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Melanoma: HELP
Articles by Paul C. Lorigan
Based on 76 articles published since 2008
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Between 2008 and 2019, P. Lorigan wrote the following 76 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Guideline Revised U.K. guidelines for the management of cutaneous melanoma 2010. 2010

Marsden, J R / Newton-Bishop, J A / Burrows, L / Cook, M / Corrie, P G / Cox, N H / Gore, M E / Lorigan, P / MacKie, R / Nathan, P / Peach, H / Powell, B / Walker, C / Anonymous4180665. ·University Hospital Birmingham, Birmingham B29 6JD, UK. jerry.marsden@uhb.nhs.uk ·Br J Dermatol · Pubmed #20608932.

ABSTRACT: -- No abstract --

2 Editorial Advances in the treatment of late stage melanoma. 2013

Walkington, L A / Lorigan, P / Danson, S J. · ·BMJ · Pubmed #23460638.

ABSTRACT: -- No abstract --

3 Editorial Identifying melanomas in primary care: can we do better? 2012

Newton-Bishop, Julia / Lorigan, Paul. · ·BMJ · Pubmed #22763394.

ABSTRACT: -- No abstract --

4 Review The role of nivolumab in melanoma. 2018

Gomes, Fabio / Serra-Bellver, Patricio / Lorigan, Paul. ·The Christie NHS Foundation Trust, Manchester, UK. ·Future Oncol · Pubmed #29328782.

ABSTRACT: The incidence of melanoma continues to rise worldwide. Prior to 2010, there had been no progress in the treatment of advanced melanoma in living memory. Since then, immunotherapy has become a standard of care in the treatment of advanced melanoma. Nivolumab is a fully human monoclonal antibody against PD-1, which is a negative regulatory checkpoint in the T cells. The clinical benefit of nivolumab as a single agent is well established, with response rates of ≥40%, durable responses and a favorable tolerability profile. The combination of nivolumab and ipilimumab has also become a standard of care and the role of nivolumab in the adjuvant setting for high-risk patients has been recently confirmed.

5 Review Relapse-Free Survival as a Surrogate for Overall Survival in the Evaluation of Stage II-III Melanoma Adjuvant Therapy. 2018

Suciu, Stefan / Eggermont, Alexander M M / Lorigan, Paul / Kirkwood, John M / Markovic, Svetomir N / Garbe, Claus / Cameron, David / Kotapati, Srividya / Chen, Tai-Tsang / Wheatley, Keith / Ives, Natalie / de Schaetzen, Gaetan / Efendi, Achmad / Buyse, Marc. ·European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium; Gustave Roussy Cancer Campus Grand Paris, Villejuif, France; The Christie NHS Foundation Trust, Manchester, UK; University of Pittsburgh Cancer Institute and School of Medicine, Pittsburgh, PA; Mayo Clinic Rochester, Rochester, MN; University of Tubingen, Tubingen, Germany; University of Edinburgh, Western General Hospital, Edinburgh, UK; Bristol-Myers Squibb, Wallingford, CT; Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK; Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK; Universitas Brawijaya, Malang, Indonesia; IDDI, Louvain-la-Neuve, Belgium. ·J Natl Cancer Inst · Pubmed #28922786.

