How to choose the first‑line treatment of the advanced and metastatic melanoma


MUDr. Eugen Kubala

Klinika onkologie a radioterapie LF UK a FN, Hradec Králové



The treatment of a metastatic melanoma has progressed so much that before we choose it, we have to ask some questions. What first-line treatment strategy should we choose for patients with the BRAF mutation? Which first-line patients are suitable for immunotherapy? Is the presence of BRAF mutation definite predictor for biological treatment? Pharmacological inhibition of mitogen-activated protein kinase signaling pathways (MAPK) has brought significant advances in the treatment of patients with BRAF-mutated metastatic melanoma. Among these successful pharmaceutics belong BRAF inhibitors (vemurafenib, dabrafenib, encorafenib), and MEK inhibitors (trametinib, selumetinib, cobinetinib, binimetinib). Their advantage is a fast induction of the overall response to 70 %, but the major disadvantage is the development of resistance in the majority of patients (100 %). Its overcoming is investigated in the use of other kinase inhibitors of the MAPK signaling pathway including RAS/RAF/MEK/ERK kinase. A certain disadvantage is the ability to induce resistance to immunotherapy anti-PD1 by inducing mesenchymal transformation. Innately resistant tumors exhibit transcriptional signature (IPRES or innate resistance to PD-1), which exhibits an increased expression of genes involved in the regulation of mesenchymal transformation, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing. The same genetic signature that induces IPRES, was observed in melanoma tissues after treatment BRAF inhibitors, and thus induces cross-resistance to anti-PD-1 treatment. Immunotherapy is another treatment option for metastatic melanoma. Its use does not require the presence of BRAF mutation, however, it also lacks a clear predictor of treatment effectiveness. The number of responses to treatment is only about 30-40 %, but the resistance occurs in only about 25 %. We can influence the immune system by blocking anti-CTLA4 antibody ipilimumab, or by blockade of a local immune response in the tumor itself using anti PD1 antibodies nivolumab. Both drugs belong to a group checkpoint inhibitors, which block the blinding of the immune system and the tumor escape from immune surveillance. At present, we can use both compounds in the first-line treatment in the monotherapy or in combination. More effective treatment is by nivolumab. If we achieve the treatment response it lasts even long after discontinuation of therapy. Evidence showed the advantages of biological treatment over immunotherapy in the first-line treatment of metastatic melanoma. This could help in the correct orientation in choosing the right method of treatment for an individual patient.



melanoma, BRAF mutations, biological therapy, immunotherapy, first-line treatment



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