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Melanoma: HELP
Articles by Paolo Antonio Ascierto
Based on 177 articles published since 2008
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Between 2008 and 2019, P. Ascierto wrote the following 177 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7 · 8
1 Editorial Checkpoint inhibitors in melanoma and early phase development in solid tumors: what's the future? 2017

Ascierto, Paolo A / McArthur, Grant A. ·Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy. paolo.ascierto@gmail.com. · Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. grant.mcarthur@petermac.org. · University of Melbourne, Parkville, VIC, Australia. grant.mcarthur@petermac.org. ·J Transl Med · Pubmed #28789707.

ABSTRACT: Anti-programmed death (PD)-1 and PD-ligand (L)-1 checkpoint inhibitors have revolutionized the therapy of several cancers. Immunotherapy of cancer can offer long-term durable benefit to patients, is active regardless of tumour histology, has a unique immune-related safety profile, and can be used in combination with other cancer treatments. In addition, recent research has shown that immune-based therapy can be used as adjuvant therapy, that outcomes may be influenced by dose, and that clinical activity is observed in patients with brain metastases. Despite our increased understanding of these agents, there are still several important questions that need to be answered. These include strategies to overcome primary and acquired resistance, the influence of mutational status on treatment outcomes, the optimal duration of treatment, and the need to identify novel combination regimens that offer increased anti-tumour potency and/or reduced toxicity. Here we review recent developments in these areas, with particular focus on new data reported at the 2017 ASCO Annual Meeting.

2 Editorial Melanoma: the role of surgery in the era of new therapies. 2014

Mozzillo, Nicola / Ascierto, Paolo A. ·Department of Melanoma and Soft Tissue, Istituto Nazionale Tumori Fondazione "G, Pascale", Via Mariano Semmola, 80131 Naples, Italy. paolo.ascierto@gmail.com. ·J Transl Med · Pubmed #25015684.

ABSTRACT: -- No abstract --

3 Editorial Ipilimumab before BRAF inhibitor treatment may be more beneficial than vice versa for the majority of patients with advanced melanoma. 2014

Ascierto, Paolo A / Margolin, Kim. ·Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", Naples, Italy. ·Cancer · Pubmed #24577788.

ABSTRACT: -- No abstract --

4 Editorial The role of BRAF V600 mutation in melanoma. 2012

Ascierto, Paolo A / Kirkwood, John M / Grob, Jean-Jacques / Simeone, Ester / Grimaldi, Antonio M / Maio, Michele / Palmieri, Giuseppe / Testori, Alessandro / Marincola, Francesco M / Mozzillo, Nicola. ·Department of Melanoma, Istituto Nazionale Tumori Fondazione G, Pascale, Naples, Italy. paolo.ascierto@gmail.com ·J Transl Med · Pubmed #22554099.

ABSTRACT: BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50 % of melanomas harbors activating BRAF mutations (over 90 % V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors. The first selective inhibitor of mutant BRAF, vemurafenib, after highly encouraging results of the phase I and II trial, was compared to dacarbazine in a phase III trial in treatment-naïve patients (BRIM-3). The study results showed a relative reduction of 63 % in risk of death and 74 % in risk of tumor progression. Considering all trials so far completed, median overall survival reached approximately 16 months for vemurafenib compared to less than 10 months for dacarbazine treatment. Vemurafenib has been extensively tested on melanoma patients expressing the BRAFV600E mutated form; it has been demonstrated to be also effective in inhibiting melanomas carrying the V600K mutation. In 2011, both FDA and EMA therefore approved vemurafenib for metastatic melanoma carrying BRAFV600 mutations. Some findings suggest that continuation of vemurafenib treatment is potentially beneficial after local therapy in a subset of patients with disease progression (PD). Among who continued vemurafenib >30 days after local therapy of PD lesion(s), a median overall survival was not reached, with a median follow-up of 15.5 months from initiation of BRAF inhibitor therapy. For patients who did not continue treatment, median overall survival from the time of disease progression was 1.4 months. A clinical phase I/II trial is evaluating the safety, tolerability and efficacy of vemurafenib in combination with the CTLA-4 inhibitor mAb ipilimumab. In the BRIM-7 trial vemurafenib is tested in association with GDC-0973, a potent and highly selective inhibitor of MEK1/2. Preliminary data seem to indicate that an additional inhibitor of mutated BRAF, GSK2118436, might be also active on a wider range of BRAF mutations (V600E-K-D-R); actually, treatment with such a compound is under evaluation in a phase III study among stage III-IV melanoma patients positive for BRAF mutations. Overall, BRAF inhibitors were well tolerated; common adverse events are arthralgia, rash, fatigue, alopecia, keratoacanthoma or cutaneous squamous-cell carcinoma, photosensitivity, nausea, and diarrhea, with some variants between different inhibitors.

5 Editorial Melanoma: a model for testing new agents in combination therapies. 2010

Ascierto, Paolo A / Streicher, Howard Z / Sznol, Mario. ·Unit of Medical Oncology and Innovative Therapy, National Tumor Institute, Naples, Italy. paolo.ascierto@gmail.com ·J Transl Med · Pubmed #20406483.

