Lucian Miron MD, PhD
Regional Institute of Oncology Iaşi
University of Medicine and Pharmacy “Grigore T. Popa” Iasi
Sistemic treatments in advanced malignant melanoma
Author: Lucian Miron
The prognosis of patients with metastatic cutaneous melanoma, is generally poor. Until recently, metastatic melanoma had historically been a challenging disease to treat, with a 10-year survival rate of less than 10%. Dacarbazine was the benchmark systemic therapy for this disease for more than 3 decades. after its initial approval in 1975.
Recently, new classes of drugs (e.g. immune checkpoint inhibitors and small-molecule targeted drugs) have significantly improved patient prognosis, which has drastically changed the landscape of melanoma therapeutic management. The recognition of BRAF as an important tumour oncogene in melanoma has led to the development of new targeted therapies.
BRAF and MEK targeted therapy are effective and shoul be use only for patients with BRAF V600 mutated melanoma. Combination BRAF (vemurafenib, dabrafenib) and MEK (trametinib) inhibition results in improved outcomes compared to single-agent BRAF inhibition. All patients with advanced cutaneous melanoma should have their tumor evaluated for the presence of an activating BRAF mutation.
The importance of the immune system in cancer, leading to the development of checkpoint inhibitors. The development of checkpoint inhibitors as a tolerable and effective therapy for metastatic melanoma, which has demonstrated improved response rates, duration of control and overall survival for patients of patients with metastatic melanoma as these therapies are being trialled in other malignancies.
The first checkpoint inhibitors approved by the FDA in 2011 was ipilimumab, a fully human, monoclonal IgG1 antibody that inhibits CTLA-4. Approval of the two anti-PD-1 antibodies—nivolumab and pembrolizumab—followed. PD-1, programmed cell death protein 1, is a negative regulator of T cell activity and is expressed by T cells with excessive exposure to antigens. The other ligand, PD-L2, is expressed mainly by antigen-presenting cells (APCs). Both ligands are members of B7 protein family.
Multiple intratumoral and vaccine approaches have been tested for treating advanced melanoma. The vaccines aim to elicit immune response against antigens expressed by melanoma tumor cells, such as tumor-associated antigens (TAAs) or mutation-derived antigens (neoantigens). Administration of ipilimumab, nivolumab, pembrolizumab, the combination of ipilimumab and nivolumab, and talimogene laherparepvec (T-VEC; for patients with accessible lesions).
Immune checkpoint blockade can achieve durable responses in many patients with metastatic melanoma, and current treatments can improve survival for many metastatic melanoma patients as well as provide hope for a cure for some of them. While meaningful progress is being made, much more work still needs to be accomplished for patients with metastatic melanoma.