Abstract
Novel immune checkpoint inhibitors are changing the treatment options for advanced melanoma. Advanced practitioners may be familiar with ipilimumab, which inhibits the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) pathway. The next generation of immune checkpoint inhibitors is comprised of agents targeting the programmed death-1 (PD-1) pathway. Pembrolizumab, a PD-1 inhibitor, was recently approved for the treatment of patients who progressed on or after ipilimumab therapy. Nivolumab, also a PD-1 inhibitor, is approved in Japan for the treatment of unresectable melanoma and was granted priority review status by the FDA. Both CTLA-4 and PD-1 have distinct but complimentary roles in regulating immune responses. Whereas CTLA-4 prevents T cell proliferation at the start of an immune response, PD-1 is thought to contribute to T cell exhaustion in peripheral tissues, including tumors. By blocking these pathways, antitumor T cell responses can be restored, leading to elimination of the cancer cells by the patient’s own immune system. In a phase Ib registrational trial of pembrolizumab, the response rate was 26% and the 1-year survival rate was 58%–63% (dose-dependent). In the first randomized, controlled phase III trial of a PD-1 inhibitor, nivolumab, the response rate was 32% versus 11% with chemotherapy.2 In a phase 1 nivolumab trial, the response rate was 31% and 1-/2-year survival was 62%/43%. A phase I trial combining ipilimumab with nivolumab showed increased efficacy (response rate: 42%; 1-/2-year survival: 85%/79%) than seen previously with monotherapy, suggesting synergy with dual blockade of both pathways. Unlike chemotherapy and targeted agents which act directly on the tumor cells, restoring antitumor responses with immune checkpoint blockade can be associated with novel response patterns and select immunologic adverse events (AEs) which are related to the mechanism of action. Practitioners should be aware that first responses may occur several months after initiating treatment, and, in some patients, show initial evidence of tumor progression, termed “pseudoprogression.” Practitioners must also be vigilant for AEs with immune etiologies which need prompt diagnosis and management. PD-1 pathway inhibitors appear to have similar types of select immunologic AEs as ipilimumab, but with lower incidences and typically of lower grade; the most common AEs are fatigue, and typically mild skin and gastrointestinal events. Select grade 3–4 AEs have also been reported, including endocrinopathies, hepatitis, and pneumonitis (each ≤ 2%). Proper education of the healthcare team and patient is key to optimal management of patients receiving immune checkpoint inhibitors.
