Modern immunotherapy together with targeted therapy has revolutionized the treatment of advanced melanoma. Inhibition of immune checkpoints significantly improved the median overall survival and gave hope to many melanoma patients. However, this treatment has three serious drawbacks: high cost, serious side effects, and an effectiveness limited only to approximately 50% of patients. Some patients do not derive any or short-term benefit from this treatment due to primary or secondary resistance. The response to immunotherapy depends on many factors that fall into three main categories: those associated with melanoma cells, those linked to a tumor and its microenvironment, and those classified as individual ontogenic and physiological features of the patient. The first category comprises expression of PD-L1 and HLA proteins on melanoma cells as well as genetic/genomic metrics such as mutational load, (de)activation of specific signaling pathways and epigenetic factors. The second category is the inflammatory status of the tumor: “hot” versus “cold” (i.e., high versus low infiltration of immune cells). The third category comprises metabolome and single nucleotide polymorphisms of specific genes. Here we present up-to-date data on those biological factors influencing melanoma response to immunotherapy with a special focus on signaling pathways regulating the complex process of anti-tumor immune response. We also discuss their potential predictive capacity.

Background Molecularly targeted therapy has revolutionized the treatment of advanced melanoma. However, despite its high efficiency, a majority of patients experience relapse within 1 year of treatment because of acquired resistance, and approximately 10-25% patients gain no benefit from these agents owing to intrinsic resistance. This is mainly caused by the genetic heterogeneity of melanoma cells. Objective We aimed to validate the predictive significance of selected genes in advanced melanoma patients before treatment with BRAF/MEK inhibitors. Patients and Methods Archival DNA derived from 37 formalin-fixed paraffin-embedded pre-treatment advanced melanoma samples of patients treated with targeted therapy was used for next-generation sequencing analysis using the Ion Torrent platform. The AmpliSeq Custom Panel comprised coding sequences or hot spots of 23 melanoma genes: ATM,

IntroductionThe use of immunotherapy in older patients remains challenging due to very few data on the efficacy and safety of treatment in this group.AimTo analyse the efficacy and safety of immunotherapy with checkpoint inhibitors in older patients (≥ 70 years) with metastatic melanoma.Material and methodsIn the Maria Skłodowska-Curie Institute – Oncology Centre, between 2011 and 2017, 318 non-resectable or metastatic melanoma patients were treated with immune checkpoint inhibitors: anti-CTLA-4 or/and anti-PD-1. Eighty-two patients were ≥ 70 years (median age: 76 years; range: 70–90 years). Among this group 10% of patients had brain metastases, 24% of patients had BRAF mutant melanoma, and co-morbidities were present in 86% of patients (mainly hypertension, cardiovascular diseases and/or diabetes).ResultsMedian PFS and OS were similar in patients < 70 years and ≥ 70 years. In the group of patients ≥ 70 years old, the 2-year OS rate (from the start of immunotherapy) was 27%, and in patients aged < 70 it was 28% (p = NS). Two-year progression-free survival was 13.7% in the group of patients ≥ 70 years old and in patients aged < 70 it was 13% (p = NS). Patients ≥ 70 years of age were significantly less likely to have a BRAF mutation (p = 0.020). The presence of co-morbidities was not associated with an increased risk of immunotherapy (p = 0.790).ConclusionsThe survival and toxicity profile in the older patients treated with immune checkpoint inhibitors are similar to younger patients. Therefore, the age as a clinical factor should not exclude this population from the most effective therapy used nowadays in melanoma treatment.

Despite considerable progress made in the treatment of patients with advanced melanoma, the majority of the patients treated with BRAF and mitogen-activated protein inhibitors (BRAFi and MEKi) experience a disease progression due to acquired resistance. Currently, ongoing studies explore the possibility to overcome or reverse this process. Our multicenter retrospective analysis included 51 patients with metastatic BRAF-mutated melanoma who had previously progressed on BRAFi/MEKi than had progressed on immunotherapy (anti-progression disease-1 or anti-cytotoxic T-lymphocyte-associated protein 4) and next were rechallenged with BRAFi/MEKi. Median age at BRAFi/MEKi rechallenge was 56 (range: 31–82 y/o). Median overall survival from the start of the first BRAFi/MEKi therapy and from rechallenge BRAFi/MEKi treatment was 29.7 and 9.3 months, respectively, whereas median progression-free survival was 10.5 and 5.9 months, respectively. Six-month, annual, and 2-year overall survival rates on both treatments were: 98% and 55%, 92% and 29%, and 69% and 2%, respectively. A response rate to treatment was higher in the group receiving BRAFi/MEKi for the first time as compared with the group receiving BRAFi/MEKi rechallenge and was overall response rate 72% and 27%; disease control rate 92% and 63%. Time interval between the end of the first BRAFi/MEKi treatment and the beginning of BRAFi/MEKi rechallenge did not influence median overall survival or progression-free survival. A lower toxicity rate was noted with BRAFi/MEKi rechallenge. BRAFi/MEKi rechallenge treatment remains clinically important and is associated with the lower toxicity. BRAFi/MEKi rechallenge efficacy is higher in patients who are in good performance status, with normal lactate dehydrogenase, and without brain metastases.

