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Melanoma: HELP
Articles by Mario Mandalá
Based on 76 articles published since 2010
(Why 76 articles?)
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Between 2010 and 2020, M. Mandalà wrote the following 76 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Review Adjuvant Treatment of Melanoma: Recent Developments and Future Perspectives. 2019

Testori, Alessandro A E / Ribero, Simone / Indini, Alice / Mandalà, Mario. ·Dermatology, Fondazione IRCCS San Matteo, Pavia, Italy. info@alessandrotestori.it. · Medical Sciences Department, Dermatologic Clinic, University of Turin, Turin, Italy. · Melanoma Unit, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. ·Am J Clin Dermatol · Pubmed #31177507.

ABSTRACT: Surgical excision is the treatment of choice for early stage melanoma, and this strategy is initially curative for the vast majority of patients. However, only approximately 40-60% of high-risk patients who undergo surgery alone will be disease-free at 5 years. These patients will ultimately experience loco-regional relapse or relapse at distant sites. The main aim of adjuvant therapies is to reduce the recurrence rate of radically operated patients at high risk and to potentially improve survival. Recent practice changing results with immune checkpoint inhibitors and targeted therapies have been published in stage III/IV melanoma patients, after surgical complete resection, and have dramatically improved the landscape of adjuvant therapy. Interferon-α, ipilimumab, and more recently anti-programmed cell death protein-1 antibodies and BRAF inhibitors plus MEK inhibitors have been approved in the adjuvant setting by the US Food and Drug Administration; similarly, the same drugs are approved by the European Medicines Agency with the exception of ipilimumab. A completely new scenario is emerging in the neoadjuvant setting as well: in locally advanced or metastatic disease, patients may partially respond to neoadjuvant therapy and become virtually resectable with systemic control of disease. This review summarizes the current state of the field and describes new strategies tracing the history of adjuvant therapy in melanoma, with a view on future projects.

2 Review Dietary compounds and cutaneous malignant melanoma: recent advances from a biological perspective. 2019

Ombra, Maria Neve / Paliogiannis, Panagiotis / Stucci, Luigia Stefania / Colombino, Maria / Casula, Milena / Sini, Maria Cristina / Manca, Antonella / Palomba, Grazia / Stanganelli, Ignazio / Mandalà, Mario / Gandini, Sara / Lissia, Amelia / Doneddu, Valentina / Cossu, Antonio / Palmieri, Giuseppe / Anonymous310992. ·1Institute of Food Sciences, National Research Council, Avellino, Italy. · 0000 0001 1940 4177 · grid.5326.2 · 2Department of Medical, Surgical and Experimental Sciences, University of Sassari, Viale San Pietro 43, 07100 Sassari, Italy. · 0000 0001 2097 9138 · grid.11450.31 · 3Department of Biomedical Sciences and Human Oncology, University of Bari 'Aldo Moro', Bari, Italy. · 0000 0001 0120 3326 · grid.7644.1 · 4Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy. · 5Istituto Scientifico Romagnolo per Studio e Cura Tumori (IRST-IRCCS), Meldola, Italy. · 0000 0004 1755 9177 · grid.419563.c · 6Medical Oncology, "Papa Giovanni XXIII" Hospital, Bergamo, Italy. · 0000 0004 1757 8431 · grid.460094.f · 7Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy. · 0000 0004 1757 0843 · grid.15667.33 ·Nutr Metab (Lond) · Pubmed #31139235.

ABSTRACT: Cutaneous malignant melanoma is a heterogeneous disease, being the consequence of specific genetic alterations along several molecular pathways. Despite the increased knowledge about the biology and pathogenesis of melanoma, the incidence has grown markedly worldwide, making it extremely important to develop preventive measures. The beneficial role of correct nutrition and of some natural dietary compounds in preventing malignant melanoma has been widely demonstrated. This led to numerous studies investigating the role of several dietary attitudes, patterns, and supplements in the prevention of melanoma, and ongoing research investigates their impact in the clinical management and outcomes of patients diagnosed with the disease. This article is an overview of recent scientific advances regarding specific dietary compounds and their impact on melanoma development and treatment.

3 Review Cobimetinib in malignant melanoma: how to MEK an impact on long-term survival. 2019

Indini, Alice / Tondini, Carlo Alberto / Mandalà, Mario. ·Unit of Medical Oncology, Department of Oncology & Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. ·Future Oncol · Pubmed #30638071.

ABSTRACT: Approximately 50% of cutaneous melanomas harbor activating mutations of the BRAF-oncogene, making BRAF inhibitors (BRAFi) the standard treatment for this disease. However, disease responses are limited in duration mainly due to acquired resistance. Dual MAPK pathway inhibition with addition of a MEK inhibitor (MEKi) to a BRAFi improved the efficacy and tolerability compared with BRAFi alone. Cobimetinib (Cotellic

4 Review Rational combination of cancer immunotherapy in melanoma. 2019

Mandalà, Mario / Rutkowski, Piotr. ·Unit of Medical Oncology, Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Piazza OMS 1, 24100, Bergamo, Italy. mariomandala@tin.it. · Maria Sklodowska-Curie Institute, Oncology Center, Warsaw, Poland. ·Virchows Arch · Pubmed #30552520.

ABSTRACT: The recent advances in cancer immunotherapy with unprecedented success in therapy of advanced melanoma represent a turning point in the landscape of melanoma treatment. Given the complexity of activation of immunological system and the physiologic multifactorial homeostatic mechanisms controlling immune responses, combinatorial strategies are eagerly needed in melanoma therapy. Nevertheless, rational selection of immunotherapy combinations should be more biomarker-guided, including not only the cancer immunogram, PD-L1 expression, interferon gene expression signature, mutational burden, and tumor infiltration by CD8+ T cells but also intratumoral T cell exhaustion and microbiota composition. In this review, we summarize the rationale to develop combination treatment strategies in melanoma and discuss biological background that could help to design new combinations in order to improve patients' outcome.

