Abstract: Cancer immunotherapy is now recognized to be fundamental in modern oncology, because immune system recruitment may represent a powerful and innovative strategy in cancer therapy. Pembrolizumab, a highly selective humanized monoclonal antibody directly blocking the interaction between programmed cell death-1 expressed by tumor-associated T-cells and its ligand programmed cell death-L1 present on tumor and stromal cells, was recently approved by US Food and Drug Administration for the treatment of patients with unresectable or metastatic melanoma and disease progression upon ipilimumab and BRAF inhibitor. This review will focus on the clinical development and use of pembrolizumab in the clinical practice and in the management of advanced melanoma.
Keywords: advanced melanoma, immunotherapy, PD-1 inhibitor, pembrolizumab
Introduction to therapy for advanced melanoma
Melanoma is among the less common but most deadly types of skin cancer. It arises from melanocytes and represents approximately <5% of all cancers. It has a strong tendency to give rise to distant metastases, most commonly to lymph nodes, skin, lungs, liver, or brain.1 Over the past decade, there has been a steady increase in the incidence of melanoma worldwide, mostly related to age but disproportionately high in young adults (15–34 years); survival rates have been continually improving for the last 30 years, with an overall 5-year survival rate of 81% for men and 90% for women, likely due to earlier diagnosis.2
Across the last decades, for patients with unresectable disease, traditional chemotherapy showed no evidence of survival benefit. Until 2009, patients with American Joint Committee on Cancer stage IV melanoma had very poor prognosis, with median survival of 8–10 months.3 Developments in basic and clinical research have led to the recent introduction of new and more effective therapies in metastatic melanoma, including treatments based on the stimulation of immune response and targeted therapies. The prognosis of metastatic melanoma has recently changed due to strategies based on the immune system checkpoint inhibitor ipilimumab or several tyrosine kinase inhibitors, such as vemurafenib, dabrafenib, and trametinib.4–8 Vemurafenib and dabrafenib are selective inhibitors of BRAF V600 mutation (present in approximately 50% of melanomas), which are approved by the major regulatory bodies for the treatment of unresectable or metastatic melanoma with mutant BRAF V600.9,10 In pivotal Phase III trials, both inhibitors (independently administered) showed improved overall survival (OS), progression-free survival (PFS), and higher response rate compared with standard chemotherapy.4,5 Trametinib (an MEK inhibitor) was investigated in a randomized Phase III study as combination therapy with dabrafenib versus vemurafenib and approved by US Food and Drug Administration (FDA) in 2013 for the treatment of unresectable or metastatic melanoma harboring BRAF V600E or V600K mutations in combination with dabrafenib.11 Of note, trametinib also showed efficacy as monotherapy in another Phase III trial, but this compound is not currently used in this setting.6
Along with the development of BRAF and MEK inhibitors, the immunotherapy approach was improved by the introduction of ipilimumab, which is a fully human IgG1 monoclonal antibody eliciting antitumor T-cell-mediated response by interference with cytotoxic T-lymphocyte antigen-4 (CTLA-4). The drug has been approved for the treatment of metastatic melanoma, as achieved a statistically improvement in OS in two different randomized Phase III trials in pretreated and in treatment-naïve patients with metastatic melanoma, without or in combination with standard chemotherapy, respectively (even though, the latter indication is not currently used).7,8
Unfortunately, despite the introduction of these therapeutic options, the prognosis of metastatic melanoma still remains very poor. Indeed, the response rate of BRAF inhibitors exceeds 50%, but median duration of response does not achieve 1 year.4–6,10–15 Most patients who respond to therapy over time develop mechanisms of acquired/secondary resistance, ultimately leading to progression of disease. In addition, approximately 15% of patients treated with BRAF inhibitors do not respond to treatment at all, likely due to intrinsic/primary mechanisms of resistance.10,15 Conversely, immunotherapy can induce dramatic responses that are generally much more durable but unfortunately occur uncommonly (by far less than 50%).7,16,17 These data may indicate that the key to long-term tumor control can be obtained by immunotherapy, but strategies improving the likelihood of selecting patients benefiting from this therapy option need to be devised.