Immune checkpoint inhibitors in melanoma

Immune checkpoint inhibitors target the dysfunctional immune system, to induce cancer-cell killing by CD8-positive T cells. Immune checkpoint inhibitors, specifically anti-CTLA4 and anti-PD-1 antibodies, have revolutionised the management of many cancers, particularly advanced melanoma, for which tumour regression and long-term durable cancer control is possible in nearly 50% of patients, compared with less than 10% historically. Despite the absence of adequately powered trial data, combined anti-CTLA4 and anti-PD-1 checkpoint inhibition has the highest 5-year overall survival rate of all therapies in advanced melanoma, and has high activity in melanoma brain metastases. A phase 3 study has shown the addition of an anti-LAG3 antibody to nivolumab improves progression-free survival, but its effect on overall survival and how this combination compares to combined anti-CTLA4 and anti-PD-1 checkpoint inhibition is unknown. At present, there are no highly sensitive and specific biomarkers of response to immune checkpoint inhibitors, and clinical factors, such as volume and sites of disease, serum lactate dehydrogenase, and BRAF mutation status, are used to select initial therapy for patients with advanced melanoma. Immune checkpoint inhibitors can induce autoimmune toxicities by virtue of their mechanism of action. These toxicities, termed immune-related adverse events, occur most frequently with combined anti-CTLA4 and anti-PD-1 checkpoint inhibition; can have a variety of presentations; can affect any organ system (most often the skin, colon, endocrine system, and liver); and appear to mimic classic autoimmune diseases. Immune-related adverse events require prompt recognition and management, which may be different from the autoimmune disease it mimics. Immune checkpoint inhibitors appear to be safe for use in patients with HIV, viral hepatitis, and patients with mild-to-moderate pre-existing autoimmune diseases. Patients with organ transplants can respond to immune checkpoint inhibitors but have a high chance of transplant loss. PD-1 inhibitors are now an established standard of care as adjuvant therapy in high-risk resected stage III or IV melanoma. Neoadjuvant checkpoint inhibition for resectable stage III melanoma, which is currently limited to clinical trials, is emerging as a highly effective therapy.