Abstract
Simple SummaryThe introduction of immune checkpoint inhibitors and targeted therapy for the treatment of unresectable advanced or metastatic melanoma has changed the prognosis of melanoma patients. Five-year overall survival rates for metastatic melanoma have increased from less than 10% up to 40–50%. Despite this revolution in advanced melanoma treatment, many patients do not benefit from currently available therapies or do not achieve durable responses. The introduction of new agents and new strategies of treatment is necessary to improve outcomes. The prognosis of patients with advanced cutaneous melanoma has radically changed in the past decade. Nevertheless, primary or acquired resistance to systemic treatment occurs in many cases, highlighting the need for novel treatment strategies. This review has the purpose of summarizing the current area of interest for the treatment of metastatic or unresectable advanced cutaneous melanoma, including data from recently completed or ongoing clinical trials. The main fields of investigation include the identification of new immune checkpoint inhibitors (anti-LAG3, GITR agonist and anti-TIGIT), adoptive cell therapy, vaccines, engineered TCR therapy, IL-2 agonists, novel targets for targeted therapy (new MEK or RAF inhibitors, HDAC, IDO, ERK, Axl, ATR and PARP inhibitors), or combination strategies (antiangiogenetic agents plus immune checkpoint inhibitors, intra-tumoral immunotherapy in combination with systemic therapy). In many cases, only preliminary efficacy data from early phase trials are available, which require confirmation in larger patient cohorts. A more in-depth knowledge of the biological effects of the molecules and identifying predictive biomarkers remain crucial for selecting patient populations most likely to benefit from novel emerging treatment strategies.
Highlights
In the recent past, the development of novel treatments has radically modified the prognosis of patients affected with advanced melanoma
Materials and Methods This review summarizes clinically relevant data from ongoing clinical trials on the systemic treatment of metastatic or unresectable advanced cutaneous melanoma, including recent data presented at the ASCO (American Society of Clinical Oncology) and ESMO (European Society of Medical Oncology) Annual Meeting
Persistent stimulation leads to prolonged LAG3 and programmed death 1 (PD-1) expression and to T cell exhaustion, a possible mechanism of resistance to immunotherapy [16]
Summary
The development of novel treatments has radically modified the prognosis of patients affected with advanced melanoma. Five-year overall survival (OS) rates for metastatic melanoma (MM) have increased substantially from less than 10% up to 40–50% [1]. The anti-programmed death 1 (PD-1) monoclonal antibodies, nivolumab, and pembrolizumab showed superior efficacy compared to ipilimumab and chemotherapy, with lower toxicities. These monoclonal antibodies achieved an overall response rate (ORR) of 40 to 50% [3,4,5] and a five-year OS rate of 41–44% [6,7]. Vemurafenib and dabrafenib, two BRAF inhibitors, have significantly improved response rates (approximately 50%), progression-free survival (PFS) and better OS than chemotherapy in patients with metastatic BRAF V600E/K mutant melanoma [9,10]. Despite the breakthrough advances in the treatment of MM, improving outcomes for those patients who do not benefit from the current standard of care remains an unmet need
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