ABSTRACT: Treatment for both early and advanced melanoma has changed little since the introduction of interferon and IL-2 in the early 1990s. Recent data from trials testing targeted agents or immune modulators suggest the promise of new strategies to treat patients with advanced melanoma. These include a new generation of B-RAF inhibitors with greater selectivity for the mutant protein, c-Kit inhibitors, anti-angiogenesis agents, the immune modulators anti-CTLA4, anti-PD-1, and anti-CD40, and adoptive cellular therapies. The high success rate of mutant B-RAF and c-Kit inhibitors relies on the selection of patients with corresponding mutations. However, although response rates with small molecule inhibitors are high, most are not durable. Moreover, for a large subset of patients, reliable predictive biomarkers especially for immunologic modulators have not yet been identified. Progress may also depend on identifying additional molecular targets, which in turn depends upon a better understanding of the mechanisms leading to response or resistance. More challenging but equally important will be understanding how to optimize the treatment of individual patients using these active agents sequentially or in combination with each other, with other experimental treatment, or with traditional anticancer modalities such as chemotherapy, radiation, or surgery. Compared to the standard approach of developing new single agents for licensing in advanced disease, the identification and validation of patient specific and multi-modality treatments will require increased involvement by several stakeholders in designing trials aimed at identifying, even in early stages of drug development, the most effective way to use molecularly guided approaches to treat tumors as they evolve over time.

6 Review Recent success and limitations of immune checkpoint inhibitors for cancer: a lesson from melanoma. 2019

Ottaviano, Margaret / De Placido, Sabino / Ascierto, Paolo Antonio. ·Department of Clinical Medicine and Surgery, Oncology Unit, Università degli Studi di Napoli Federico II, Via Sergio Pansini 5, 80131, Naples, Italy. margaretottaviano@gmail.com. · Department of Clinical Medicine and Surgery, Oncology Unit, Università degli Studi di Napoli Federico II, Via Sergio Pansini 5, 80131, Naples, Italy. · Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori - IRCCS - "Fondazione G. Pascale", Via Mariano Semmola, 80131, Naples, Italy. ·Virchows Arch · Pubmed #30747264.

ABSTRACT: Several researches have been carried over the last few decades to understand of how cancer evades the immune system and thus to identify therapies that could directly act on patient's immune system in the way of restore or induce a response to cancer. As a consequence, "cancer immunotherapy" is conquering predominantly the modern scenario of the fight against cancer. The recent clinical success of immune checkpoint inhibitors (ICIs) has created an entire new class of anti-cancer drugs and restored interest in the field of immuno-oncology, leading to regulatory approvals of several agents for the treatment of a variety of malignancies. The first to be approved in 2011 was the anti-CTLA-4 antibody ipilimumab for the treatment of unresectable or metastatic melanoma. Subsequently, the anti-PD-1s, nivolumab and pembrolizumab, received regulatory approvals for the treatment of melanoma and several other cancers. More recently, three anti-PD-L1 antibodies have received approval: atezolizumab and durvalumab for locally advanced or metastatic urothelial carcinoma and metastatic non-small cell lung cancer (NSCLC) and avelumab for the treatment of locally advanced or metastatic urothelial carcinoma and metastatic Merkel cell carcinoma. This review, starting from the results of melanoma trials, highlights in turn different ICIs and data for different indications in several malignancies are included under each drug class.

7 Review Encorafenib in combination with binimetinib for unresectable or metastatic melanoma with BRAF mutations. 2019

Trojaniello, Claudia / Festino, Lucia / Vanella, Vito / Ascierto, Paolo A. ·a Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics , Istituto Nazionale Tumori IRCCS Fondazione G. Pascale , Napoli , Italy. ·Expert Rev Clin Pharmacol · Pubmed #30652516.

ABSTRACT: INTRODUCTION: Combination treatment with a BRAF inhibitor and MEK inhibitor is the standard of care for patients with advanced BRAF

8 Review The potential of BRAF-associated non-coding RNA as a therapeutic target in melanoma. 2019

Fattore, Luigi / Mancini, Rita / Ascierto, Paolo Antonio / Ciliberto, Gennaro. ·a IRCCS , Regina Elena National Cancer Institute , Rome , Italy. · b Department of Molecular and Clinical Medicine , University of Roma "Sapienza" , Rome , Italy. · c IRCCS , National Cancer Institute of Naples "Fondazione G. Pascale" , Naples , Italy. ·Expert Opin Ther Targets · Pubmed #30507327.

ABSTRACT: INTRODUCTION: The advent of targeted therapies and immune checkpoints inhibitors has enhanced the treatment of metastatic melanomas. Despite striking improvements of patients' survival, drug resistance continues to limit the efficacy of such treatments. Genetic and nongenetic/adaptive mechanisms of resistance could be involved; in the latter mechanism, noncoding RNAs (ncRNAs) are emerging as key players. Areas covered: This article outlines the current knowledge of ncRNA involvement in BRAF-mutant melanomas and the development of resistance to targeted/immunotherapies. We also discuss how ncRNAs can be exploited for the development of therapeutic and diagnostic approaches. Expert opinion: ncRNAs can be envisaged as powerful diagnostics and therapeutics. Despite progress in our knowledge about their deregulation in cancer, it is still difficult to derive universal and robust ncRNAs unique signatures of malignancy for diagnostic purposes, which need validation in large cohort of patients. Also, ncRNA specific targeting to melanoma cells in vivo requires the development of improved systemic delivery tools. In this regard, the development of stable nanodelivery particles seems to offer renewed hope for success in the clinic.

