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Background Previous studies have suggested that elevated neutrophil-to-lymphocyte ratio (NLR) is prognostic for worse outcomes in patients with a variety of solid cancers, including those treated with immune checkpoint inhibitors. Methods This was a retrospective analysis of 97 consecutive patients with stage IV melanoma who were treated with nivolumab. Baseline NLR and derived (d) NLR were calculated and, along with other characteristics, correlated with progression-free survival (PFS) and overall survival (OS) in univariate and multivariate analyses. The best cutoff values for NLR and dNLR were derived using Cutoff Finder software based on an R routine which optimized the significance of the split between Kaplan-Meier survival curves. Results In univariate analysis, increasing absolute neutrophil count (ANC), NLR, dNLR and lactate dehydrogenase (LDH) (continuous variables) were all significantly associated with OS. Only NLR (hazard ratio [HR] = 2.85; 95% CI 1.60–5.08; p

Cytotoxic T lymphocyte-associated antigen (CTLA-4) is a coinhibitory transmembrane protein which binds to the B-71 and B7-2 ligands on antigen presenting cells (APCs) with an affinity approximately 20-fold higher than that of CD28. While CD28 has a costimulatory function and helps facilitate and maintain a T cell response, CTLA-4 plays a role in blocking T cell activation. Understanding the precise mechanism of CTLA-4 activity in vivo, and by extension, the mechanism of antitumor immune activity mediated by CTLA-4 blockade, is an area of active investigation, and two hypotheses to explain CTLA-4 activity—distinct but not mutually exclusive—involve intrinsic and extrinsic cellular mechanisms. Several models have been proposed to explain the intrinsic inhibitory function of CTLA-4, including recruitment of inhibitory proteins to T cell synapsis, nonligand binding CTLA-4 splice variant, ligand competition to prevent CD28 signaling, inhibition of lipid-raft and microcluster formation and inhibition of the T cell stop signal. Proposed models for extrinsic mechanisms include transendocytosis of CD80/CD86, reverse signaling through CD80 and CD86 on APCs, modulation of inhibitory cytokine production, blocking CD80 capture and the cell-mediated cytotoxicity of regulatory T cells. The identification of CTLA-4 has led to the clinical development of CTLA-4 blocking antibodies that are able to stimulate potent antitumor immunity. Clinical studies have confirmed that the CTLA-4 inhibitor ipilimumab can induce durable responses and improve overall survival in patients with advanced melanoma.

Immune checkpoint inhibitors are immunomodulatory monoclonal antibodies that block inhibitory immune pathways that tumor cells use to evade immune suppression. The main targets are the cytotoxic T lymphocyte-associated antigen (CTLA)-4 receptor on T lymphocytes and the programmed cell death (PD)-1 receptor and its PD-1 ligand (PD-L1). The first checkpoint inhibitor to be approved for treating cancer patients was ipilimumab, an anti-CTLA-4 antibody. Ipilimumab resulted in significant improvements in overall survival (OS) when compared with standard chemotherapy in phase III studies and is now approved as frontline therapy for patients with metastatic melanoma. However, another anti-CTLA-4 antibody, tremelimumab, did not show any OS benefit over standard chemotherapy in first-line treatment of patients with metastatic melanoma but is being investigated in combination regimens in other tumor types.

The prognosis of metastatic melanoma has changed markedly in recent years because of the advent of newer targeted therapies such as BRAF inhibitors. However, the response to BRAF inhibitor therapy is frequently nondurable in patients with advanced melanoma. Novel approaches are thus needed to overcome resistance to these agents and to improve the management of advanced melanoma patients after disease progression. Here, we present the case of a 44-year-old man diagnosed with advanced melanoma in July 2010, harboring a BRAF mutation. Melanoma progressed during first-line chemotherapy with dacarbazine, but showed significant benefit after the initiation of vemurafenib on August 2011. Six months later, the patient experienced disease progression in left-obturator lymphadenopathy; still, anti-BRAF treatment was continued together with stereotactic radiotherapy, and was interrupted only shortly for intestinal occlusion secondary to melanoma metastasis of the bowel. When his conditions were stable, after 1 month of vemurafenib treatment discontinuation, anti-BRAF therapy was reinitiated, with a positive outcome. Vemurafenib treatment was definitively discontinued for disease progression in the brain, peritoneum, lymph node, intestine, and skin in March 2013, after about 20 months from initiation, and the patient died a few weeks later. The clinical case presented here shows that treatment beyond progression with vemurafenib can yield a survival benefit in melanoma patients whose disease progresses in a few sites, which can be treated with locoregional therapies. This clinical strategy needs further validation in prospective clinical trials.

