Oral Presentation ESA-SRB Conference 2015

Endocrinopathies associated with immune modulation therapy for the treatment of metastatic melanoma (#196)

Emma Scott 1 , Alexander Menzies 2 3 , Georgina Long 2 3 , Lyndal Tacon 1 4 , Alex Guminski 2 3 , Venessa Tsang 1 4
  1. Department of Endocrinology, Royal North Shore Hospital, Sydney
  2. Department of Oncology, Royal North Shore Hospital, Sydney
  3. Melanoma Institute, Mater Hospital, University of Sydney, Sydney
  4. Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney

BACKGROUND

Immune modulator therapy has a demonstrated survival benefit in the treatment of metastatic melanoma.  Monoclonal antibodies against regulatory immune checkpoints can enhance the immune activity against cancer cells.  Agents include Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), and Nivolumab, a monoclonal antibody against programmed death-1 (PD-1) receptor.  As a consequence of immunomodulation, endocrine immune related adverse events (irAEs) can occur1, but the incidence in combination or sequential immunotherapy has not been reported in large series.

METHODS

Patients with metastatic melanoma at the Melanoma Institute Australia, between April 2014 and May 2015 were treated with Anti CTLA-4 (Ipilimumab) or Anti-PD-1 (Nivolumab or Pembrolizumab) therapy alone, sequentially or in combination.  The incidence of endocrine irAEs was assessed with regular monitoring of pituitary and thyroid function. 

RESULTS

26 (15%) patients were diagnosed with an endocrinopathy. 12 (6.9%) patients were diagnosed with hypophysitis, 1 (0.5%) with autoimmune diabetes, 19 (11%) with thyroid dysfunction and 2 (1.16%) with isolated hypogonadism. 9 (15.8%) in the Anti-CTLA-4 arm developed endocrinopathies, compared to 5 (5.7%) in the PD-1 arm. Combination Anti-CTLA-4 and PD1 was associated with increased endocrinopathies 18 (62.1%).

DISCUSSION
Immune related endocrinopathies as a result of immunotherapy are underreported, as there are few screening requirements2. Endocrine irAEs associated with Anti-CTLA4 are hypophysitis, thyroid dysfunction and primary adrenal insufficiency1.  Studies suggest a 5% incidence of hypophysitis, and 0-4% incidence of thyroid dysfunction1. Endocrine irAEs occur less frequently with anti-PD1 therapy3.  Combination ipilimumab and nivolumab therapy is associated with increased irAEs, particularly thyroid dysfunction2,4. There does not appear to be any predictors for the development of endocrinopathy. The time course appears more rapid than for autoimmune hypophysitis and thyroiditis with disease occurring in weeks. A heightened clinical suspicion and regular monitoring will prevent the development of morbidity especially adrenal crises.

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