ABSTRACT: Background: We assessed whether relapse-free survival (RFS; time until recurrence/death) is a valid surrogate for overall survival (OS) among resected stage II-III melanoma patients through a meta-analysis of randomized controlled trials. Methods: Individual patient data (IPD) on RFS and OS were collected from 5826 patients enrolled in 11 randomized adjuvant trials comparing interferon (IFN) to observation. In addition, IPD from two studies comparing IFN and vaccination in 989 patients were included. A two-level modeling approach was used for assessing Spearman's patient-level correlation (rho) of RFS and OS and the trial-level coefficient of determination (R²) of the treatment effects on RFS and on OS. The results were validated externally in 13 adjuvant studies without available IPD. We then tested the results on the European Organisation for Research and Treatment of Cancer (EORTC) 18071 double-blind trial comparing ipilimumab 10 mg/kg with placebo, which showed a statistically significant impact of the checkpoint inhibitor on RFS and OS. All statistical tests were two-sided. Results: With a median follow-up of seven years, 12 of 13 trials showed a consistency between the IFN vs No IFN differences regarding RFS (hazard ratio [HR]RFS = 0.88) and OS (HROS = 0.91), but the small trial, Eastern Cooperative Oncology Group 2696, was an outlier (HRRFS = 0.72 vs HROS = 1.11). Therefore, even if rho was high, R² was low and could not reliably be estimated. Based on the 12 trials, rho remained high (0.89), and the hazard ratios for RFS and OS were strongly correlated (R² = 0.91). The surrogate threshold effect for RFS was estimated to be 0.77. For the EORTC 18071 trial, the hazard ratio for RFS was 0.75, predicting an effect of ipilimumab on OS. This was subsequently confirmed (HROS = 0.72, 95.1% confidence interval = 0.58 to 0.88, P = .001). Conclusions: In high-risk stage II-III melanoma, RFS appeared to be a valid surrogate end point for OS for adjuvant randomized studies assessing interferon or a checkpoint inhibitor. In future similar adjuvant studies, a hazard ratio for RFS of 0.77 or less would predict a treatment impact on OS.

6 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.

7 Review Adjuvant interferon-α for the treatment of high-risk melanoma: An individual patient data meta-analysis. 2017

Ives, Natalie J / Suciu, Stefan / Eggermont, Alexander M M / Kirkwood, John / Lorigan, Paul / Markovic, Svetomir N / Garbe, Claus / Wheatley, Keith / Anonymous3260912. ·Birmingham Clinical Trials Unit, College of Medical and Dental Sciences, Public Health Building, University of Birmingham, Birmingham, B15 2TT, UK. · EORTC Headquarters, Avenue Emmanuel Mounier 83/11, 1200 Brussels, Belgium. · Gustave Roussy Cancer Campus Grand Paris, 114 Rue Edouard Vaillant, 94800, Villejuif, France. · University of Pittsburgh Cancer Institute and School of Medicine, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA. · The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester, M20 4BX, UK. · Mayo Clinic Rochester, 200 First St. SW, Rochester, MN, 55905, USA. · University of Tubingen, Liebermeisterstraße 25, 72076, Tübingen, Germany. · Cancer Research UK Clinical Trials Unit, College of Medical and Dental Sciences, Robert Aitken Institute, University of Birmingham, Birmingham, B15 2TT, UK. Electronic address: k.wheatley@bham.ac.uk. ·Eur J Cancer · Pubmed #28692949.

ABSTRACT: BACKGROUND: Many randomised trials assessing interferon-α (IFN-α) as adjuvant therapy for high-risk malignant melanoma have been undertaken. To better assess the role of IFN-α, an individual patient data (IPD) meta-analysis of these trials was undertaken. METHODS: IPD was sought from all randomised trials of adjuvant IFN-α versus no IFN-α for high-risk melanoma. Primary outcomes were event-free survival (EFS) and overall survival (OS). Standard methods for quantitative IPD meta-analysis were used. Subgroup analyses by dose, duration of treatment and various patient and disease-specific parameters were performed. FINDINGS: Fifteen trials were included in the analysis (eleven with IPD). EFS was significantly improved with IFN-α (hazard ratio [HR] = 0.86, CI 0.81-0.91; P < 0.00001), as was OS (HR = 0.90, CI 0.85-0.97; P = 0.003). The absolute differences in EFS at 5 and 10 years were 3.5% and 2.7%, and for OS were 3.0% and 2.8% respectively in favour of IFN-α. There was no evidence that the benefit of IFN-α differed depending on dose or duration of treatment, or by age, gender, site of primary tumour, disease stage, Breslow thickness, or presence of clinical nodes. Only for ulceration was there evidence of an interaction (test for heterogeneity: P = 0.04 for EFS; P = 0.002 for OS); only patients with ulcerated tumours appeared to obtain benefit from IFN-α. CONCLUSION: This meta-analysis provides clear evidence that adjuvant IFN-α significantly reduces the risk of relapse and improves survival and shows no benefit for higher doses compared to lower doses. The increased benefit in patients with ulcerated tumours, and lack of benefit in patients without ulceration, needs further investigation.