Background Extensive squamous cell carcinoma has few therapeutic options. In such cases, electrochemotherapy involving electroporation combined with antineoplastic drug appears to be a new potential option and may be considered as an alternative treatment. The aim of this retrospective single-center study was to evaluate electrochemotherapy efficacy in treatment of locally advanced stage III squamous cell carcinoma, in which surgical procedures would have entailed wide tissue sacrifice. Methods Clinical features, treatment response, and adverse effects were evaluated in 22 patients treated with electrochemotherapy with intravenous injection of bleomycin for extensive stage III cutaneous squamous cell carcinoma. Treatment of cutaneous lesions were performed according to the European Standard Operating Procedures of Electrochemotherapy. Results Overall response to electrochemotherapy treatment was observed in 18 (81.8%) patients. Clinical response with necrosis of tumor mass was observed from the first session and lasted for all follow up period that ranged between 5 and 48 months with a median of 34 months. Overall the treatment was well tolerated with a very low complication rate. Conclusions Electrochemotherapy represents a safe and effective therapeutic approach, associated with a good tolerability.

Raf-mitogen-activated protein kinase (Raf-MAPK) pathway inhibition with the BRAF inhibitors vemurafenib and dabrafenib, alone or in combination with a MEK inhibitor, has become a standard therapeutic approach in patients with BRAF-mutated metastatic melanoma. Both vemurafenib and dabrafenib have shown good safety and efficacy as monotherapy compared with chemotherapy. However, the duration of response is limited in the majority of patients treated with BRAF inhibitor monotherapy because of the development of acquired resistance. The addition of a MEK inhibitor can improve blockade of the MAPK pathway and may help to overcome resistance and thereby prolong efficacy, as well as reduce cutaneous toxicity. Combinations of BRAF inhibitors and MEK inhibitors (dabrafenib plus trametinib and vemurafenib plus cobimetinib) have been approved for the treatment of BRAF-mutant metastatic melanoma and may become a new standard of care. However, acquired resistance is still a significant concern with BRAF and MEK inhibitor combination therapy, and other strategies are being investigated, including the use of sequential and intermittent schedules. The combination of BRAF or MEK inhibitors with immunotherapy has been shown to hold considerable promise, with several combinations being evaluated in clinical trials. Preliminary results from clinical trials involving triple combination therapy with BRAF-MEK inhibitors and anti-PD-L1 antibodies appear promising and may indicate a new strategy to treat patients with BRAF-mutated metastatic melanoma. Biomarkers are needed to help identify patients with BRAFV600 mutations most likely to benefit from first-line BRAF/MEK inhibitor therapy rather than immunotherapy and vice versa.

SUMMARY Lung cancers harboring mutations in the EGFR respond to EGF receptor-tyrosine kinase inhibitor, which at present represent the most appropriate treatment for EGFR mutation-positive advanced non-small-cell lung cancer. Unfortunately drug resistance invariably emerges with different known mechanisms, including the EGFR T790M mutation, MET gene amplification, EGFR amplification, mutations in the PIK3CA gene, mutations in the HER2 gene, IGF1R amplification, transformation of non-small-cell lung cancer into small-cell lung cancer and moreover epithelial-to-mesenchymal transition. Various strategies to manage secondary resistance have been explored and in this review we will analyze scientific data in support of these different strategies to assess the most adequate to use in relation to the progression disease.

Traditional therapeutic approaches for patients with advanced neuroendocrine tumors (NETs) have included treatment with somatostatin analogs, hepatic-directed therapies, interferon and cytotoxic chemotherapy. Current knowledge about biological behavior of pancreatic neuroendocrine tumors (pNETs) has increased in the last decade, and some studies have been conducted to translate in the clinical setting. Among several molecular agents investigated in patients with progressive pNETs, everolimus and sunitinib have been studied in large Phase III trials. Both have produced significant benefit, with improvement in progression-free survival. These results were published last year by NEJM and were updated at the ASCO Annual Meeting in June 2011.This review focuses on the potential molecular targets in pancreatic NETs in the light of recent advances. Furthermore, it summarizes the available data for targeted agents from Phase II and III trials open to patients with this tumor.These new agents are likely to play an increasingly important role in the future management of advanced pNETs. Their use in earlier phases of the disease could improve clinical outcome, avoiding side effects of the more toxic chemotherapy. The challenge in medical treatment of pNET is to define the patients who can benefit from this innovative therapy; future research should be directed to find predictive markers for response to the targeted agent.

