Program death-1 (PD-1) receptor pathway inhibition in cancer medicine: a perspective on clinical efficacy and associated toxicities

Abstract

Enlisting the host’s immune system to destroy and eradicate tumors in patients with advanced cancer has long been pursued by researchers and clinicians worldwide. The development of immune checkpoint inhibitors—agents targeting co-stimulatory T cell receptors or their ligands—have demonstrated substantial and durable anti-tumor activity in selected patients with different tumor types, renewed our enthusiasm for immunotherapy, and generated large research efforts, establishing Immuno-Oncology as a solid discipline of cancer medicine. The first immune checkpoint inhibitor, ipilimumab—a cytotoxic T lymphocyte associated antigen-4 (CTLA-4) inhibitor received FDA approval for patients with melanoma in different stages of disease. PD-1 inhibitors have better efficacy and safety profile than their predecessor. Several agents inhibiting this pathway have completed early stages of drug development (biology, pharmacokinetics, safety, efficacy, etc.) and are rapidly finding their way to the clinic. Of these, three already received FDA approval for different indications: Nivolumab (Bristol Myers Squibb), Pembrolizumab (Merck & Co), and Alemtuzumab (Genentech). As expected, their toxicity profile predominantly includes immune related adverse events. The majority of these adverse events are manageable and grade 3/4 toxicities are only observed in 1–3% of patients. Other aspects of clinical interest include: (I) while toxicities are consistent among different agents, their incidence vary slightly among different tumor types; (II) stabilization of tumor growth is observed in a large number of patients; however, objective responses are still reserved to a minority; (III) PD-L1 expression on tumor cells is the most predictive biomarker. Nonetheless, a considerable number of PD-L1 (−) patients experience objective responses and differences in survival according to PD-L1 status are not uniform; and (IV) when compared with cytotoxic chemotherapy and other targeted therapies, the duration of responses and safety profile seem to be major advantages among responders to this group of novel biologicals.