8 Review Operable Melanoma: Screening, Prognostication, and Adjuvant and Neoadjuvant Therapy. 2017

Tarhini, Ahmad A / Lorigan, Paul / Leachman, Sancy. ·From the University of Pittsburgh, Pittsburgh, PA; University of Manchester, Manchester, United Kingdom; Oregon Health & Science University, Portland, OR. ·Am Soc Clin Oncol Educ Book · Pubmed #28561661.

ABSTRACT: The importance of reducing the numbers of patients with late-stage melanoma, identifying which patients are most likely to progress, and treating these patients at the earliest possible stage cannot be overemphasized. Improved screening of patients prior to diagnosis has the advantage of identifying early-stage disease that is for the most part treatable by surgical methods. The process of melanoma screening is rapidly evolving through population-based programs, mobile health technologies, and advanced imaging tools. For patients with newly diagnosed melanoma, accurately estimating disease prognosis has important implications for management and follow-up. Prognostic factors are individual host- or tumor-related factors or molecules that correlate with genetic predisposition and clinical course. These include clinical covariates and host and tumor proteomic/genomic markers that allow the prognostic subclassification of patients. Adjuvant therapy for high-risk surgically resected melanoma targets residual micrometastatic disease with the goal of reducing the risk of relapse and mortality. In the United States, three regimens have achieved regulatory approval for adjuvant therapy, including high-dose interferon alpha, pegylated interferon alpha, and ipilimumab at 10 mg/kg. Phase III trials have reported benefits in relapse-free survival (all regimens) and overall survival (high-dose interferon alpha and ipilimumab). The management of locally/regionally advanced melanoma may benefit from neoadjuvant therapy, which is the subject of several ongoing studies. Recent studies have shown promising clinical activity and yielded important biomarker findings and mechanistic insights.

9 Review Surgical Management and Adjuvant Therapy for High-Risk and Metastatic Melanoma. 2016

van Akkooi, Alexander C J / Atkins, Michael B / Agarwala, Sanjiv S / Lorigan, Paul. ·From the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; St. Luke's University Hospital, Temple University, Allentown, PA; University of Manchester, The Christie NHS Foundation Trust, Manchester, United Kingdom. ·Am Soc Clin Oncol Educ Book · Pubmed #27249760.

ABSTRACT: Wide local excision is considered routine therapy after initial diagnosis of primary melanoma to reduce local recurrences, but it does not impact survival. Sentinel node staging is recommended for melanomas of intermediate thickness, but it has also not demonstrated any indisputable therapeutic effect on survival. The prognostic value of sentinel node staging has been long established and is therefore considered routine, especially in light of the eligibility criteria for adjuvant therapy (trials). Whether completion lymph node dissection after a positive sentinel node biopsy improves survival is the question of current trials. The MSLT-2 study is best powered to show a potential benefit, but it has not yet reported any data. Another study, the German DECOG study, presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting did not show any benefit but is criticized for the underpowered design and insufficient follow-up. There is no consensus on the use of adjuvant interferon in melanoma. This topic has been the focus of many studies with different regimens (low-, intermediate-, or high-dose and/or short- or long-term treatment). Adjuvant interferon has been shown to improve relapse-free survival but failed to improve overall survival. More recently, adjuvant ipilimumab has also demonstrated an improved relapse-free survival. Overall survival data have not yet been reported due to insufficient follow-up. Currently, studies are ongoing to analyze the use of adjuvant anti-PD-1 and molecular targeted therapies (vemurafenib, dabrafenib, and trametinib). In the absence of unambiguously positive approved agents, clinical trial participation remains a priority. This could change in the near future.

10 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.

