Abstract
In recent years, the introduction and Federal Drug Administration approval of immune checkpoint inhibitor antibodies has dramatically improved the clinical outcomes for patients with advanced melanoma. These antagonist monoclonal antibodies are capable of unleashing dormant or exhausted antitumor immunity, which has led to durable complete and partial responses in a large number of patients. Ipilimumab targets the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) receptor. Nivolumab and pembrolizumab target programmed cell death protein 1 (PD-1) receptors and have proven to be superior to ipilimumab alone. The combination of ipilimumab and nivolumab has yielded higher response rates, greater tumor shrinkage, and longer progression-free survival than either monotherapy alone. As other promising immunotherapies for melanoma proceed through clinical trials, future goals include defining the role of immune checkpoint inhibitors as adjuvant therapy, identifying optimal combination strategies, and developing reliable predictive biomarkers to guide treatment selection for individual patients.
Highlights
Advanced melanoma has historically been associated with a poor prognosis, with a median overall survival (OS) of 8–10 months and a 5-year survival rate of 10 % [1]
The Checkmate-067 study was a randomized phase III trial of ipilimumab monotherapy compared to nivolumab monotherapy or the combination of nivolumab and ipilimumab in patients with advanced melanoma who were naive to immune checkpoint inhibitor therapy [37]; the objective response rate (ORR) was 43.7 % with nivolumab compared to 19.0 % with ipilimumab
It is this activity that may be driving adaptive immune escape by tumors via the Programmed cell death protein 1 (PD-1)/programmed deathligand 1 (PD-L1) axis and other mechanisms. This presence seems to correlate with response to anti-PD-1 therapy. These findings provide a basis from which to hypothesize that addition of ipilimumab to anti-PD-1 inhibitor therapy can provide additional immune support in patients without brisk CD8+ tumor infiltrating lymphocytes (TIL) infiltration
Summary
Advanced melanoma has historically been associated with a poor prognosis, with a median overall survival (OS) of 8–10 months and a 5-year survival rate of 10 % [1]. Anti-CTLA-4 therapy Ipilimumab demonstrated clinical activity in early phase trials [14,15,16] and was approved by the FDA following the release of phase III data, which showed a significantly improved OS relative to the glycoprotein 100 (gp100) peptide vaccine in previously treated melanoma patients [17].
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