Selected articles

03/2021 MUDr. Eugen Kubala
Adjuvant therapy is considered the standard approach to the treatment of patients with locally advanced stage IIIA, IIIB and IIIC melanoma. The EORTC 1325-MG/KEYNOTE-045 study, which compared pembrolizumab with placebo, clearly demonstrated its efficacy. Long-term follow-up showed that 3-year relapse free survival (RFS) was achieved in 63.7 patients with pembrolizumab versus 44.1% in placebo patients (HR 0.56; 95% CI, 0.47-0.68; p < 0.001). This treatment has been shown to be highly safe with a low incidence of side effects. At the same time, the incidence of immunotherapy-related adverse events has been shown to be associated with better treatment outcomes than without them, especially in endocrine toxicity (p = 0.03). However, the absence of immunotherapy-related adverse events does not lead to a significant reduction in the efficacy of pembrolizumab over placebo.

06/2020 MUDr. Eugen Kubala
Treatment of advanced and metastatic melanoma with the BRAF V600 mutation by combination therapy with BRAF and MEK inhibitors encorafenib and binimetinib was demonstrated in the COLUMBUS study, the results of which were updated in June 2020. Encorafenib is an ATP-competitive BRAF inhibitor capable of blocking several mutated forms of BRAF kinase for 30 hours (e.g. V600E, V600D and V600K) in tumor melanoma cells against other BRAF inhibitors dabrafenib (2 hours) or vemurafenib (0.5 hours). It allows almost permanent inhibition of the mutated form of BRAF protein kinase. According to the updated results of the COLUMBUS study, the median PFS results for the combination of encorafenib + binimetinib at 14.9 months versus vemurafenib were confirmed at 7.3 months. Significant is the comparison of the two BRAF inhibitors encorafenib and vemurafenib, which indicated a higher efficacy of encorafenib versus vemurafenib median PFS 9.6 vs 7.3 months HR 0.68 (95% CI 0.52-0.88; p = 0.0038) Combination of the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib significantly shifted the median PFS of 16.4 months and the median overall survival (OS) of 33.6 months without increasing toxicity over the established and used combinations of BRAF and MEK inhibitors used in the treatment of BRAF V600 mutant melanoma. In long-term follow-up of COMBO 450 (the combination encorafenib 450 mg and binimetinib 45 mg) vs vemurafenib (vemurafenib 960 mg) patients, 26% vs 12% of patients achieved 48-month PFS. Another primary endpoint of the COLUMBUS study was an updated outcome of OS.4-year survival was achieved in 39% of patients treated with COMBO450 combination therapy, 37% of patients treated with encorafenib 300 mg (ENCO300) monotherapy, and 26% of patients treated with vemurafenib (VEM). The updated results of the COLUMBUS study presented at ASCO (American Society of Clinical Oncology Congress) 2020 confirmed that the combination of encorafenib and binimetinib is a highly effective treatment for BRAF V600 mutant melanoma.

02/2020 MUDr. Eugen Kubala
The successful journey continues. After success in advanced and metastatic melanoma, melanoma treatment has been transferred to adjuvant therapy. It is essential to determine early stages of melanoma suitable for adjuvant treatment. According to the new classification, the prognosis for stages IIB and IIC is worse than for stage IIIA. This group of patients is currently denied adjuvant therapy and we are awaiting the results of ongoing trials. Because the risk of disease relapse is high, between 40 and 60%, the aims of current research to move adjuvant therapy to the stage II. The Keynote 716 study (MK 3475-716 - NCT03553836) sought to determine whether adjuvant therapy with pembrolizumab at risk stages IIB and IIC would delay the relapse of the disease. The focus of the main studies of targeted treatment of COMBI AD and immunotherapy EORTC 18071, CheckMate-238, Keynote 054 was the stage III. The question is not whether to treat, but what treatment to start especially for melanoma with BRAF V600 mutation. Adjuvant treatment at this stage has shown a clear benefit and its use is undoubted. Unfortunately, we are not clear about subsequent treatment at relapse during or after adjuvant treatment.

