The 2011 U.S. Food and Drug Administration (FDA) approval of immunotherapy ipilimumab was the first in a series of approvals to treated patients with advanced melanoma in recent years. Modern immunotherapies for melanoma, called immune checkpoint inhibitors, fall into 2 categories: cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, like ipilimumab, and programmed death-1 (PD-1) inhibitors, like pembrolizumab and nivolumab.
“In terms of achieving some kind of benefit, roughly one-half of patients with advanced melanoma are helped by these immune checkpoint inhibitors,” Adil I. Daud, MD, of the Helen Diller Family Comprehensive Cancer Center in San Francisco, California, told Cancer Therapy Advisor.
Each checkpoint inhibitor works in a different way. CTLA-4 exists on the surface of immune system T cells and acts as a kind of brake on the T cell, preventing them from being activated to attack cancer cells. By blocking CTLA-4, ipilimumab increases the activation of T cells. PD-1, on the other hand, prevents activated T cells from attacking cancer cells that have the PD-ligand protein on their surface. When PD-1 binds to its ligand, PD-L1, on normal or cancerous cells, it prevents T cells from attacking other cells in the body. Pembrolizumab and nivolumab bind to PD-1, and prevent activated T cells from turning “off”.
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Choosing Therapy
Knowledge of which patients with melanoma could benefit from CTLA-4 inhibition compared with PD-1 inhibition would be of great benefit; however, according to Ryan J. Sullivan, MD, of the Massachusetts General Hospital Cancer Center in Boston, there are few data comparing the 2 types of therapies from the standpoint of a specific biomarker.
“Clinical data suggest that there is probably a minimally overlapping population that benefit from both drugs,” Dr Sullivan said. “Meaning that patients who benefit from PD-1 inhibitors probably do not benefit much from single-agent CTLA-4 inhibitors and vice versa.”
The most obvious biomarker explored to identify patients that would benefit most from PD-1 inhibitors is expression of PD-L1.
“In melanoma, if a patient has high PD-L1 expression they are more likely to benefit from a PD-1 inhibitor,” Dr Sullivan explained. “If you do not have a high expression of PD-L1 you are less likely to benefit.”
However, he noted that PD-L1 is not a very strong biomarker and is not clinically relevant when deciding who to treat with PD-1 inhibitors.
“There is still a high response rate of 20% to 30% in patients who do not have high PD-L1 expression, so we would never use that to exclude patients from treatment,” Dr Sullivan said.
