Abstract
Until recently, distant metastatic melanoma was considered refractory to systemic therapy. A better understanding of the interactions between tumors and the immune system and the mechanisms of regulation of T-cells led to the development of immune checkpoint inhibitors. This review summarizes the current novel data on the treatment of metastatic melanoma with anti-programmed cell death protein 1 (PD-1) antibodies and anti-PD-1-based combination regimens, including clinical trials presented at major conference meetings. Immune checkpoint inhibitors, in particular anti-PD-1 antibodies such as pembrolizumab and nivolumab and the combination of nivolumab with the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody ipilimumab can achieve long-term survival for patients with metastatic melanoma. The anti-PD-1 antibodies nivolumab and pembrolizumab were also approved for adjuvant treatment of patients with resected metastatic melanoma. Anti-PD-1 antibodies appear to be well tolerated, and toxicity is manageable. Nivolumab combined with ipilimumab achieves a 5 year survival rate of more than 50% but at a cost of high toxicity. Ongoing clinical trials investigate novel immunotherapy combinations and strategies (e.g., Talimogene laherparepvec (T-VEC), Bempegaldesleukin (BEMPEG), incorporation or sequencing of targeted therapy, incorporation or sequencing of radiotherapy), and focus on poor prognosis groups (e.g., high tumor burden/LDH levels, anti-PD-1 refractory melanoma, and brain metastases).
Highlights
Until recently, distant metastatic melanoma was considered refractory to systemic therapy
This review summarizes the current novel data on the treatment of metastatic melanoma with anti-programmed cell death protein 1 (PD-1) antibodies and anti-PD-1-based combination regimens, including clinical trials presented at major conference meetings
In particular anti-PD-1 antibodies such as pembrolizumab and nivolumab and the combination of nivolumab with the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody ipilimumab can achieve long-term survival for patients with metastatic melanoma
Summary
Distant metastatic melanoma was considered refractory to systemic therapy. Patients with metastatic melanoma had a median overall survival of 6–10 months. The United States Food and Drug Administration (FDA) approval of the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody ipilimumab in 2011 and the anti-programmed cell death protein 1 (PD-1) antibodies nivolumab and pembrolizumab in 2014 has radically changed the systemic treatment of metastatic melanoma and significantly improved its clinical outcome. The second breakthrough in the systemic therapy of metastatic melanoma was the targeted therapy with BRAF and MEK inhibitors that may be used if tumor cells harbor a BRAF-V600 mutation. This review summarizes the current novel data on the treatment of metastatic melanoma with anti-PD-1 antibodies and combinations with other treatment modalities, including clinical trials presented at major conference meetings
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