5 Review Molecular Pathways in Melanomagenesis: What We Learned from Next-Generation Sequencing Approaches. 2018

Palmieri, Giuseppe / Colombino, Maria / Casula, Milena / Manca, Antonella / Mandalà, Mario / Cossu, Antonio / Anonymous6000961. ·Unit of Cancer Genetics, National Research Council (CNR), Institute of Biomolecular Chemistry (ICB), Traversa La Crucca 3, Baldinca Li Punti, 07100, Sassari, Italy. gpalmieri@yahoo.com. · Unit of Cancer Genetics, National Research Council (CNR), Institute of Biomolecular Chemistry (ICB), Traversa La Crucca 3, Baldinca Li Punti, 07100, Sassari, Italy. · PAPA GIOVANNI XXIII Cancer Center Hospital, Bergamo, Italy. · Institute of Pathology, Azienda Ospedaliero Universitaria (AOU), Sassari, Italy. ·Curr Oncol Rep · Pubmed #30218391.

ABSTRACT: PURPOSE OF REVIEW: Conventional clinico-pathological features in melanoma patients should be integrated with new molecular diagnostic, predictive, and prognostic factors coming from the expanding genomic profiles. Cutaneous melanoma (CM), even differing in biological behavior according to sun-exposure levels on the skin areas where it arises, is molecularly heterogeneous. The next-generation sequencing (NGS) approaches are providing data on mutation landscapes in driver genes that may account for distinct pathogenetic mechanisms and pathways. The purpose was to group and classify all somatic driver mutations observed in the main NGS-based studies. RECENT FINDINGS: Whole exome and whole genome sequencing approaches have provided data on spectrum and distribution of genetic and genomic alterations as well as allowed to discover new cancer genes underlying CM pathogenesis. After evaluating the mutational status in a cohort of 686 CM cases from the most representative NGS studies, three molecular CM subtypes were proposed: BRAF

6 Review [Pembrolizumab for the treatment of melanoma: updates and perspectives.] 2017

Chiarion Sileni, Vanna / Mandalà, Mario / Queirolo, Paola. ·Istituto Oncologico Veneto, Padova. · Ospedale Papa Giovanni XXIII, Bergamo. · Oncologia Medica 2, Ospedale San Martino, Genova. ·Recenti Prog Med · Pubmed #29297903.

ABSTRACT: Checkpoint inhibitors immunotherapy was a breakthrough in anti-tumor treatments. Anti-PD-1 monoclonal antibodies are now a standard of treatment for advanced melanoma patients, with a 3-year overall survival of over 50% and a low rate (<20%) of severe toxicities in the phase 3 studies. The aim of this review was to report the most important updates on anti-PD-1 drug pembrolizumab from ASCO (American Society of Clinical Oncology) and ESMO (European Society for Medical Oncology) 2017 Annual Meetings.

7 Review Rationale for New Checkpoint Inhibitor Combinations in Melanoma Therapy. 2017

Mandalà, Mario / Tondini, Carlo / Merelli, Barbara / Massi, Daniela. ·Unit of Medical Oncology, Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Piazza OMS 1, 24100, Bergamo, Italy. mariomandala@tin.it. · Unit of Medical Oncology, Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Piazza OMS 1, 24100, Bergamo, Italy. · Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy. ·Am J Clin Dermatol · Pubmed #28432648.

ABSTRACT: The use of monoclonal antibodies that block immunologic checkpoints, which mediate adaptive immune resistance, has revolutionized the treatment of metastatic melanoma patients. Specifically, targeting single immune suppressive molecules such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4), or programmed cell death protein 1 (PD-1) expressed on T cells or its primary ligand, programmed cell death ligand 1 (PD-L1), resulted in pronounced clinical benefit for a subset of melanoma patients. Although single-agent immune checkpoint inhibitor therapy has demonstrated promising clinical activity in metastatic melanoma patients, there is still a significant proportion of patients who show primary resistance to these therapies. Increased clinical efficacy was reported in phase II and III randomized studies by co-targeting CTLA-4 and PD-1 in the treatment of advanced melanoma, indicating the existence of multiple non-redundant immunosuppressive pathways in the tumor microenvironment. Nevertheless, only 50% of patients responded to combined anti-CTLA-4 and anti-PD-1 treatment. Additionally, the combination regimen was associated with severe toxicity in >50-60% of patients. In this review we summarize the rationale for new checkpoint inhibitor combinations in melanoma therapy and discuss how biologic-driven stratification enables the design of optimal combination therapies tailored to target different tumor microenvironments.

8 Review Immunomodulating property of MAPK inhibitors: from translational knowledge to clinical implementation. 2017

Mandalà, Mario / De Logu, Francesco / Merelli, Barbara / Nassini, Romina / Massi, Daniela. ·Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy. · Unit of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy. · Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy. ·Lab Invest · Pubmed #27991907.

ABSTRACT: Treatment of metastatic melanoma was radically changed by the introduction of inhibitors of BRAF, an oncogene mutated in 40-50% of patients. Another area of advancement was the use of immunotherapy, and specifically, immune checkpoint inhibitors. There is compelling evidence that oncogenic BRAF, in addition to driving melanoma proliferation, differentiation and survival, induces T-cell suppression directly through the secretion of inhibitory cytokines or through membrane expression of co-inhibitory molecules such as the PD-1 ligands PD-L1 or PD-L2. Furthermore, the presence of oncogenic BRAF leads to an immune suppressive phenotype characterized by the presence of inhibitory immune cells such as regulatory T cells, myeloid-derived suppressor cells, or tumor-associated macrophages, which can in turn inhibit the function of tumor-infiltrating T cells. Growing evidence suggests that, in addition to their established molecular mechanism of action, the therapeutic efficacy of BRAF inhibitors and MEK inhibitors relies on additional factors that affect the tumor-host interactions, including the enhancement of melanoma antigen expression and the increase in immune response against tumor cells. Focus of the present review is to summarize the off target mechanisms of response to BRAF inhibitors and MEK inhibitors and the synergy between targeted therapy and immunotherapy as the biological source to open a window of strategic opportunities for the design of new exciting clinical trials.