9 Review Emerging Strategies in Systemic Therapy for the Treatment of Melanoma. 2018

Ascierto, Paolo A / Flaherty, Keith / Goff, Stephanie. ·From the Istituto Nazionale Tumori "Fondazione G. Pascale," Naples, Italy; Massachusetts General Hospital Cancer Center, Boston, MA; Center for Cancer Research, National Cancer Institute, Bethesda, MD. ·Am Soc Clin Oncol Educ Book · Pubmed #30231371.

ABSTRACT: Recent years have seen major improvements in survival of patients with advanced melanoma with the advent of various novel systemic immunotherapies and targeted therapies. As our understanding of these agents and their various mechanisms of action improves, even more impressive outcomes are being achieved through use of various combination strategies, including the combining of different immunotherapies with one another as well as with other modalities. However, despite the improved outcomes that have been achieved in advanced melanoma, responses to treatment are heterogeneous and may not always be durable. Additional advances in therapy are required, and several emerging strategies are a focus of interest. These include the investigation of several new immunotherapy and/or targeted therapy combinations, such as checkpoint inhibitors (anti-PD-1/anti-CTLA-4) with other immunotherapies (e.g., indoleamine 2,3 dioxygenase [IDO] inhibitors, antilymphocyte activation 3 [anti-LAG-3], histone deacetylase [HDAC] inhibitors, Toll-like receptor 9 [TLR-9] agonists, antiglucocorticoid-induced tumor necrosis factor receptor [anti-GITR], pegylated interleukin-2 [IL-2]), combined targeted therapies (e.g., MEK and CDK4/6 coinhibition), and combined immunotherapy and targeted therapy (e.g., the triplet combination of BRAF/MEK inhibition with anti-PD-1s). The identification of novel therapeutic targets in the MAP kinase pathway also offers opportunities to improve outcomes by overcoming de novo and acquired resistance to BRAF/MEK inhibition (e.g., the development of ERK inhibitors). In addition, adoptive cell transfer, the infusion of large numbers of activated autologous lymphocytes, may have a potential role in patients whose disease has progressed after immunotherapy. Taken together, these new approaches offer further potential to increase systemic treatment options and improve long-term outcomes for patients with advanced melanoma.

10 Review Survival of patients with advanced metastatic melanoma: the impact of novel therapies-update 2017. 2017

Ugurel, Selma / Röhmel, Joachim / Ascierto, Paolo A / Flaherty, Keith T / Grob, Jean Jacques / Hauschild, Axel / Larkin, James / Long, Georgina V / Lorigan, Paul / McArthur, Grant A / Ribas, Antoni / Robert, Caroline / Schadendorf, Dirk / Garbe, Claus. ·Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. Electronic address: selma.ugurel@uk-essen.de. · Bremen, Germany. · Melanoma, Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", Naples, Italy. · Massachusetts General Hospital, Boston, MA, USA. · Department of Dermatology, Timone Hospital and Aix-Marseille University, Marseille, France. · Department of Dermatology, University Hospital of Schleswig-Holstein, Kiel, Germany. · Royal Marsden Hospital NHS Foundation Trust, London, UK. · Melanoma Institute Australia, The University of Sydney, and Royal North Shore Hospital, Sydney, NSW, Australia. · University of Manchester, The Christie NHS Foundation Trust, Manchester, UK. · Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia and University of Melbourne, Parkville, VIC, Australia. · University of California, Los Angeles, CA, USA. · Gustave Roussy Cancer Campus, Villejuif Grand-Paris, France. · Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. · Center for Dermatooncology, Department of Dermatology, University of Tuebingen, Tuebingen, Germany. ·Eur J Cancer · Pubmed #28756137.

ABSTRACT: The treatment of metastatic melanoma is still undergoing a process of major change. The two most important novel therapeutic strategies, selective kinase inhibitors and immune checkpoint blockers, both significantly prolong survival times of patients with advanced metastatic disease. Different agents, dose regimens and combinations have been tested against each other vigorously within these two groups. However, results from prospective head-to-head comparative studies of both strategies are still lacking. We performed an exploratory analysis of survival data from selected clinical trials representative for the new treatment strategies in advanced metastatic melanoma. Eighty-three Kaplan-Meier survival curves from 25 trials were digitised and grouped by therapeutic strategy and treatment line. For each of these groups, mean survival curves were generated for progression-free (PFS) and overall survival (OS) by weighted averaging. Survival curves grouped together by therapeutic strategy revealed a high concordance, particularly in the first-line setting. For kinase inhibitors, the most favourable PFS and OS in all therapy lines were observed for combined BRAF plus MEK inhibition. For immune checkpoint inhibitors, combined PD-1 plus CTLA-4 inhibition demonstrated the best survival outcome in all categories except for OS in first-line therapy. For the latter, combined PD-1 plus CTLA-4 inhibition showed similar outcomes as single-agent PD-1 inhibition. Comparison of kinase inhibitors and checkpoint blockers revealed a superiority of combined BRAF plus MEK inhibition within the first 6 months, later changing to a superiority of PD-1 blockers alone or in combination with CTLA-4 blockers. These results need confirmation by prospective clinical trials.