Poster: "ECR 2018 / C-2079 / Immuno-related adverse events (irAE) from check-Point inhibitors during immunotherapy for cancer. Imaging Findings." by: "F. Sandomenico1, S. Pizza2, G. De Rosa1, O. Catalano3, E. simeone1, L. festino1, A. M. grimaldi1, P. Ascierto3, A. Petrillo3; 1Napoli/IT, 2Napoli (NA)/IT, 3Naples/IT"

The development of novel treatments that selectively inhibit the RAS-RAF-MAPK pathway represents a milestone in the history of melanoma treatment. BRAF mutations occur in approximately 45% of cutaneous melanomas, while mutations in NRAS occur in 15-25%. Vemurafenib was the first BRAF inhibitor to be approved in 2011, based on the results of a phase III trial (BRIM-3) that showed higher progression-free survival and overall survival compared with dacarbazine chemotherapy in metastatic BRAF-mutated melanoma. Dabrafenib, another BRAF inhibitor, has shown similar results and was approved in 2013. Preclinical studies suggested that another novel group of agents, the MEK inhibitors, showed stronger inhibition of both mutated BRAF and NRAS cell cultures than vemurafenib. Trametinib was the first MEK inhibitor approved in 2014, both as a single agent and in combination with dabrafenib for the treatment of advanced BRAF-mutated melanoma. Other MEK inhibitors are also in development. Concomitant inhibition of both MEK and BRAF has shown more durable and greater tumor response than BRAF monotherapy, by overcoming the multiple genetic mechanisms of escape. Combined therapy prevents the development of acquired resistance as well as decreasing cutaneous toxicity secondary to paradoxical activation of the MAPK pathway induced by BRAF inhibitors. Various combinations of BRAF and MEK inhibitors have shown promising results. Moreover, triple combination therapies involved other agents with novel mechanisms of action are also being evaluated. These and other combination strategies involving immunotherapies and targeted therapies offer the hope of improving outcomes beyond those already achieved with anti-BRAF treatments.

Checkpoint inhibitors have improved survival for patients with melanoma, non-small-cell lung cancer (NSCLC), bladder, head and neck and other cancers. Antibodies against PD-L1, including atezolizumab, avelumab and durvalumab, are also being developed and have been approved for various cancers. Compared with anti-CTLA-4 drugs, studies with anti-PD-1/PD-L1 agents have suggested higher response rates and improved survival. Targeting PD-L1 rather than PD-1 may also theoretically offer further benefit, with the potential for improved efficacy and reduced toxicity, although this has not been clearly shown by clinical experience to date. Anti-PD-L1 agents have shown good efficacy and manageable toxicity in several tumor types.

The optimal sequencing of targeted treatment and immunotherapy in the treatment of advanced melanoma is a key question and prospective studies to address this are ongoing. Previous observations suggest that treating first with targeted therapy may select for more aggressive disease, meaning that patients may not gain full benefit from subsequent immunotherapy. In a single-center retrospective analysis, we investigated whether response to pembrolizumab was affected by previous BRAF inhibitor therapy. A total of 42 patients with metastatic cutaneous or mucosal melanoma who had received previous treatment with ipilimumab were treated with pembrolizumab as part of the Italian expanded access program. Sixteen of these patients had BRAF-mutated melanoma and had also been previously treated with a BRAF inhibitor (vemurafenib or dabrafenib), while 26 had BRAF wild-type melanoma (no previous BRAF inhibitor). Patients with BRAF-mutant melanoma who were previously treated with BRAF inhibitors had a significantly lower median progression-free survival (3 [2.3-3.7] versus not reached [2-8+] mo; p = 0.001) and disease control rate (18.6% versus 65.4%; p = 0.005) than patients with BRAF wild-type, while there was also a trend toward a lower response rate (assessed using immune-related response criteria) although this was not significantly different between groups (12.5% versus 36.4%; p = 0.16). These data are consistent with previous reports that BRAF inhibitor therapy may affect subsequent response to immunotherapy.

Introduction: Metformin is a widely used antidiabetic drug, which also displays significant growth inhibitory and proapoptotic effects in several cancer models, including lung cancer, alone or in combination with chemotherapeutic drugs. Areas covered: The role of metformin as a chemopreventive drug in lung cancer is still an object of debate as epidemiological studies have shown contrasting results. More preclinical data support its role as an adjuvant drug in the treatment of lung cancer, in combination with chemotherapy or targeted molecular drugs, although the complete mechanism of action of metformin is still unclear, and potentially may exert unexpected effects with contradictory clinical implications. Expert opinion: Future perspective studies are required in nonsmall-cell lung cancer (NSCLC) patients to better investigate the effect of metformin action on the RAS/RAF/MAPK pathway and the best context in which to use metformin in combination with molecularly targeted agents.