9 Review PD-L1 in melanoma: facts and myths. 2016

Mandalà, Mario / Merelli, Barbara / Massi, Daniela. ·Unit of Medical Oncology, Department of Oncology & Hematology, Papa Giovanni XXIII Cancer Center Hospital, Piazza OMS 1, 24100, Bergamo, Italy. · Division of Pathological Anatomy, Department of Surgery & Translational Medicine, University of Florence, Italy. ·Melanoma Manag · Pubmed #30190888.

ABSTRACT: The use of monoclonal antibodies that block immunologic checkpoints that would otherwise mediate the adaptive immune resistance have paved the way in cancer treatment. There is evidence that blocking the PD-1/PD-L1 axis is a strategy of overriding importance in the treatment of patients with metastatic melanoma and other solid malignancies, some of which (NSCLC, colorectal cancer, renal cell cancer, head and neck cancer) were not considered to be 'immune-responsive' diseases until recently. In this perspective article, the biological and clinical relevance of PD-L1 is summarized in the context of the immune checkpoint inhibitors as a therapeutic strategy in metastatic melanoma patients.

10 Review Wnt/β-catenin signaling in melanoma: Preclinical rationale and novel therapeutic insights. 2016

Xue, Gongda / Romano, Emanuela / Massi, Daniela / Mandalà, Mario. ·Department of Biomedicine, University Hospital Basel, Basel, Switzerland. · Immunotherapy Unit, Department of Oncology, INSERM Research Unit 932, Institut Curie, Paris, France. · Department of Surgery and Translational Medicine, University of Florence, Florence, Italy. · Unit of Medical Oncology, Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy. Electronic address: mariomandala@tin.it. ·Cancer Treat Rev · Pubmed #27395773.

ABSTRACT: WNT signaling regulates embryonic development and tissue homeostasis in the adult stage. Evolutionarily, activation of the WNT pathway is triggered by a large family of cytokines and activates a broad spectrum of downstream targets through two independent branches mediated by β-catenin (defined as canonical pathway) or PLC and small GTPase (defined as non-canonical pathway), respectively. Recent studies revealed the crucial role of WNT in the maintenance of cell metabolism and stemness as well as its deregulation in tumourigenesis and malignant transformation through oncogenic reprogramming, which contributes to cancer cell proliferation and differentiation, survival, stress response and resistance. In addition, multiple functional mutations discovered in human tumours have been reported to cause malignancy, indicating this pathway as a novel therapeutic target in oncology. Notably, emerging data highlights its involvement in the crosstalk between immune and cancer cells. However, contradictory effects have been also observed in different pre-clinical models when strategic(???) inhibitors are tested. In this review, we address the multifaceted regulatory mechanisms of WNT signaling in cancer, with a particular focus on current melanoma therapy, which has witnessed dramatic improvement in the last five years.

11 Review The complex management of atypical Spitz tumours. 2016

Massi, Daniela / De Giorgi, Vincenzo / Mandalà, Mario. ·Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Italy. Electronic address: daniela.massi@unifi.it. · Division of Dermatology, University of Florence, Italy. · Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. ·Pathology · Pubmed #27020385.

ABSTRACT: In recent years, advances in molecular genetic characterisation have revealed that atypical Spitz tumours (ASTs) are basically heterogeneous diseases, although the clinical relevance of these findings is yet to be determined. Evidence of molecularly-defined diverse groups of lesions continues to accumulate; however, conflicting, confusing, and overlapping terminology has fostered ambiguity and lack of clarity in the field in general. The lack of fundamental diagnostic (morphological) unambiguous classification framework results in a number of challenges in the interpretation of the molecular genetic data. In this review, we discuss the main difficulties for pathologists and clinicians in the complex management of ASTs, with particular emphasis on the different genetic and biological features of recently-described entities, and offer our view of what could be medically reasonable to guide a rational approach in light of current data.

12 Review PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: A systematic review and meta-analysis. 2016

Gandini, Sara / Massi, Daniela / Mandalà, Mario. ·Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy. · Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Italy. · Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. Electronic address: mariomandala@tin.it. ·Crit Rev Oncol Hematol · Pubmed #26895815.

ABSTRACT: BACKGROUND: Despite the success of immunotherapy directed at inhibiting of programmed death-1 (PD-1)/PD-ligand (L)1 signaling, it is not established whether PD-L1 expression correlates with the clinical response and outcome in different tumors. The present meta-analysis investigates whether the PD-L1 status, detected by immunohistochemistry, is associated with clinical response and mortality in patients treated with anti-PD-1/PD-L1 therapy. METHODS: A systematic literature search and quantitative analysis were planned, conducted and reported following CONSORT and QUORUM checklists, up to December 2015, to identify clinical trials with information on cancer outcome by PD-L1 immunohistochemical expression in tumor tissues. We used random effects models to estimate Summary Objective Response Rates (SORRs) and Summary Odd Ratio (SOR) for the comparison of PD-L1 positive and negative patients. RESULTS: We summarized 20 trials carried out in metastatic melanoma (MM), non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC) patients receiving anti-PD-1/PD-L1 antibodies (4230 MM, 1417 NSCLC and 312 RCC patients). Positive PD-L1 MM patients showed a significant decrease (53%) in the risk of mortality vs. negative cases with no heterogeneity. Furthermore, SORRs were 45% and 27% in PD-L1 positive and negative patients, respectively, and SOR indicates a significant difference in term of responses: 2.14 (95% CI: 1.65, 2.77), with low between-study heterogeneity (I(2)=35%). Furthermore, results from randomized clinical trials on MM showed that PD-L1 expression is significantly associated with greater clinical response rates to anti-PD1 treatments (SOR 1.89; 95%CI: 1.35, 2.64) but not to other treatments (SOR 0.96; 95%CI: 0.5, 1.87). In non-squamous NSCLC SORRs were 29% and 11% in PD-L1 positive and negative patients, respectively, and SOR indicates a significant difference between responses: 3.78 (1.54, 9.24), with no between-study heterogeneity. Squamous NSCLC and RCC did not show any significant difference in response according to the PD-L1 status. CONCLUSION: PD-L1 expression is significantly associated with mortality and clinical response to anti-PD-1/PD-L1 antibodies in MM patients and with clinical response in patients with non-squamous NSCLC.