11 Review MEK Inhibitors in the Treatment of Metastatic Melanoma and Solid Tumors. 2017

Grimaldi, Antonio M / Simeone, Ester / Festino, Lucia / Vanella, Vito / Strudel, Martina / Ascierto, Paolo A. ·Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy. · Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy. paolo.ascierto@gmail.com. ·Am J Clin Dermatol · Pubmed #28537004.

ABSTRACT: The mitogen-activated protein kinase (MAPK) cascade is an intracellular signaling pathway involved in the regulation of cellular proliferation and the survival of tumor cells. Several different mutations, involving BRAF or NRAS, exert an oncogenic effect by activating the MAPK pathway, resulting in an increase in cellular proliferation. These mutations have become targets for new therapeutic strategies in melanoma and other cancers. Selective MEK inhibitors have the ability to inhibit growth and induce cell death in BRAF- and NRAS-mutant melanoma cell lines. MEK inhibitor therapy in combination with a BRAF inhibitor is more effective and less toxic than treatment with a BRAF inhibitor alone, and has become the standard of care for patients with BRAF-mutated melanoma. Trametinib was the first MEK inhibitor approved for the treatment of BRAF-mutated metastatic melanoma not previously treated with BRAF inhibitors, and is also approved in combination with the BRAF inhibitor dabrafenib. Furthermore, cobimetinib is another MEK inhibitor approved for the treatment of BRAF-mutated metastatic melanoma in combination with a BRAF inhibitor, vemurafenib. The MEK inhibitor binimetinib in combination with the BRAF inhibitor encorafenib is in clinical development. The addition of an anti-PD-1/PD-L1 agent, such as pembrolizumab, durvalumab or atezolizumab, to combined BRAF and MEK inhibition has shown considerable promise, with several trials ongoing in metastatic melanoma. Binimetinib has also shown efficacy in NRAS-mutated melanoma patients. Future possibilities for MEK inhibitors in advanced melanoma, as well as other solid tumors, include their use in combination with other targeted therapies (e.g. anti-CDK4/6 inhibitors) and/or various immune-modulating antibodies.

12 Review Mucosal melanoma of the head and neck. 2017

Ascierto, Paolo Antonio / Accorona, Remo / Botti, Gerardo / Farina, Davide / Fossati, Piero / Gatta, Gemma / Gogas, Helen / Lombardi, Davide / Maroldi, Roberto / Nicolai, Piero / Ravanelli, Marco / Vanella, Vito. ·Department Melanoma, Soft Tissues, Musculoskeletal and Head & Neck, Italian National Cancer Institute - IRCCS Pascale Foundation, Naples, Italy. Electronic address: paolo.ascierto@gmail.com. · Department of Otorhinolaryngology, University of Brescia, Italy. · Department of Pathology and Cytopathology, Italian National Cancer Institute - IRCCS Pascale Foundation, Naples, Italy. · Department of Radiology, University of Brescia, Italy. · Particle Therapy Cancer Research Institute, CNAO Foundation, Milan, Italy. · Evaluative Epidemiology Unit, Fondazione IRCCS "Istituto Nazionale dei Tumori", Milan, Italy. · First Department of Medicine, Laiko General Hospital, Athens, Greece. · Department Melanoma, Soft Tissues, Musculoskeletal and Head & Neck, Italian National Cancer Institute - IRCCS Pascale Foundation, Naples, Italy. ·Crit Rev Oncol Hematol · Pubmed #28325255.

ABSTRACT: Mucosal melanoma of the head and neck is a very rare and aggressive malignancy with a very poor prognosis. The nasal cavity, paranasal sinuses, and oral cavity are the most common locations. One-, 3- and 5-year survival rates between 2000 and 2007 were 63%, 30% and 20%, respectively. Cigarette smoking seems to be a risk factor even though the evidence for this is very low. Clinical signs and symptoms are usually nonspecific. While surgery is considered the mainstay of treatment for most mucosal melanomas of the head and neck region, radiotherapy has a role in local control of the disease after surgery. Many new treatment options in the last years, in particular targeted therapies (i.e. inhibitors of c-KIT, NRAS/MEK or BRAF) and immunotherapies (anti CTLA-4 and anti PD-1/PD-L1 antibodies), have changed the history of cutaneous melanoma. Despite the different biology, mucosal melanoma is currently treated in the same way as cutaneous melanoma; however, patients with mucosal melanoma were excluded from the majority of recent clinical trials. Recent molecular findings offer new hope for the development of more effective systemic therapy.