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Neutrophil-to-lymphocyte ratio (NLR) has been shown to be prognostic in several solid malignancies. There are limited data regarding its value during novel therapies in patients with melanoma. The aim of the study was to assess the practical utility of this ratio in patients with BRAF-mutant melanoma treated with a combination of BRAF and MEK inhibitors (BRAFi/MEKi). We included 215 patients with inoperable or metastatic melanoma who underwent BRAFi/MEKi treatment between October 2015 and June 2017. Baseline NLR and other complete blood count-derived inflammatory markers were tested for association with overall survival and progression-free survival in univariate and multivariate models. On-treatment NLR was also assessed for relationship with these outcomes using the time-dependent Cox's proportional hazard model. Prognostic model based on NLR and lactate dehydrogenase (LDH) levels was also developed. Patients with NLR values more than four had poorer progression-free survival (P<0.001, 1-year rates 51.6 vs. 26.7%) and overall survival (P<0.001, 1-year rates 77.3 vs. 53.1%). In a multivariate model adjusted for LDH levels, metastatic sites and age baseline NLR ratio and delay in starting MEKi were deemed statistically significant (hazard ratio: 1.81; 95% confidence interval: 1.16-2.85; P=0.009 and hazard ratio: 2.06; 95% confidence interval: 1.24-3.44, P=0.005 respectively). In a model based on NLR and LDH, 1-year survival rates were 57, 40 and 23%, respectively if zero, one or both factors were elevated. Our results demonstrate the usefulness of NLR and a predictive model based on combinations of NLR and LDH as a prognostic markers during BRAFi/MEKi treatment. Our real-world data confirm the efficacy of BRAFi/MEKi therapy showed in the clinical trials.

Introduction: Previous studies showed that high and low body mass index (BMI) was associated with worse prognosis in metastatic CRC (mCRC). Whether BMI is a prognostic or predictive factor in mCRC is unclear. We aimed to assess efficacy outcomes according to BMI in patient with metastatic colorectal cancer treated with bevacizumab plus FOLFOX chemotherapy regimen in second-line treatment. Material and methods: The analysis of 237 patients with metastatic colorectal cancer treated with bevacizumab plus FOLFOX in the second line (treated from January 2014 to August 2018) in 4 reference oncological centers in Poland. Results: The median age of the patients was 65 years (range 34-82). The median overall survival (OS) and progression-free survival (PFS) of the all 237 patient was 14.6 and 8.8 months, respectively. Comparison of obese patient (BMI > 30 kg/m 2) vs. overweight patients (BMI ≥ 25 to < 30 kg/m 2) vs. normal BMI range patients revealed a significant improvement of median OS (17.5 vs. 14.3 vs. 13.1 months, p = 0.01) and median PFS (9.4 vs. 9.1 vs. 7.3 months, p = 0.03). The Cox hazard model showed that the BMI class is an important risk factor. However, the Cox model also showed that the significance of the BMI class applies only to patients with BMI < 25 kg/m 2. This rule applies to both OS and PFS. The regression analysis also confirmed that there is a statistically significant relationship between the length of OS and PFS and the BMI value. Higher BMI was associated with a better prognosis. There were no differences in responses to treatment bevacizumab and FOLFOX chemotherapy and number adverse events according to BMI values. Conclusions: Patients with mCRC treated with chemotherapy with bevacizumab in second-line treatment with higher BMI compared with normal weight patients have better prognosis in terms of PFS and OS. In this group, we found no evidence of changes in safety profile depending on BMI. Nevertheless, further large randomized studies are needed to assess the body weight on the effectiveness of chemotherapy in combination with bevacizumab.

IntroductionThe use of vemurafenib in melanoma has improved the survival of patients; however, it is associated with skin toxicities.AimTo assess skin toxicities by dermoscopy in patients treated with vemurafenib.Material and methodsEight patients with BRAF V600 mutation positive metastatic melanoma were examined dermoscopically during vemurafenib treatment. All skin lesions occurring during therapy were assessed clinically and dermoscopically using a hand-held dermoscope with polarised and non-polarised light. Skin lesions suspected for malignancy appearing during therapy were totally surgically excised with consecutive histopathological examination.ResultsAll 8 examined patients developed skin toxicity. The majority of patients (7/8) presented G1 skin toxicity according to CTCAE version 4.3. Only 1 of them had G2 skin toxicity. The most common dermoscopy findings in our study were hyperkeratotic verrucas in 5 patients (5/8) with structureless pattern. In some of them we also observed central dots, exophytic proliferation, hairpin vessels and homogeneous haemorrhage. Other findings were hyperkeratosis of the nipples (5/8) with brownish to yellowish, angular clods with a tendency to be more confluent in dermoscopy. Palmar plantar erythrodysaesthesia (3/8) showed dermoscopically a yellowish, homogeneous pattern. Four melanocytic skin lesions in 2 patients were surgically excised due to suspected malignant transformation. In most of them we observed an atypical pigmented network (abrupt cut-off, big holes), atypical globules and a homogeneous blue pattern; however, histopathological diagnosis excluded any malignancy.ConclusionsDermoscopy seems to be an easily performed and valuable method for assessment of skin toxicities during oncological therapy, at any time of the treatment.