13 Review Nras in melanoma: targeting the undruggable target. 2014

Mandalà, Mario / Merelli, Barbara / Massi, Daniela. ·Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. Electronic address: mariomandala@tin.it. · Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. · Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Italy. ·Crit Rev Oncol Hematol · Pubmed #24985059.

ABSTRACT: RAS belongs to the guanosine 5'-triphosphate (GTP)-binding proteins' family, and oncogenic mutations in codons 12, 13, or 61 of RAS family occur in approximately one third of all human cancers with N-RAS mutations found in about 15-20% of melanomas. The importance of RAS signaling as a potential target in cancer is emphasized not only by the prevalence of RAS mutations, but also by the high number of RAS activators and effectors identified in mammalian cells that places the RAS proteins at the crossroads of several, important signaling networks. Ras proteins are crucial crossroads of signaling pathways that link the activation of cell surface receptors with a wide variety of cellular processes leading to the control of proliferation, apoptosis and differentiation. Furthermore, oncogenic ras proteins interfere with metabolism of tumor cells, microenvironment's remodeling, evasion of the immune response, and finally contributes to the metastatic process. After 40 years of basic, translational and clinical research, much is now known about the molecular mechanisms by which these monomeric guanosine triphosphatase-binding proteins promote cellular malignancy, and it is clear that they regulate signaling pathways involved in the control of cell proliferation, survival, and invasiveness. In this review we summarize the biological role of RAS in cancer by focusing our attention on the biological rational and strategies to target RAS in melanoma.

14 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.

15 Review Tissue prognostic biomarkers in primary cutaneous melanoma. 2014

Mandalà, Mario / Massi, Daniela. ·Unit of Clinical and Translational Research, Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. ·Virchows Arch · Pubmed #24487785.

ABSTRACT: Cutaneous melanoma (CM) causes the greatest number of skin cancer-related deaths worldwide. Predicting CM prognosis is important to determine the need for further investigation, counseling of patients, to guide appropriate management (particularly the need for postoperative adjuvant therapy), and for assignment of risk status in groups of patients entering clinical trials. Since recurrence rate is largely independent from stages defined by morphological and morphometric criteria, there is a strong need for identification of additional robust prognostic factors to support decision-making processes. Most data on prognostic biomarkers in melanoma have been evaluated in tumor tissue samples by conventional morphology and immunohistochemistry (IHC) as well as DNA and RNA analyses. In the present review, we critically summarize main high-quality studies investigating IHC-based protein biomarkers of melanoma outcome according to Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK)-derived criteria. Pathways have been classified and conveyed in the "biologic road" previously described by Hanahan and Weinberg. Data derived from genomic and transcriptomic technologies have been critically reviewed to better understand if any of investigated proteins or gene signatures should be incorporated into clinical practice or still remain a field of melanoma research. Despite a wide body of research, no molecular prognostic biomarker has yet been translated into clinical practice. Conventional tissue biomarkers, such as Breslow thickness, ulceration, mitotic rate and lymph node positivity, remain the backbone prognostic indicators in melanoma.

16 Review Targeting the PD1/PD-L1 axis in melanoma: biological rationale, clinical challenges and opportunities. 2014

Merelli, Barbara / Massi, Daniela / Cattaneo, Laura / Mandalà, Mario. ·Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. Electronic address: bmerelli@hpg23.it. · Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Italy. Electronic address: daniela.massi@unifi.it. · Division of Pathological Anatomy, Papa Giovanni XXIII Hospital, Bergamo, Italy. Electronic address: lcattaneo@hpg23.it. · Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. Electronic address: mariomandala@tin.it. ·Crit Rev Oncol Hematol · Pubmed #24029602.

ABSTRACT: A dynamic interplay exists between host and tumor, and the ability of the tumor to evade immune recognition often determines the clinical course of the disease. Significant enthusiasm currently exists for a new immunotherapeutic strategy: the use of immunomodulatory monoclonal antibodies that directly enhance the function of components of the anti-tumor immune response such as T cells, or block immunologic checkpoints that would otherwise restrain effective anti-tumor immunity. This strategy is based on the evidence that development of cancer is facilitated by the dis-regulation and exploitation of otherwise physiological pathways that, under normal circumstances, down-regulate immune activation and maintain tolerance to self. Among these pathways an important role is covered by the Programmed death-1 (PD-1)/PD-Ligand (L) 1 axis. An emerging concept in cancer immunology is that inhibitory ligands such as PD-L1 are induced in response to immune attack, a mechanism termed "adaptive resistance". This potential mechanism of immune resistance by tumors suggests that therapy directed at blocking the interaction between PD-1 and PD-L1 might synergize with other treatments that enhance endogenous antitumor immunity. The anti-PD-1 strategy can be effective in several solid tumors such as renal cell carcinoma (RCC) or non-small cell lung cancer (NSCLC), however in this review we summarize the biological role of PD-1/PD-L1 on cancer by focusing our attention in the biological rationale, clinical challenges and opportunities to target the PD-1/PD-L1 axis in melanoma.

17 Review Cutaneous toxicities of BRAF inhibitors: clinical and pathological challenges and call to action. 2013

Mandalà, Mario / Massi, Daniela / De Giorgi, Vincenzo. ·Medical Oncology Unit, Papa Giovanni XXIII Hospital, Bergamo, Italy. Electronic address: mariomandala@tin.it. ·Crit Rev Oncol Hematol · Pubmed #23830782.

