WHAT CAN WE LEARN REGARDING IMMUNOTHERAPY FROM MALIGNANT MELANOMA

Abstract

ICB History: 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 1980's and 1990's 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 with ICs. It represents a major paradigm shift that marks the beginning of a new era. The impact of the first ICBs, i.e. anti-CTLA-4 (CytotoxicT Lymphocyte Antigen-4) and anti-PD1 / anti-PDL1 (Programmed death-1 receptor and its ligand PD-L1) is unprecedented. Advanced Disease: 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. 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). Adjuvant Therapy: 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. Combinations: 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. Transversal Development:Thanks to in particular anti-PD1/anti-PDL1- based immunotherapies and 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&neck, oesophageal and gastric, liver, MSI-colorectal, MSI-any tumor type, renal, bladder, and Merkel cell cancers and Hodgkin-lymphoma with unprecedented success. Toxicities: Success however does come at a price, both in terms of side-effects, in particular immune-related adverse events (irAEs), as well in terms of financial toxicity. irAEs come in many forms. With ipilimumab at 10 mg/Kg the most frequent are Gastro-Intestinal (diarrhea, colitis, perforations); Hepatic (grade 3-4 hepatitis in 16%); Endocrinopathies (hypophysitis in up to 16%, grade 3-4 in up to 5%) and hyper/hypothyroiditis; Dermatitis; Arthralgia; Rare but important are neurodegenerative irAEs, Guillain-Barré syndrome, pneumonitis, and myocarditis. Anti-PD1/PDL1 agents are much less toxic in general. The combination of anti-CTLA-4 and anti-PD1/L1 are associated with increased irAEs. Algorithms have been established including administration of high dose corticosteroids and anti-TNF agents. All treatment regimens with ICBs have reported drug-related fatalities range. Smart Combos: Anti-PD1/PDL1 has become the central drug in all further development strategies to be combined with other ICBs, agonists, cytokines, vaccines, targeted agents, chemotherapeutics and radiotherapy.