The lack of valid clinical management options for patients affected by metastatic colorectal cancer, which has progressed after all approved standard treatments, has lead to research into new active molecules. Regorafenib is an oral small-molecule multi kinase inhibitor, binding to several intracellular kinases, with powerful inhibitory activity against vascular endothelial growth factor receptors (VEGFR-1,VEGFR-2, and VEGFR-3), platelet-derived growth factor receptor, fibroblast growth factor receptor 1, Raf, TIE-2, and the kinases KIT, RET, and BRAF. The antitumor activity of regorafenib has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in several cancer models, particularly colorectal cancer and gastrointestinal stromal tumors. The most frequent adverse events of grade 3 or higher related to regorafenib were hand-foot skin reaction, fatigue, diarrhea, hypertension, and rash or desquamation. Only a few Phase I–II trials, and most recently a Phase III trial in pretreated colorectal cancer, have been carried out to date. Several ongoing trials are testing the efficacy of regorafenib in combination with chemotherapy. At this point in time, regorafenib is the first small-molecule tyrosine kinase inhibitor to gain approval by the US Food and Drug Administration for pretreated metastatic colorectal cancer patients.

Melanoma is responsible for most skin cancer-related deaths and is one of the most common cancers diagnosed in young adults. In melanoma, tumors can become established by activation of the negative regulator of cytotoxic T lymphocytes (CTLs), CTL antigen-4 (CTLA-4). Ipilimumab blocks the interaction of CTLA-4 with CD80/CD86 and augments T-cell activation and proliferation. In electrochemotherapy (ECT), local application of short high-voltage pulses renders cell membranes transiently permeable to chemotherapeutic drugs. The combination of ipilimumab and ECT may be beneficial for the treatment of metastatic melanoma; however, no prospective data are available to date. Here, we report the retrospective analysis of patients treated with ipilimumab in an expanded access program (EAP) who also received ECT. Fifteen patients with previously treated metastatic melanoma who received ipilimumab 3 mg/kg every three weeks for four cycles and underwent ECT for local disease control and/or palliation of cutaneous lesions with bleomycin 15 mg/m2 after the first ipilimumab infusion were included in the analysis. Over the study period, a local objective response was observed in 67% of patients (27% complete response [CR] and 40% partial response [PR]). According to immune-related response criteria, a systemic response was observed in nine patients (five PR and four stable disease [SD]), resulting in a disease control rate of 60%. Evaluation of circulating T-regulatory (T-reg) cells demonstrated significant differences between responders and non-responders. Overall, treatment was well-tolerated and without notable toxicity. In conclusion, the combination of ipilimumab and ECT appears to be beneficial to patients with advanced melanoma, warranting further investigation in prospective trials.

Meeting abstracts Immunomodulation with pembrolizumab (anti-PD-1) has been shown to reach significant objective response (RR) and extend overall survival (OS) both in ipilimumab pre-treated and naive patients with metastatic melanoma. While this immunotherapy gives OS and OR benefits, it can also

Acquired resistance is the most common cause of BRAF inhibitor monotherapy treatment failure, with the majority of patients experiencing disease progression with a median progression-free survival of 6-8 months. As such, there has been considerable focus on combined therapy with dual BRAF and MEK inhibition as a means to improve outcomes compared with monotherapy. In the COMBI-d and COMBI-v trials, combined dabrafenib and trametinib was associated with significant improvements in outcomes compared with dabrafenib or vemurafenib monotherapy, in patients with BRAF-mutant metastatic melanoma. The combination of vemurafenib and cobimetinib has also been investigated. In the phase III CoBRIM study in patients with unresectable stage III-IV BRAF-mutant melanoma, treatment with vemurafenib and cobimetinib resulted in significantly longer progression-free survival and overall survival (OS) compared with vemurafenib alone. One-year OS was 74.5% in the vemurafenib and cobimetinib group and 63.8% in the vemurafenib group, while 2-year OS rates were 48.3% and 38.0%, respectively. The combination was also well tolerated, with a lower incidence of cutaneous squamous-cell carcinoma and keratoacanthoma compared with monotherapy. Dual inhibition of both MEK and BRAF appears to provide a more potent and durable anti-tumour effect than BRAF monotherapy, helping to prevent acquired resistance as well as decreasing adverse events related to BRAF inhibitor-induced activation of the MAPK-pathway. Combined BRAF and MEK inhibition is the standard of care in patients with advanced BRAF-mutant melanoma.

Meeting abstracts Identifying molecular biomarkers in melanoma may provide useful diagnostic and therapeutic tools. Melanoma delivers immune suppressive stimuli through the pathway PDL-1/PD-1. Recent data suggest tumour-cell expression of PD-L1 in melanoma may be driven by constitutive oncogenic

Meeting abstracts About 50% of melanoma (MM) have BRAF V600 mutation and BRAF inhibitors, such as vemurafenib and dabrafenib, have shown an high response rate (RR) and overall survival (OS) improvement in BRAF-mutated MM patients (pts). Pembrolizumab, a monoclonal antibody anti-PD-1, has shown a