypophysitis.Results and conclusionsIpilimumab-induced hypophysitis (IH) was diagnosed in 25 patients (8.15%). A decline in TSH was observed in hypophysitis cohort during the first three cycles but it did not reach statistical significance (P = 0.053). A significant fall in FT4 (P < 0.001), TSH index (P < 0.001) and standardised TSH index (P < 0.001) prior to cycles 3 and 4 in hypophysitis cohort was observed. TSH is not useful in predicting development of IH. FT4, TSH index and standardised TSH index may be valuable but a high index of clinical suspicion remains paramount in early detection of hypophysitis.

Highlights

Advanced malignant melanoma had historically poor prognosis and a median survival of only 6 to 9 months before the availability of immunotherapy [1]
The cohort consisted of 308 ipilumumab treated patients; 277 patients received ipilimumab alone and 31 received ipilimumab and nivolumab in combination. 25 patients (8.11%) were identified to have ipilimumab-induced hypophysitis
This study has examined a single centre cohort of patients treated with ipilimumab as monotherapy or in combination with Nivolumab for advanced melanoma, defining all those with hypophysitis through rigorous diagnostic criteria

Summary

Introduction

Advanced malignant melanoma had historically poor prognosis and a median survival of only 6 to 9 months before the availability of immunotherapy [1]. The introduction of immunotherapy using immune checkpoint inhibitors (ICPIs) and targeted therapy has shown remarkable improvement in progression-free and overall survival compared with chemotherapy. Ipilimumab is a humanized monoclonal antibody that acts as an inhibitor of cytotoxic. Ipilimumab was the first drug in a randomised trial to show a survival benefit in patients with advanced melanoma [2]. A primary analysis of overall survival (OS) data from 12 ipilimumab phase II and phase III trials calculated a median OS of 11.4 months and 3-year survival rates of 22%

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