PD-1 Pathway Inhibitors: Immuno-Oncology Agents for Restoring Antitumor Immune Responses

Abstract

Immune checkpoint inhibitors are designed to restore a patient's own antitumor immune response that has been suppressed during tumor development. The first monoclonal antibodies against the immune checkpoint programmed death 1 (PD-1) receptor, nivolumab and pembrolizumab, are now approved for clinical use. Both agents are indicated for the treatment of advanced melanoma, as well as for the treatment of metastatic non-small cell lung cancer (NSCLC). Nivolumab is also approved for the treatment of advanced renal cell carcinoma. In patients with melanoma, these agents result in objective response rates of ~25-40%, with durable responses lasting more than 2 years in some cases. Results from phase III trials have shown improved survival with nivolumab versus standard-of-care chemotherapy in both patients with advanced melanoma and those with advanced NSCLC. In patients with advanced melanoma, both PD-1 inhibitors (nivolumab and pembrolizumab) have shown improved survival versus ipilimumab. PD-1 inhibitors are associated with adverse events that have immune etiologies, with grade greater than 3 adverse events typically reported in 16% or less of patients. However, most immune-mediated adverse events (including grade 3-4 adverse events) can be managed by using published management algorithms without permanent discontinuation of the agent. As nivolumab and pembrolizumab enter the clinic, and with more PD-1 pathway agents in development for a range of tumor types, this review aims to provide pharmacists with a basic understanding of the role of PD-1 in modulating the immune system and their use in the cancer treatment. The most recent clinical efficacy and safety data are discussed, highlighting the response characteristics distinctive to immune checkpoint inhibitors, along with pharmacokinetic and pharmacodynamic data and cost considerations.

Keywords: PD-1; adverse event; cancer; immune checkpoint blockade; immuno-oncology; oncology; programmed death-1 pathway.

Figure 1

Combination strategies with immune checkpoint inhibitors may improve antitumor responses. Tumor cells die as a result of genomically targeted therapies with release of tumor antigens. Tumor antigens are taken up by antigen‐presenting cells (APCs) and are presented in the context of B7 costimulatory molecules to T cells. T cells recognize antigens on APCs to become activated; activated T cells also upregulate inhibitory checkpoints such as cytotoxic T‐lymphocyte‐associated antigen 4 (CTLA‐4) and programmed death 1 (PD‐1). Immune checkpoint therapy prevents attenuation of T‐cell responses, thereby allowing T cells to kill tumor cells, and T cells may differentiate into memory T cells that can reactivate in the presence of recurrent tumor. MHC = major histocompatibility complex; TCR = T‐cell receptor. (Reprinted with permission from reference 13.)