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Melanoma Investigators Strive to Overcome PD-1 Inhibitor Resistance

Approximately one-third to one-half of patients with advanced melanoma respond to PD-1 inhibitor therapy, which is superior to response rates observed with systemic chemotherapy or even single-agent ipilimumab (Yervoy)—a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blocker and the first checkpoint inhibitor approved for melanoma.1-4Nevertheless, a significant proportion of patients have primary, or innate, resistance to PD-1 inhibition and derive no benefit from these therapies that have become the standard of care for advanced melanoma.5 In addition, several years have passed since the first patients received PD-1 inhibitors in clinical trials, and it has become clear that although most responses are durable and last several years, one-fourth to one-third of patients relapse despite ongoing treatment.3,6,7 These patients are categorized as having secondary, or acquired, resistance.5

The lack of adequate therapies for advanced melanoma that is resistant to immune checkpoint inhibitors (ICIs) remains an important unmet need in this tumor type. To address this problem, investigators across the globe have expended considerable effort attempting to identify mechanisms of response and resistance to ICIs. The general conclusion is that each patient’s response to immunotherapy is likely complex and highly individualized.5

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