34. Melanoma: Immunotherapy in Advanced Melanoma and in the Adjuvant Setting
Authors: Alexander M. M. Eggermont, Caroline Robert
Publisher: Springer International Publishing
Melanoma has been the most important cancer to drive immunotherapy development in the field of solid tumors. Where immune-stimulating approaches with cytokines in the 1980s and 1990s lead to approvals of interferon-alpha and interleukin-2, the clinical impact was rather small. Since 2010 immunotherapy has been revolutionized by the concept of breaking tolerance. It represents a major paradigm shift that marks the beginning of a new era. The impact of the first checkpoint inhibitors, i.e., anti-CTLA-4 (cytotoxic T lymphocyte antigen-4) and anti-PD1/anti-PDL1 (programmed death-1 receptor and its ligand PD-L1), is unprecedented. In only 5 years advanced melanoma has been transformed from an incurable disease into a curable disease in over 50% of metastatic patients. We are only at the beginning of discovering its transversal impact throughout oncology. FDA-approved treatments for melanoma are at present: interferon-alpha as adjuvant therapy (1996), interleukin-2 (1998) for advanced disease, and more recently pegylated interferon-alpha as adjuvant therapy (2011). For the treatment of advanced disease approvals were obtained for the immune checkpoint inhibitors ipilimumab (2011), nivolumab (2014), pembrolizumab (2014) and the combination ipilimumab + nivolumab (2015), and the oncolytic virus vaccine laherparepvec (T-VEC) in 2015. Ipilimumab is the first checkpoint inhibitor that has also been approved as adjuvant therapy for high-risk stage III melanoma (2015). Results regarding adjuvant therapy with either nivolumab or pembrolizumab are expected in 2018. Further developments in the field of melanoma are focused on combination therapies between various immunotherapeutic agents, such as vaccines and antibodies, and combination therapies between immunotherapeutic agents with chemotherapeutic or targeted agents or even radiation therapy. Thanks to in particular anti-PD1/anti-PDL1-based immunotherapies, the activity of the combination of anti-PD1/anti-CTLA4 immunotherapy is now developed in a transversal manner across multiple tumor types (a.o. lung, head and neck, esophageal/gastric, liver, MSI-colorectal, MSI-any tumor type, renal, bladder cancers, and Hodgkin lymphoma) with unprecedented success.