ABSTRACT: Somatic mutations in the BRAF gene have been identified as the most frequent and relevant to develop targeted molecular therapies in melanoma. Recently, seminal clinical trials have provided indisputable evidence that BRAF inhibitors improve response rate, progression free and overall survival in BRAFV600 mutated metastatic melanoma patients, thus representing the novel standard of care. Dermatological "off target" effects of these so-called 'targeted therapies' have to be considered, however, and among them the most intriguing are cutaneous adverse reactions. Skin toxicity is of relevance for at least three reasons: (1) it worsens the patient's quality of life and may be difficult to manage, (2) its heterogeneous clinical presentation differs from the clinico-pathological pictures observed in patients who do not receive BRAF inhibitors, and; (3) onset of skin cancer represents a model of carcinogenesis which may help to better understand the potential visceral tumorigenesis induced by BRAF inhibitors. This manuscript summarizes and critically reviews the state of the art of skin toxicity associated with BRAF inhibitors. Special attention will be paid to clinical presentation and histopathological findings, as well as related challenges for clinicians, pathologists, and basic scientists.

18 Review Targeting BRAF in melanoma: biological and clinical challenges. 2013

Mandalà, Mario / Voit, Christiane. ·Unit of Medical Oncology, Papa Giovanni XXIII Hospital, Bergamo, Italy. mariomandala@tin.it ·Crit Rev Oncol Hematol · Pubmed #23415641.

ABSTRACT: Melanoma is an aggressive form of skin cancer that causes the greatest number of skin cancer-related deaths worldwide. In its early stages malignant melanoma can be cured by surgical resection, but once it has progressed to the metastatic stage it is extremely difficult to treat and does not respond to current therapies. A majority of cutaneous melanomas show activating mutations in the NRAS or BRAF proto-oncogenes, components of the Ras-Raf-Mek-Erk (MAPK) signal transduction pathway. The discovery of activating BRAF mutations in ∼50% of all melanomas has proved to be a turning point in the therapeutic management of the disseminated disease. This review summarizes the critical role of BRAF in melanoma pathophysiology, the clinical and pathological determinants of BRAF mutation status and finally addresses the current state of the art of BRAF inhibitors. We further outline the most recent findings on the mechanisms that underlie intrinsic and acquired BRAF inhibitor resistance and describe ongoing preclinical and clinical studies designed to delay or abrogate the onset of therapeutic escape.

19 Clinical Trial Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. 2019

Robert, Caroline / Grob, Jean J / Stroyakovskiy, Daniil / Karaszewska, Boguslawa / Hauschild, Axel / Levchenko, Evgeny / Chiarion Sileni, Vanna / Schachter, Jacob / Garbe, Claus / Bondarenko, Igor / Gogas, Helen / Mandalá, Mario / Haanen, John B A G / Lebbé, Celeste / Mackiewicz, Andrzej / Rutkowski, Piotr / Nathan, Paul D / Ribas, Antoni / Davies, Michael A / Flaherty, Keith T / Burgess, Paul / Tan, Monique / Gasal, Eduard / Voi, Maurizio / Schadendorf, Dirk / Long, Georgina V. ·From Institut Gustave Roussy and Paris-Sud-Paris-Saclay University, Villejuif (C.R.), Aix-Marseille University, Marseille (J.J.G.), and Assistance Publique-Hôpitaux de Paris Dermatology and Clinical Investigation Center, Unité 976, Université de Paris, Hôpital Saint-Louis, Paris (C.L.) - all in France · Moscow City Oncology Hospital, Moscow (D. Stroyakovskiy), and the Petrov Research Institute of Oncology, St. Petersburg (E.L.) - both in Russia · Przychodnia Lekarska Komed, Konin (B.K.), the University of Medical Sciences, Poznań (A.M.), and the Maria Skłodowska-Curie Institute-Oncology Center, Warsaw (P.R.) - all in Poland · the University Hospital Schleswig-Holstein, Kiel (A.H.), the Department of Dermatology, University of Tübingen, Tübingen (C.G.), University Hospital Essen, Essen (D. Schadendorf), and the German Cancer Consortium, Heidelberg (D. Schadendorf) - all in Germany · the Veneto Institute of Oncology, Padua (V.C.S.), and Papa Giovanni XXIII Hospital, Bergamo (M.M.) - both in Italy · the Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Sheba Medical Center, Tel Hashomer (J.S.), and Sackler Medical School, Tel Aviv University, Tel Aviv (J.S.) - both in Israel · Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine (I.B.) · Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens (H.G.) · the Netherlands Cancer Institute, Amsterdam (J.B.A.G.H.) · Mount Vernon Cancer Centre, Northwood, United Kingdom (P.D.N.) · the University of California, Los Angeles, Los Angeles (A.R.) · the University of Texas M.D. Anderson Cancer Center, Houston (M.A.D.) · Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston (K.T.F.) · Novartis Pharma, Basel, Switzerland (P.B.) · Novartis Pharmaceuticals, East Hanover, NJ (M.T., E.G., M.V.) · and the Melanoma Institute Australia, the University of Sydney, and Royal North Shore and Mater Hospitals, Sydney (G.V.L.). ·N Engl J Med · Pubmed #31166680.

ABSTRACT: BACKGROUND: Patients who have unresectable or metastatic melanoma with a METHODS: We analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively. RESULTS: A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years. The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (95% CI, 62 to 79) at 5 years. CONCLUSIONS: First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a

20 Clinical Trial Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. 2018

Dummer, Reinhard / Ascierto, Paolo A / Gogas, Helen J / Arance, Ana / Mandala, Mario / Liszkay, Gabriella / Garbe, Claus / Schadendorf, Dirk / Krajsova, Ivana / Gutzmer, Ralf / Chiarion Sileni, Vanna / Dutriaux, Caroline / de Groot, Jan Willem B / Yamazaki, Naoya / Loquai, Carmen / Moutouh-de Parseval, Laure A / Pickard, Michael D / Sandor, Victor / Robert, Caroline / Flaherty, Keith T. ·Department of Dermatology, University Hospital Zürich Skin Cancer Center, Zürich, Switzerland. Electronic address: reinhard.dummer@usz.ch. · Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy. · Department of Internal Medicine, National and Kapodistrian University of Athens, Laikon Hospital, Athens, Greece. · Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain. · Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy. · Department of Dermatology, National Institute of Oncology, Budapest, Hungary. · Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany. · Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. · Department of Dermato-oncology, University Hospital Prague and Charles University First Medical Faculty, Prague, Czech Republic. · Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany. · Melanoma Cancer Unit, Oncology Institute of Veneto IRCCS, Padua, Italy. · Department of Oncologic Dermatology, Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux Cédex, France. · Department of Medical Oncology, Isala, Zwolle, Netherlands. · Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Department of Dermatology, University Medical Center Mainz, Mainz, Germany. · Translational Clinical Oncology, Novartis Pharma AG, Basel, Switzerland. · Array BioPharma, Boulder, CO, USA. · Service of Dermatology, Department of Medicine and Paris-Sud University, Gustave Roussy, Villejuif Cedex, France. · Cancer Center, Massachusetts General Hospital, Boston, MA, USA. ·Lancet Oncol · Pubmed #30219628.