13 Review MicroRNAs in melanoma development and resistance to target therapy. 2017

Fattore, Luigi / Costantini, Susan / Malpicci, Debora / Ruggiero, Ciro Francesco / Ascierto, Paolo Antonio / Croce, Carlo M / Mancini, Rita / Ciliberto, Gennaro. ·Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", Napoli, Italia. · CROM, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Napoli, Italia. · Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Catanzaro "Magna Graecia", Catanzaro, Italia. · Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. · Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Roma, Italia. · IRCCS Istituto Nazionale Tumori "Regina Elena", Roma, Italy. ·Oncotarget · Pubmed #28118616.

ABSTRACT: microRNAs constitute a complex class of pleiotropic post-transcriptional regulators of gene expression involved in the control of several physiologic and pathologic processes. Their mechanism of action is primarily based on the imperfect matching of a seed region located at the 5' end of a 21-23 nt sequence with a partially complementary sequence located in the 3' untranslated region of target mRNAs. This leads to inhibition of mRNA translation and eventually to its degradation. Individual miRNAs are capable of binding to several mRNAs and several miRNAs are capable of influencing the function of the same mRNAs. In recent years networks of miRNAs are emerging as capable of controlling key signaling pathways responsible for the growth and propagation of cancer cells. Furthermore several examples have been provided which highlight the involvement of miRNAs in the development of resistance to targeted drug therapies. In this review we provide an updated overview of the role of miRNAs in the development of melanoma and the identification of the main downstream pathways controlled by these miRNAs. Furthermore we discuss a group of miRNAs capable to influence through their respective up- or down-modulation the development of resistance to BRAF and MEK inhibitors.

14 Review Combination Treatment of Patients with BRAF-Mutant Melanoma: A New Standard of Care. 2017

Simeone, Ester / Grimaldi, Antonio M / Festino, Lucia / Vanella, Vito / Palla, Marco / Ascierto, Paolo A. ·Melanoma, Cancer Immunotherapy and Innovative Therapies Unit, Istituto Nazionale Tumori di Napoli Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy. · Melanoma, Cancer Immunotherapy and Innovative Therapies Unit, Istituto Nazionale Tumori di Napoli Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy. paolo.ascierto@gmail.com. ·BioDrugs · Pubmed #28058658.

ABSTRACT: 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.

15 Review Systematic review of the use of granulocyte-macrophage colony-stimulating factor in patients with advanced melanoma. 2016

Hoeller, Christoph / Michielin, Olivier / Ascierto, Paolo A / Szabo, Zsolt / Blank, Christian U. ·Department of Dermatology, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. christoph.hoeller@meduniwien.ac.at. · Department of Oncology, Lausanne University Hospital, Champ de l'Air, Rue du Bugnon 21, 1011, Lausanne, Switzerland. · Ludwig Centre and Swiss Institute of Bioinformatics, Génopode Building, 1015, Lausanne, Switzerland. · Istituto Nazionale Tumori, Fondazione 'G. Pascale', Via Mariano Semmola, 52, 80131, Naples, Italy. · Clinical Development, Amgen Europe GmbH, Dammstrasse 23, 6300, Zug, Switzerland. · Division of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands. ·Cancer Immunol Immunother · Pubmed #27372293.

ABSTRACT: Several immunomodulatory checkpoint inhibitors have been approved for the treatment of patients with advanced melanoma, including ipilimumab, nivolumab and pembrolizumab. Talimogene laherparepvec is the first oncolytic virus to gain regulatory approval in the USA; it is also approved in Europe. Talimogene laherparepvec expresses granulocyte-macrophage colony-stimulating factor (GM-CSF), and with other GM-CSF-expressing oncolytic viruses in development, understanding the clinical relevance of this cytokine in treating advanced melanoma is important. Results of trials of GM-CSF in melanoma have been mixed, and while GM-CSF has the potential to promote anti-tumor responses, some preclinical data suggest that GM-CSF may sometimes promote tumor growth. GM-CSF has not been approved as a melanoma treatment. We undertook a systematic literature review of studies of GM-CSF in patients with advanced melanoma (stage IIIB-IV). Of the 503 articles identified, 26 studies met the eligibility criteria. Most studies investigated the use of GM-CSF in combination with another treatment, such as peptide vaccines or chemotherapy, or as an adjuvant to surgery. Some clinical benefit was reported in patients who received GM-CSF as an adjuvant to surgery, or in combination with other treatments. In general, outcomes for patients receiving peptide vaccines were not improved with the addition of GM-CSF. GM-CSF may be a valuable therapeutic adjuvant; however, further studies are needed, particularly head-to-head comparisons, to confirm the optimal dosing regimen and clinical effectiveness in patients with advanced melanoma.

16 Review Melanoma: the intersection of molecular targeted therapy and immune checkpoint inhibition. 2016

Lau, Peter Kar Han / Ascierto, Paolo A / McArthur, Grant. ·Department of Cancer Medicine, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia. · Melanoma, Cancer Immunotherapy, and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", Via Mariano Semmola, 80131 Napoli, Italy. Electronic address: paolo.ascierto@gmail.com. ·Curr Opin Immunol · Pubmed #26765776.

