Endocrinopathies induced by immune-checkpoint inhibitors in advanced non-small cell lung cancer

ABSTRACT

The advent of immunotherapy has recently expanded the therapeutic options in advanced non-small cell lung cancer (NSCLC). In these patients, the recent efficacy demonstration of antibodies against immune checkpoints: the anti-programmed death-1 (PD-1) and anti-programmed death ligand-1 (PD-L1), has led to approval of nivolumab and pembrolizumab (anti-PD-1) in the treatment of advanced NSCLC. The mechanism of action of checkpoint inhibitors explains the development of autoimmune diseases as a side-effect of these medications. Among these, a spectrum of endocrine disorders has been also reported. This manuscript focuses particularly on endocrine disorders induced by immuno-checkpoint inhibitors employed in NSCLC, in order to suggest the strategies for their diagnosis and effective management.

KEYWORDS:

• CTLA-4
• endocrine toxicities
• immunotherapy
• NSCLC
• PD-1
• PD-L1

Financial & competing interests disclosure

C Gridelli has received honoraria as advisory board member and speaker bureau for Bristol Myers Squibb, Merck Sharp & Dohme Ltd, Roche and Astra Zeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Nivolumab, anti-PD-1 agent, has been approved by FDA in advanced squamous NSCLC pretreated with platin-based chemotherapy.

• Pembrolizumab, anti-PD-1 agent, has been approved by FDA for the treatment of advanced NSCLC PD-L1 positive pretreated with platin-based chemotherapy.

• Several endocrine toxicities have been reported with immune therapy, including hypothyroidism, hyperthyroidism, adrenal insufficiency and hypophysitis, the last one can be associated to hypopituitarism.

• The endocrine toxicity prevalent with the use of PD-1 and PD-L1 inhibitors mainly affects the thyroid gland, while hypophysitis and hypopituitarism are more frequent in the case of therapy with anti-CTLA-4.

• The combination of anti-CTLA-4 and PD-1 and PD-L1 inhibitors increases endocrine toxicity.

• Pituitary MRI should be performed if suspected hypophysitis. Hypophysitis treatment includes hormone substitution and high-dose oral glucocorticoids, for eventual adrenal insufficiency and reducing pituitary swelling.

• Serum anti-thyroglobulin and/or anti-thyroid peroxidase antibodies can confirm the suspect of autoimmune thyroiditis. Thyroid hormone replacement, without treatment discontinuation, is recommended in presence of hypothyroidism.

• Beta-blockers and/or anti-thyroid pharmacotherapy, without treatment discontinuation, is recommended in presence of hyperthyroidism.

• Adrenal crisis requires hospitalization and treatment with hydrocortisone hemisuccinate as quickly as possible. Oral hydrocortisone or cortisone acetate is recommended in chronic therapy.

• Identification of specific patient characteristics, e.g. genetic risk factors (HLA) for autoimmune disease, is required to improve management of immune-regulatory anticancer drugs.