ABSTRACT: BACKGROUND: Encorafenib plus binimetinib and encorafenib alone improved progression-free survival compared with vemurafenib in patients with BRAF METHODS: COLUMBUS was a two-part, randomised, open-label, phase 3 study done at 162 hospitals in 28 countries. Eligible patients were aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, BRAF FINDINGS: Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). Median follow-up for overall survival was 36·8 months (95% CI 35·9-37·5). Median overall survival was 33·6 months (95% CI 24·4-39·2) with encorafenib plus binimetinib and 16·9 months (14·0-24·5) with vemurafenib (hazard ratio 0·61 [95% CI 0·47-0·79]; two-sided p<0·0001). The most common grade 3 or 4 adverse events did not change substantially from the first report; those seen in more than 5% of patients treated with encorafenib plus binimetinib were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased blood creatine phosphokinase (14 [7%]), and hypertension (12 [6%]); those seen with encorafenib alone were palmar-plantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and with vemurafenib the most common grade 3 or 4 adverse event was arthralgia (11 [6%] of 186 patients). One death in the combination treatment group was considered by the investigator to be possibly related to treatment. INTERPRETATION: The combination of encorafenib plus binimetinib provided clinically meaningful efficacy with good tolerability as shown by improvements in both progression-free survival and overall survival compared with vemurafenib. These data suggest that the combination of encorafenib plus binimetinib is likely to become an important therapeutic option in patients with BRAF FUNDING: Array BioPharma, Novartis.

21 Clinical Trial Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. 2018

Eggermont, Alexander M M / Blank, Christian U / Mandala, Mario / Long, Georgina V / Atkinson, Victoria / Dalle, Stéphane / Haydon, Andrew / Lichinitser, Mikhail / Khattak, Adnan / Carlino, Matteo S / Sandhu, Shahneen / Larkin, James / Puig, Susana / Ascierto, Paolo A / Rutkowski, Piotr / Schadendorf, Dirk / Koornstra, Rutger / Hernandez-Aya, Leonel / Maio, Michele / van den Eertwegh, Alfonsus J M / Grob, Jean-Jacques / Gutzmer, Ralf / Jamal, Rahima / Lorigan, Paul / Ibrahim, Nageatte / Marreaud, Sandrine / van Akkooi, Alexander C J / Suciu, Stefan / Robert, Caroline. ·From the Gustave Roussy Cancer Campus Grand Paris and University Paris-Saclay, Villejuif (A.M.M.E., C.R.), Hospices Civils de Lyon Cancer Institute, Cancer Research Center of Lyon, Lyon University, Lyon (S.D.), and Aix-Marseille University, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille (J.-J.G.) - all in France · Netherlands Cancer Institute-Antoni van Leeuwenhoek (C.U.B., A.C.J.A.) and VU University Medical Center (A.J.M.E.), Amsterdam, and Radboud University Medical Center Nijmegen, Nijmegen (R.K.) - all in the Netherlands · Azienda Ospedaliera Papa Giovanni XXIII, Bergamo (M. Mandala), Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Fondazione G. Pascale, Naples (P.A.A.), and Universita Degli Studi Di Siena-Policlinico le Scotte, Siena (M. Maio) - all in Italy · Melanoma Institute Australia, the University of Sydney, and Mater and Royal North Shore Hospitals (G.V.L.) and Westmead and Blacktown Hospitals, Melanoma Institute Australia and the University of Sydney (M.S.C.), Sydney, Princess Alexandra Hospital, University of Queensland, Brisbane (V.A.), Alfred Hospital (A.H.) and Peter MacCallum Cancer Centre (S. Sandhu), Melbourne, VIC, and Fiona Stanley Hospital-University of Western Australia-Edith Cowan University Perth, Perth (A.K.) - all in Australia · Cancer Research Center, Moscow (M.L.) · Royal Marsden Hospital, London (J.L.) · Hospital Clinic Universitari de Barcelona, Barcelona (S.P.) · Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.) · University Hospital Essen, Essen and German Cancer Consortium, Heidelberg (D.S.), and the Skin Cancer Center, Department of Dermatology, Hannover Medical School, Hannover (R.G.) - all in Germany · Washington University School of Medicine, St. Louis (L.H.-A.) · Centre Hospitalier de l'Université de Montréal (CHUM), Centre de Recherche du CHUM, Montreal (R.J.) · Christie NHS Foundation Trust, Manchester, United Kingdom (P.L.) · Merck, Kenilworth, NJ (N.I.) · and the European Organization for the Research and Treatment of Cancer Headquarters, Brussels (S.M., S. Suciu). ·N Engl J Med · Pubmed #29658430.

ABSTRACT: BACKGROUND: The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma. METHODS: Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated. RESULTS: At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group. CONCLUSIONS: As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .).