ABSTRACT: Melanoma is at the forefront of development of systemic therapeutics with both molecular targeted therapies and immune checkpoint inhibitors as cornerstones of treatment. Although responses to molecularly targeted therapy is largely from blockade of oncogenic pathways, evidence is emerging of the immunomodulatory effects from BRAF inhibition. Additionally programmed-death-1 (PD-1) inhibitors have revolutionized the treatment of melanoma and are set to pave future improvements in other solid tumors. Combinations of PD-1 inhibitors with novel immune checkpoints or with molecularly targeted therapies are under investigation and may improve on the considerable progress made.

17 Review Survival of patients with advanced metastatic melanoma: The impact of novel therapies. 2016

Ugurel, Selma / Röhmel, Joachim / Ascierto, Paolo A / Flaherty, Keith T / Grob, Jean Jacques / Hauschild, Axel / Larkin, James / Long, Georgina V / Lorigan, Paul / McArthur, Grant A / Ribas, Antoni / Robert, Caroline / Schadendorf, Dirk / Garbe, Claus. ·Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. Electronic address: selma.ugurel@uk-essen.de. · 28355 Bremen, Germany. · Melanoma, Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples, Italy. · Massachusetts General Hospital, Boston, MA, USA. · Dermatology Department, Timone Hospital and Aix-Marseille University, Marseille, France. · University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany. · Royal Marsden Hospital NHS Foundation Trust, London, UK. · Melanoma Institute Australia and The University of Sydney, Sydney, NSW, Australia. · University of Manchester, The Christie NHS Foundation Trust, Manchester, UK. · Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; University of Melbourne, Parkville, VIC, Australia. · University of California, Los Angeles, CA, USA. · Gustave Roussy Cancer Campus, Villejuif Grand-Paris, France. · Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. · Center for Dermatooncology, Department of Dermatology, University Tuebingen, 72074 Tuebingen, Germany. ·Eur J Cancer · Pubmed #26707829.

ABSTRACT: The survival of advanced metastatic melanoma has been greatly improved within the past few years. New therapeutic strategies like kinase inhibitors for BRAF-mutant melanoma and immune checkpoint blockers proved to prolong survival times within clinical trials, and many of them have already entered routine clinical use. However, these different treatment modalities have not yet been tested against each other, which complicate therapy decisions. We performed an explorative analysis of survival data from recent clinical trials. Thirty-five Kaplan-Meier survival curves from 17 trials were digitised, re-grouped by matching inclusion criteria and treatment line, and averaged by therapy strategy. Notably, the survival curves grouped by therapy strategy revealed a very high concordance, even if different agents were used. The greatest survival improvement was observed with the combination of BRAF plus MEK inhibitors as well as with Programmed-death-1 (PD1) blockers with or without cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockers, respectively, with these two treatment strategies showing similar survival outcomes. For first-line therapy, averaged survival proportions of patients alive at 12 months were 74.5% with BRAF plus MEK inhibitor treatment versus 71.9% with PD-1 blockade. This explorative comparison shows the kinase inhibitors as similarly effective as immune checkpoint blockers with regard to survival. However, to confirm these first trends for implementation into an individualised treatment of melanoma patients, data from prospective clinical trials comparing the different treatment strategies head-to-head have to be awaited.

18 Review Single versus combination immunotherapy drug treatment in melanoma. 2016

Grimaldi, Antonio Maria / Marincola, Francesco M / Ascierto, Paolo Antonio. ·a Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy , Istituto Nazionale Tumori Fondazione G. Pascale , Napoli , Italy. · b Sidra Medical and Research Centre , Doha , Qatar. ·Expert Opin Biol Ther · Pubmed #26642234.

ABSTRACT: INTRODUCTION: The advent of new immunotherapies for the treatment of metastatic melanoma has resulted in various novel combination strategies. Because of their distinct modes of action, different immunotherapies have been investigated in combination with one another, as well as combined with targeted therapies and other treatment modalities. AREAS COVERED: Anti-CTLA-4 and anti-PD-1 treatments enhance antitumor immunity through complementary and non-redundant mechanisms. The combination of the anti-CTLA-4 agent ipilimumab and the anti-PD-1 agent nivolumab has been shown to improve progression-free survival and objective response rate compared with either agent alone as monotherapy in patients with advanced melanoma. However, the combination was associated with significant toxicity, with around one-third of patients discontinuing treatment as a result. The sequential use of nivolumab and ipilimumab was associated with similar outcomes and comparable toxicity to concurrent therapy. Clinical trials assessing various combinations of immunomodulating antibodies are ongoing or planned. Ipilimumab and pembrolizumab have also been investigated in combination with the oncolytic virus, talimogene laherparepvec (T-VEC), with promising results. In addition, immunotherapies have also been combined with chemotherapy, radiotherapy and electrochemotherapy. EXPERT OPINION: Investigation of combination approaches represents the start of a new story that begins with melanoma treatment and expands to embrace other solid and hematological cancers.

