Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution

Abstract

Novel immune checkpoint blockade with ipilimumab, an antibody blocking the cytotoxic T-lymphocyte antigen 4 (CTLA4), is revolutionizing cancer therapy. However, ipilimumab induces symptomatic, sometimes severe, endocrine immune-related adverse events (irAEs) that are inconsistently recognized and reported. The objective of this review was to comprehensively characterize the incidence, presentation, and management of endocrinopathies following ipilimumab therapy in a single center that is highly specialized in immune checkpoint blockade. We carried out a retrospective analysis of endocrine irAEs in melanoma patients receiving ipilimumab therapy in clinical trials between 2007 and 2013. A total of 256 patients were included in this analysis. We reviewed pituitary-, thyroid-, and adrenal-related hormone test results, as well as radiographic studies and the clinical histories of patients, to identify and characterize cases of hypophysitis, hypothyroidism, thyroiditis, and adrenal dysfunction. Following ipilimumab therapy, the overall incidence of hypophysitis was 8% and that of hypothyroidism/thyroiditis 6%. Primary adrenal dysfunction was rare. Therapy with a combination of ipilimumab and nivolumab, an anti-programmed cell death 1 (PDCD1, also called PD1) receptor antibody, was associated with a 22% incidence of either thyroiditis or hypothyroidism and a 9% incidence of hypophysitis. Symptomatic relief, in particular, for hypophysitis, was achieved in all patients with hormone replacement, although endogenous hormone secretion rarely recovered. In summary, we observed that CTLA4 blockade alone, and in particular in combination with PD1 blockade, is associated with an increased risk of symptomatic, sometimes severe, hypophysitis as well as thyroid dysfunction. Prompt initiation with hormone replacement reverses symptoms. Evaluation and reporting of endocrine irAEs in clinical trials should be done using standardized diagnostic criteria and terminology.

Is autoimmunity the Achilles' heel of cancer immunotherapy?

“…For instance, some cases of graft-versus-host disease after hematopoietic stem cell transplantation (HSCT) can take more than a year to manifest 4 . Onset of thyroiditis has been reported as late as 3 years after the initiation of therapy with the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antagonist ipilimumab 5 . Adding more complexity, the natural history of certain autoimmune diseases, such as type 1 diabetes (T1D), is unpredictable; the onset of clinical disease manifestations can vary from weeks to decades after the appearance of islet autoantibodies 6 .…”

“…In humans, autoimmune manifestations caused by drugs targeting the CTLA-4 and PD-1 pathways seem to be dependent on the pathway(s) targeted 5,10,28,29 . For example, the most commonly reported endocrine irAE following therapy with the CTLA-4-blocking antibody ipilimumab is hypophysitis, an event that is rarely observed after PD-1-antibody therapy.…”

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“…The onset occurs in the weeks following the initiation of treatment with ICPIs, usually on average after 6 weeks for anti-CTLA-4 therapies and 10 weeks for anti-PD-1 antibodies [7,10] but a delayed onset has also been reported [33].…”

“…Subclinical or mild hypothyroidism is more common with a less than 1% of patients developing severe and life-threatening symptoms [2,4,19,25,36]. Most cases present as silent thyroiditis secondary to antithyroglobulin and antithyroperoxidase antibodies and hypothyroidism or after transient subclinical hyperthyroidism [33,36] and very rarely as a thyroid storm [37].…”

“…Subclinical or mild hypothyroidism is more common with a less than 1% of patients developing severe and life-threatening symptoms [2,4,19,25,36]. Most cases present as silent thyroiditis secondary to antithyroglobulin and antithyroperoxidase antibodies and hypothyroidism or after transient subclinical hyperthyroidism [33,36] and very rarely as a thyroid storm [37].The management of irreversible hypothyroidism involves hormone replacement with levothyroxine which can be initiated at a dose of 1-1.5 mcg/kg /day and the immunotherapy can be continued with no discontinuation [5,7,36]. Symptomatic hyperthyroidism with tremor and tachycardia can be treated with beta-blockers or corticosteroids.…”