22 Clinical Trial Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. 2018

Dummer, Reinhard / Ascierto, Paolo A / Gogas, Helen J / Arance, Ana / Mandala, Mario / Liszkay, Gabriella / Garbe, Claus / Schadendorf, Dirk / Krajsova, Ivana / Gutzmer, Ralf / Chiarion-Sileni, Vanna / Dutriaux, Caroline / de Groot, Jan Willem B / Yamazaki, Naoya / Loquai, Carmen / Moutouh-de Parseval, Laure A / Pickard, Michael D / Sandor, Victor / Robert, Caroline / Flaherty, Keith T. ·Department of Dermatology, University Hospital Zürich Skin Cancer Center, Zürich, Switzerland. Electronic address: reinhard.dummer@usz.ch. · Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy. · Department of Internal Medicine, National and Kapodistrian University of Athens, Laikon Hospital, Athens, Greece. · Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain. · Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy. · Department of Dermatology, National Institute of Oncology, Budapest, Hungary. · Department of Dermatology, University Hospital Tüebingen, Tüebingen, Germany. · Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. · Department of Dermato-oncology, University Hospital Prague, Charles University First Medical Faculty, Prague, Czech Republic. · Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany. · Melanoma Cancer Unit, Oncology Institute of Veneto IRCCS, Padua, Italy. · Department of Oncologic Dermatology, Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux, France. · Department of Medical Oncology, Isala, Zwolle, Netherlands. · Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Department of Dermatology, University Medical Center Mainz, Mainz, Germany. · Translational Clinical Oncology, Novartis Pharma AG, Basel, Switzerland. · Array BioPharma, Boulder, CO, USA. · Service of Dermatology, Department of Medicine, Paris-Sud University, Gustave Roussy, Villejuif, France. · Cancer Center, Massachusetts General Hospital, Boston, MA, USA. ·Lancet Oncol · Pubmed #29573941.

ABSTRACT: BACKGROUND: Combined BRAF-MEK inhibitor therapy is the standard of care for BRAF METHODS: COLUMBUS was conducted as a two-part, randomised, open-label phase 3 study at 162 hospitals in 28 countries. Eligible patients were aged 18 years or older and had histologically confirmed locally advanced (American Joint Committee on Cancer [AJCC] stage IIIB, IIIC, or IV), unresectable or metastatic cutaneous melanoma, or unknown primary melanoma; a BRAF FINDINGS: Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to either the encorafenib plus binimetinib group (n=192), the encorafenib group (n=194), or the vemurafenib group (n=191). With a median follow-up of 16·6 months (95% CI 14·8-16·9), median progression-free survival was 14·9 months (95% CI 11·0-18·5) in the encorafenib plus binimetinib group and 7·3 months (5·6-8·2) in the vemurafenib group (hazard ratio [HR] 0·54, 95% CI 0·41-0·71; two-sided p<0·0001). The most common grade 3-4 adverse events seen in more than 5% of patients in the encorafenib plus binimetinib group were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased creatine phosphokinase (13 [7%]), and hypertension (11 [6%]); in the encorafenib group they were palmoplantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and in the vemurafenib group it was arthralgia (11 [6%] of 186 patients). There were no treatment-related deaths except for one death in the combination group, which was considered possibly related to treatment by the investigator. INTERPRETATION: Encorafenib plus binimetinib and encorafenib monotherapy showed favourable efficacy compared with vemurafenib. Overall, encorafenib plus binimetinib appears to have an improved tolerability profile compared with encorafenib or vemurafenib. Encorafenib plus binimetinib could represent a new treatment option for patients with BRAF-mutant melanoma. FUNDING: Array BioPharma, Novartis.

23 Clinical Trial Adjuvant vemurafenib in resected, BRAF 2018

Maio, Michele / Lewis, Karl / Demidov, Lev / Mandalà, Mario / Bondarenko, Igor / Ascierto, Paolo A / Herbert, Christopher / Mackiewicz, Andrzej / Rutkowski, Piotr / Guminski, Alexander / Goodman, Grant R / Simmons, Brian / Ye, Chenglin / Yan, Yibing / Schadendorf, Dirk / Anonymous7910937. ·Division of Medical Oncology and Immunotherapy, Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy. Electronic address: mmaiocro@gmail.com. · University of Colorado Comprehensive Cancer Center, Aurora, CO, USA. · N N Blokhin Russian Cancer Research Center, Ministry of Health, Moscow, Russia. · Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy. · Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine. · Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. · Bristol Haematology and Oncology Centre, Bristol, UK. · Department of Cancer Immunology, Poznan University for Medical Sciences, Med-POLONIA, Poznan, Poland. · Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland. · Melanoma Translational Research Group, Melanoma Institute Australia, Wollstonecraft, NSW, Australia. · Genentech, Inc, South San Francisco, CA, USA. · Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. ·Lancet Oncol · Pubmed #29477665.

ABSTRACT: BACKGROUND: Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC-III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAF METHODS: BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC-IIIA-IIIB (cohort 1) or stage IIIC (cohort 2) BRAF FINDINGS: The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9-41·6) in cohort 2 and 30·8 months (25·5-40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6-26·5) in the vemurafenib group versus 15·4 months (11·1-35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54-1·18; log-rank p=0·26). In cohort 1 (patients with stage IIC-IIIA-IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4-not estimable) in the placebo group (HR 0·54 [95% CI 0·37-0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3-4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3-4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3-4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug. INTERPRETATION: The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC-IIIA-IIIB BRAF FUNDING: F Hoffman-La Roche Ltd.

24 Clinical Trial Health-related quality of life impact of cobimetinib in combination with vemurafenib in patients with advanced or metastatic BRAF 2018

Dréno, Brigitte / Ascierto, Paolo A / Atkinson, Victoria / Liszkay, Gabriella / Maio, Michele / Mandalà, Mario / Demidov, Lev / Stroyakovskiy, Daniil / Thomas, Luc / de la Cruz-Merino, Luis / Dutriaux, Caroline / Garbe, Claus / Bartley, Karen / Karagiannis, Thomas / Chang, Ilsung / Rooney, Isabelle / Koralek, Daniel O / Larkin, James / McArthur, Grant A / Ribas, Antoni. ·Department of Dermato Cancerology, Nantes University, Nantes 44093, France. · Istituto Nazionale Tumori Fondazione G. Pascale, Naples 80131, Italy. · Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia. · National Institute of Oncology, Budapest 1122, Hungary. · Azienda Ospedaliera Universitaria Senese, Siena 53100, Italy. · Department of Oncology and Haematology, Papa Giovanni XXIII Hospital, Bergamo 24127, Italy. · N. N. Blokhin Russian Cancer Research Center, Moscow 115478, Russia. · Moscow City Oncology Hospital 62, Krasnogorsk 14301, Russia. · Service de Dermatologie, Centre Hospitalier Lyon Sud, Pierre-Bénite 69495, France. · Hospital Universitario Virgen Macarena, Seville 41009, Spain. · Hôpital Saint André, Bordeaux 33075, France. · Department of Dermatology, University of Tübingen, Tübingen 72074, Germany. · Genentech, Inc., South San Francisco, CA 94080, USA. · The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. · Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia. · University of Melbourne, Parkville, VIC 3052, Australia. · Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA. ·Br J Cancer · Pubmed #29438370.