19 Review Integrating first-line treatment options into clinical practice: what's new in advanced melanoma? 2015

Dummer, Reinhard / Schadendorf, Dirk / Ascierto, Paolo A / Larkin, James / Lebbé, Celeste / Hauschild, Axel. ·aDepartment of Dermatology, University Hospital Zürich, Zürich, Switzerland bDepartment of Dermatology, University Hospital Essen, Essen cDepartment of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany dIstituto Nazionale Tumori Fondazione 'G. Pascale', Naples, Italy eRoyal Marsden NHS Foundation Trust, London, UK fAPHP Oncodermatology Unit, University Paris 7 Diderot U976, Paris, France. ·Melanoma Res · Pubmed #26426764.

ABSTRACT: Melanoma remains a serious form of skin cancer in Europe and worldwide. Localized, early-stage melanomas can usually be treated with surgical excision. However, the prognosis is poorer for patients with advanced disease. Before 2011, treatment for advanced melanoma included palliative surgery and/or radiotherapy, and chemotherapy with or without immunotherapy, such as interleukin-2. As none of these treatments had shown survival benefits in patients with advanced melanoma, European guidelines had recommended that patients be entered into clinical trials. The lack of approved first-line options and varying access to clinical trials meant that European clinicians relied on experimental regimens and chemotherapy-based treatments when no other options were available. Since 2011, ipilimumab, an immuno-oncology therapy, and vemurafenib and dabrafenib, targeted agents that inhibit mutant BRAF, have been approved by the European Medicines Agency for the treatment of advanced melanoma. More recently, the MEK inhibitor, trametinib, received European marketing authorization for use in patients with BRAF mutation-positive advanced melanoma. In 2014, the anti-PD-1 antibody nivolumab was approved as a first-line therapy in Japan. Whereas nivolumab and another anti-PD-1 antibody, pembrolizumab, were approved as second-line therapies in the USA, their recent approval in Europe are for first-line use based on new clinical trial data in this setting. Together these agents are changing clinical practice and making therapeutic decisions more complex. Here, we discuss current and emerging therapeutic options for the first-line treatment of advanced melanoma, and how these therapies can be optimized to provide the best possible outcomes for patients.

20 Review Novel mechanisms and therapeutic approaches in melanoma: targeting the MAPK pathway. 2015

Grimaldi, Antonio Maria / Simeone, Ester / Festino, Lucia / Vanella, Vito / Palla, Marco / Ascierto, Paolo Antonio. ·O.U. Melanoma, Cancer Immunotherapy and Innovative Therapies, National Cancer Institute of Naples "G. Pascale" Foundation, Naples, Italy. ·Discov Med · Pubmed #26175403.

ABSTRACT: 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.

21 Review 2015: The Year of Anti-PD-1/PD-L1s Against Melanoma and Beyond. 2015

Ascierto, Paolo A / Marincola, Francesco M. ·Istituto Nazionale Tumori, Fondazione "G. Pascale", Napoli, Italy. · Sidra Medical and Research Centre, Doha, Qatar. ·EBioMedicine · Pubmed #26137543.

ABSTRACT: -- No abstract --

22 Review The use of interferon in melanoma patients: a systematic review. 2015

Di Trolio, Rossella / Simeone, Ester / Di Lorenzo, Giuseppe / Buonerba, Carlo / Ascierto, Paolo Antonio. ·Unit of Melanoma, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, Italy. Electronic address: rosselladitrolio@yahoo.it. · Unit of Melanoma, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, Italy. Electronic address: ester.simeone@gmail.com. · Oncology Division, Department of Clinical Medicine, University "Federico II" of Naples, Italy. Electronic address: giuseppedilorenzoncol@hotmail.com. · Oncology Division, Department of Clinical Medicine, University "Federico II" of Naples, Italy. Electronic address: carbuone@hotmail.com. · Unit of Melanoma, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, Italy. Electronic address: paolo.ascierto@gmail.com. ·Cytokine Growth Factor Rev · Pubmed #25511547.

ABSTRACT: Interferon (IFN) and PEG-IFN are the only drugs approved as adjuvant therapy in patients with melanoma at high-risk of recurrence after surgical resection. Several clinical trials of adjuvant IFN, using different doses and durations of therapy, have been conducted in these patients. Results generally suggest relapse-free survival and overall survival benefits; however, questions over the optimal dose and duration of treatment and concerns over toxicity have limited its use. IFN exerts its biological activity in melanoma via multiple mechanisms of action, most of which can be considered as indirect immunomodulatory effects. As such, IFN may also be of benefit in the neoadjuvant setting, where it may have a role in melanoma patients with locally advanced disease for whom immediate surgical excision is not possible. However, this has not been well studied. The use of IFN in patients with metastatic melanoma is controversial, with limited data and no convincing evidence of a survival benefit. However, IFN therapy combined with novel biological and immunotherapies offers the potential for a synergistic effect and improved clinical outcomes. Predictive and prognostic factors to better select melanoma patients for IFN treatment have been identified (e.g. disease stage, ulceration, various cytokines) and may also enhance its therapeutic efficacy, but their incorporation into the clinical decision-making process requires validation in prospective trials. In conclusion, the modest efficacy of IFN shown in clinical trials is largely a reflection of differences in response between patients. Despite advancements in the understanding of its biological mechanisms of action, the huge potential of IFN remains to be fully explored and utilized in patients with melanoma.

