It has been shown that combination of these two drugs was more effective with an objective response rate of 42% months whereas nivolumab monotherapy resulted in 20% or 6% ORR (in asymptomatic and neurologically symptomatic patients respectively)

It has been shown that combination of these two drugs was more effective with an objective response rate of 42% months whereas nivolumab monotherapy resulted in 20% or 6% ORR (in asymptomatic and neurologically symptomatic patients respectively). from 2 III phase, 8 II phase trials, 2 observational studies as well as 2965 patients who received ipilimumab in an expanded access program. The follow-up period reached 10 years. The 3-year survival rate was equal to 21% and after this period was observed with the safety issue related to the effect of activation of the autoreactive lymphocytes, which occurred in DP2 18-23% of the patients. The most common ones included colitis, skin lesions and endocrinopathies [8, 9]. Antibody against programmed Peptide 17 death-1 (PD-1) In the 1990s, Okazaki codon V600 which is present in about Peptide 17 50% of cases [11]. It has been proven in a number of studies that the most effective treatment for this group of patients consists of the combination of a BRAF inhibitor and MEK inhibitor [12C14]. IO agents approved globally for routine clinical usage include three checkpoint inhibitors C two anti-PD1 antibodies (nivolumab and pembrolizumab), one anti-CLTA-4 immunoglobulin (ipilimumab) and a representative of a new therapeutic group, oncolytic virus, talimogene laherparepvec (T-VEC). Adjuvant therapy Until recently, the standard of care for resected melanoma was treatment with interferon. The implication of this treatment on survival were limited. However the published results from the EORTC 18071 trial have changed this standard of care. This phase 3 randomized trial compared ipilimumab (10 mg/kg) to placebo in patients who had undergone complete resection of stage III melanoma. In this study, 951 patients were randomly (1 : 1) Peptide 17 assigned to treatment with ipilimumab every 3 weeks for 4 doses, then every 3 months for up to 3 years or until disease recurrence or to placebo. The 5-year rate of recurrence-free survival was 41% in the ipilimumab group and 30% in the placebo group. The 5-year overall survival was 65% in the ipilimumab group and 54% in the placebo group. With 2.7 median follow up, the median relapse-free survival (RFS) on ipilimumab arm was significantly superior that in placebo; 26.1 vs. 17.1 months respectively. The improvement was noticed in both populations: with macro- and/or micrometastases to the regional lymph nodes. The effect of treatment was even more remarkable in population with ulceration of primary site. The treatment related side effects were significantly more commonly observed in ipilimumab group than in placebo: 54% patients experienced 3/4 grade of toxicity acc. CTCEA v.4 in comparison to 25% of the placebo group. What is more, in half of population treatment with ipilimumab, the therapy must have been stopped Peptide 17 due to the safety issue, 5 patients (1%) died because of ipilimumab toxicity [27]. In 2015 this adjuvant ipilimumab gained US Food and Drug Administration (FDA) approval, but practically this treatment has limited usage due to the high rated of toxicity and cost (about 1 million US dollar per patient). On the other hand, the presented in 2016 update of trial (with 5.3 median follow up), indicates the significant improvement of RFS, and overall survival (OS). The 5-year OS in ipilimumab group was 65,4%, and was significantly higher than in placebo group C 54,4%; (HR 0,72, 95,1% CI: 0,58C0,88; = 0,001) [28]. Nowadays the clinical trials are ongoing with anti-PD1 antibodies in adjuvant settings. The first data presented in 2017 showed, that nivolumab administered in patients with melanoma after lymphadenectomy (IIIB, IIIC and IV Stage) is related to the 10% of RFS improvement with lower toxicity as compared with ipilimumab [29]. The trial with combination anti-CTLA-4 and anti-PD-1 are ongoing, as well, the results are pending. Future directions As mentioned above, currently first line therapeutic options for advanced melanoma include immunotherapy with anti-PD1 antibodies (combination of PD1/CTLA-4 blockers can be an option in a specific group of patients) or targeted therapy with.