ABSTRACT: BACKGROUND: In the coBRIM study, cobimetinib plus vemurafenib (C+V) significantly improved survival outcomes vs placebo and vemurafenib (P+V) in patients with advanced/metastatic BRAF METHODS: Patients completing the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline and ⩾1 time point thereafter constituted the analysis population. Change from baseline ⩾10 points was considered clinically meaningful. RESULTS: Mean baseline scores for all QLQ-C30 domains were similar between arms. Most on-treatment scores for QLQ-C30 domains were also comparable between arms. A transient deterioration in role function in cycle 1 day 15 (C1D15; -14.7 points) in the P+V arm and improvement in insomnia in the C+V arm at C2D15 (-12.4 points) was observed. Among patients who experienced a ⩾10-point change from baseline (responders), between-group differences were greatest for insomnia (16%), social functioning (10%), fatigue (9%) and pain (7%), all favouring C+V. Diarrhoea, photosensitivity reaction, pyrexia, and rash did not meaningfully affect global health status (GHS). Serous retinopathy was associated with a transient decrease in GHS at C1D15 assessment. CONCLUSIONS: In patients with advanced/metastatic BRAF

25 Clinical Trial Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. 2017

Weber, Jeffrey / Mandala, Mario / Del Vecchio, Michele / Gogas, Helen J / Arance, Ana M / Cowey, C Lance / Dalle, Stéphane / Schenker, Michael / Chiarion-Sileni, Vanna / Marquez-Rodas, Ivan / Grob, Jean-Jacques / Butler, Marcus O / Middleton, Mark R / Maio, Michele / Atkinson, Victoria / Queirolo, Paola / Gonzalez, Rene / Kudchadkar, Ragini R / Smylie, Michael / Meyer, Nicolas / Mortier, Laurent / Atkins, Michael B / Long, Georgina V / Bhatia, Shailender / Lebbé, Celeste / Rutkowski, Piotr / Yokota, Kenji / Yamazaki, Naoya / Kim, Tae M / de Pril, Veerle / Sabater, Javier / Qureshi, Anila / Larkin, James / Ascierto, Paolo A / Anonymous9301111. ·From New York University Perlmutter Cancer Center, New York (J.W.) · Papa Giovanni XXIII Cancer Center Hospital, Bergamo (M. Mandala), Medical Oncology, National Cancer Institute, Milan (M.D.V.), Oncology Institute of Veneto Istituti di Ricovero e Cura a Carattere Scientifico, Padua (V.C.-S.), Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena (M. Maio), Ospedale Policlinico San Martino, Genoa (P.Q.), and Istituto Nazionale Tumori Fondazione Pascale, Naples (P.A.A.) - all in Italy · National and Kapodistrian University of Athens, Athens (H.J.G.) · Hospital Clinic de Barcelona, Barcelona (A.M.A.), and General University Hospital Gregorio Marañón, Madrid (I.M.-R.) - both in Spain · Texas Oncology-Baylor Cancer Center, Dallas (C.L.C.) · Hospices Civils de Lyon, Pierre Bénite (S.D.), Aix-Marseille University, Hospital de la Timone, Marseille (J.-J.G.), Institut Universitaire du Cancer de Toulouse and Centre Hospitalier Universitaire (CHU), Toulouse (N.M.), Université Lille, INSERM Unité 1189, CHU Lille, Lille (L.M.), and Assistance Publique-Hôpitaux de Paris, Dermatology and Centres d'Investigation Clinique, INSERM Unité 976, Hôpital Saint Louis, Université Paris Diderot, Paris (C.L.) - all in France · Oncology Center Sf. Nectarie, Craiova, Romania (M. Schenker) · Princess Margaret Cancer Centre, University of Toronto, Toronto (M.O.B.), and Cross Cancer Institute, Edmonton, AB (M. Smylie) - both in Canada · the Department of Oncology, University of Oxford, Oxford (M.R.M.), and Royal Marsden NHS Foundation Trust, London (J.L.) - both in the United Kingdom · Gallipoli Medical Research Foundation and University of Queensland, Queensland, VIC (V.A.), and Melanoma Institute Australia, University of Sydney, and Royal North Shore and Mater Hospitals, Sydney (G.V.L.) - all in Australia · University of Colorado, Denver (R.G.) · Winship Cancer Institute, Emory University School of Medicine, Atlanta (R.R.K.) · Georgetown-Lombardi Comprehensive Cancer Center, Washington DC (M.B.A.) · University of Washington, Seattle (S.B.) · Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.) · Nagoya University Graduate School of Medicine, Nagoya (K.Y.), and the National Cancer Center Hospital, Tokyo (N.Y.) - both in Japan · Seoul National University Hospital, Seoul, South Korea (T.M.K.) · and Bristol-Myers Squibb, Princeton, NJ (V.P, J.S., A.Q.). ·N Engl J Med · Pubmed #28891423.

ABSTRACT: BACKGROUND: Nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma. METHODS: In this randomized, double-blind, phase 3 trial, we randomly assigned 906 patients (≥15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence-free survival in the intention-to-treat population. RESULTS: At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment. CONCLUSIONS: Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 238 ClinicalTrials.gov number, NCT02388906 ; Eudra-CT number, 2014-002351-26 .).

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