23 Review Side effects and toxicities of targeted therapies in stage IV melanoma. 2015

Ascierto, Paolo A / Bastholt, Lars / Hersey, Peter / Cinat, Gabriela / Eggermont, Alexander M M / Hauschild, Axel / Espinosa, Enrique / Robert, Caroline. ·1Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori-Fondazione G. Pascale, Naples, Italy; 2Odense University Hospital, Odense, Denmark; 3Newcastle University, Newcastle, Australia; 4Instituto de Oncologia Angel Rolfo, Buenos Aires, Argentina; 5Institut Gustave Roussy, Villejuif, France; 6University of Kiel, Kiel, Germany; 7Hospital La Paz, Madrid, Spain; and 8Institut Gustave Roussy, Villejuif, France. ·Am J Ther · Pubmed #24185314.

ABSTRACT: As the incidence of melanoma continues to increase worldwide, the search for new therapies for advanced (stage IV) melanoma brings with it new patterns of toxicity to contend with. This review covers the toxicity profiles of new treatments for advanced melanoma currently in development. Therefore, the latest literature on melanoma treatment was surveyed for data on reported toxicities. The new types of treatments can be roughly divided into targeted tyrosine kinase inhibitors and immunomodulating agents. Each has its own set of toxicities particular to type and to individual drug. Targeted tyrosine kinase inhibitors generally cause fatigue, whereas immunomodulatory agents induce a specific set of adverse events known as immune-related adverse events (irAEs). Despite the incidence of adverse events, these agents hold promise for the treatment of stage IV melanoma. With new treatment opportunities come increased chance of toxic reactions. The key to successful melanoma treatment in the future is likely to be novel combinations of new therapeutic agents.

24 Review Who benefits most from adjuvant interferon treatment for melanoma? 2015

Gogas, Helen / Abali, Huseyin / Ascierto, Paolo A / Demidov, Lev / Pehamberger, Hubert / Robert, Caroline / Schachter, Jacob / Eggermont, Alexander M M / Hauschild, Axel / Espinosa, Enrique. ·1First Department of Medicine, Athens University Medical School, Athens, Greece; 2Division of Medical Oncology, Baskent University School of Medicine, Adana, Turkey; 3Unit of Medical Oncology and Innovative Therapy, Istituto Nazionale Tumori Fondazione "G. Pascale," Naples, Italy; 4Department of Biotherapy, Blokhin Cancer Center, Moscow, Russia; 5Department of Dermatology, Medical University of Vienna, Vienna, Austria; 6Department of Dermatology, Institute Gustave Roussy, Villejuif Cedex, France; 7Department of Oncology, Sheba Medical Center, Tel Hashomer, Israel; 8Department of Dermatologie, University of Kiel, Kiel, Germany; and 9Oncology Service, Hospital La Paz, Madrid, Spain. ·Am J Ther · Pubmed #24176884.

ABSTRACT: Metastatic melanoma has a poor prognosis; the median survival for patients with stage IV melanoma ranges from 8 to 18 months after diagnosis. Interferon-α provides significant improvement in disease-free survival at the cost of poor tolerability. Identifying patients who benefit the most may improve the cost:benefit ratio. In addition, no data exist for the role of adjuvant therapy in noncutaneous melanoma. Molecular profiles may help to identify patients who benefit the most from adjuvant interferon therapy. In this review, the American Joint Commission on Cancer 2009 staging criteria and emerging biomarker data to guide adjuvant treatment decisions will be discussed. Several criteria to guide selection of patients are discussed in detail. These include Breslow thickness, number of positive lymph nodes, whether or not the primary lesion has ulcerated, immunologic markers, and cytokine profiles. Substantial progress has been made in deciding which patients benefit from interferon-α adjuvant therapy. Interferon-α is the only agent currently approved for the adjuvant treatment of this deadly disease, despite its side effect profile. More effective drugs with better tolerability are needed.

25 Review Interferon alpha for the adjuvant treatment of melanoma: review of international literature and practical recommendations from an expert panel on the use of interferon. 2014

Ascierto, Paolo A / Chiarion-Sileni, Vanna / Muggiano, Antonio / Mandalà, Mario / Pimpinelli, Nicola / Del Vecchio, Michele / Rinaldi, Gaetana / Simeone, Ester / Queirolo, Paola. · ·J Chemother · Pubmed #24621162.

ABSTRACT: The degree to which interferon (IFN) alpha-2b offers real clinical benefits in the adjuvant therapy of melanoma at high risk of recurrence is a subject of debate. This, together with questions over optimal treatment scheme and concerns over toxicity, has limited its clinical use. On the basis of a review of the literature, an Italian Expert Panel has made practical recommendations for a consistent approach in the use of IFN. Although it is clear that more research into predictive factors to identify patients most likely to benefit from adjuvant IFN therapy is required, IFN remains the only currently available adjuvant option for melanoma. Based on meta-analyses of clinical trials, there is clear evidence that treatment with IFN is beneficial with regard to overall and recurrence-free survival (RFS). As such, IFN should be offered to patients who are at high risk of recurrence. Specific recommendations with regard to disease stage are provided.

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