06/2019 MUDr. Eugen Kubala
Treatment of patients with advanced and metastatic melanoma with BRAF V600 mutation has been enriched with new combination therapy with BRAF and MEK inhibitors encorafenib and binimetinib. Pharmacological inhibition of the mitogen-activated protein kinase (MAPK) signaling pathway has brought significant progress in the treatment of metastatic melanoma. A key role is played by the product of the mutated BRAF V600E kinase¹ gene, which is part of the MAPK signaling pathway. Encorafenib is an ATP competitive inhibitor of BRAF kinase that is able to block several mutated forms of BRAF kinase (e.g. V600E, V600D and V600K) in tumor melanoma cells with much greater efficacy - up to ten times higher half-life, i.e. more than 30 hours longer effect of either dabrafenib (2 hours) or vemurafenib (0,5 hours). The COLUMBUS study has achieved its primary goal of increasing the median progression free survival (PFS) of combination therapy with encorafenib and binimetinib for 14,9 months comparing to vemurafenib treatment with 7,3 months PFS. Significant is the comparison of the two BRAF inhibitors encorafenib and vemurafenib, which indicated a higher efficacy of encorafenib over vemurafenib - PFS median 9,6 versus 7,3 months (HR 0,68; 95% CI 0,52-0,88; p = 0,0038 The combination of the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib significantly shifted the PFS median to 16,4 months and the median overall survival to 33,6 months without increasing toxicity against the established combinations of BRAF and MEK inhibitors that we use in the treatment of BRAF V600 mutated melanoma.

03/2019 MUDr. Eugen Kubala
Dissatisfaction with the current state of the complex metastatic colorectal cancer treatment leads to a deeper analysis of the right choice of consecutive treatment line. Metastatic colorectal cancer remains incurable in most cases. We have a variety of cytostatics and biological treatments available. The right choice for the 1^st line of treatment, which is crucial for the outcome of the whole treatment, seems to be crucial. The selection is based on knowledge of biological markers of RAS and BRAF and clinical factors. The result of successive lines depends on choosing the correct 1^st line. In the 2^nd line, anti-angiogenic agents (bevacizumab, ramucirumab and aflibercept) were used. Epidermal growth factor receptor (EGFR) inhibitors do not increase 2^nd-line survival. The 3^rd line is dependent on the molecular examination of the tumor. Knowing the status of the RAS BRAF mutation determines whether we use anti EGFR antibodies or BRAF and MEK inhibitors. The state of microsatellite stability is critical to the use of immunotherapy (pembrolizumab, nivolumab, and ipilimumab. Proper understanding of the mechanisms of selection of sequential therapy and its de-escalation and re-escalation may lead to prolonged positive treatment outcomes. A significant difference between progression to full treatment or de-escalated treatment, the latter allowing reuse of the substance that was used at the start of treatment, knowledge of the molecular profile of tumors that appears to be essential in the choice of treatment should contribute to the correct management of treatment. In the 1^st, 2^nd and 3^rd line of therapy, the selective pressure of treatment on cell subpopulations of the tumor limits the success of the next treatment line.

06/2017 MUDr. Eugen Kubala
Fluoropyrimidines have represented the cornerstone of treatment of colorectal cancer for a long time. Lonsurf is an orally administered combination of a thymidine-based nucleic acid analogue - trifluridine and a thymidine phosphorylase inhibitor - tipiracil hydrochloride with trifluridine being the active cytotoxic component of this combination. Its triphosphate form is incorporated into DNA appearing to result in antitumor effects. Tipiracil hydrochloride is a strong inhibitor of the thymidine phosphorylase and, when combined with trifluridine prevents the rapid degradation of the trifluridine, allowing longer maintenance of adequate plasma concentration of the active drug. The results of the placebo-controlled, double-blind, phase 3 clinical trial RECOURSE confirmed the results of previous assessments of oral Lonsurf in patients with metastatic colorectal cancer, who had already undergone extensive treatment. Lonsurf was associated with a clinically relevant prolongation of overall survival in essentially all treatment subgroups. Combination of trifluridine and tipiracil is able to replace 5-fluorouracil in patients who have developed resistance to this treatment. It turns out that the combination with a biologic therapy or oxaliplatin and irinotecan has a great future in the treatment of not only metastatic colorectal cancer.

03/2017 MUDr. Eugen Kubala
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.