11 Review Circulating tumour cells as tumour biomarkers in melanoma: detection methods and clinical relevance. 2015

Khoja, L / Lorigan, P / Dive, C / Keilholz, U / Fusi, A. ·Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester. · Clinical and Experimental Pharmacology, The Paterson Institute for Cancer Research, Manchester, UK. · Department of Medical Oncology, Charité Comprehensive Cancer Center, Berlin, Germany. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester Department of Medical Oncology, Charité Comprehensive Cancer Center, Berlin, Germany alberto.fusi@christie.nhs.uk. ·Ann Oncol · Pubmed #24907634.

ABSTRACT: Circulating tumour cells (CTCs) are cells of solid tumour origin detectable in the peripheral blood. Their occurrence is considered a prerequisite step for establishing distant metastases. Metastatic melanoma was the first malignancy in which CTCs were detected and numerous studies have been published on CTC detection in melanoma at various stages of disease. In spite of this, there is no general consensus as to the clinical utility of CTCs in melanoma, largely due to conflicting results from heterogeneous studies and discrepancies in methods of detection between studies. In this review, we examine the possible clinical significance of CTCs in cutaneous, mucosal and ocular melanoma, focusing on detection methods and prognostic value of CTC detection.

12 Review No longer an untreatable disease: how targeted and immunotherapies have changed the management of melanoma patients. 2014

Girotti, Maria Romina / Saturno, Grazia / Lorigan, Paul / Marais, Richard. ·Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, UK. · University of Manchester, Christie NHS Foundation Trust, Manchester, UK. · Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, UK. Electronic address: richard.marais@cruk.manchester.ac.uk. ·Mol Oncol · Pubmed #25178978.

ABSTRACT: The discovery that BRAF is a driver oncogene in cancer, and complementary improvements in our understanding of the immune system have resulted in new targeted and immune-therapies for metastatic melanoma. Targeted therapies achieve impressive clinical results in carefully selected patients but the development of resistance seems inevitable in most cases. Conversely, immune-checkpoints inhibitors can achieve long-term remission and cures, but in a smaller proportion of patients, and biomarkers to predict which patients will respond are not available. Nevertheless, melanoma has led the evolution of cancer treatment from relatively nonspecific cytotoxic agents to highly selective therapies and here we review the lessons from this paradigm shift in treatment and the opportunities for further improvements in outcomes for melanoma patients.

13 Review Advances in the management of melanoma: targeted therapy, immunotherapy and future directions. 2012

Dean, Emma / Lorigan, Paul. ·The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK. emma.dean@manchester.ac.uk ·Expert Rev Anticancer Ther · Pubmed #23249108.

ABSTRACT: Metastatic melanoma is an aggressive, immunogenic and molecularly heterogeneous disease for which most patients require systemic treatment. Recently, significant clinical breakthroughs have revolutionized the treatment of advanced melanoma, leading to the licensing of ipilimumab, a monoclonal antibody targeting cytotoxic T-lymphocyte-associated antigen 4, and vemurafenib, a BRAF inhibitor used in patients whose tumors contain a V600 mutation in the BRAF gene. This recent success has led to optimism and momentum has gathered with updated trial results from these therapies, next-generation compounds that target validated molecular pathways and novel agents that are mechanistically distinct. This review summarizes the recent advances and updated results since the licensing of vemurafenib and ipilimumab, the benefits and limitations of these agents, future strategies to improve upon existing treatments and overcome acquired resistance, in-progress and future clinical trials, as well as novel therapeutic targets, pathways and therapies that hold promise in advancing clinical benefit.

14 Review Systematic review and network meta-analysis of overall survival comparing 3 mg/kg ipilimumab with alternative therapies in the management of pretreated patients with unresectable stage III or IV melanoma. 2012

Dequen, Pascale / Lorigan, Paul / Jansen, Jeroen P / van Baardewijk, Marc / Ouwens, Mario J N M / Kotapati, Srividya. ·MAPI Group, Houten, The Netherlands. ·Oncologist · Pubmed #23024154.

ABSTRACT: OBJECTIVE: To compare the overall survival (OS) of patients treated with 3 mg/kg ipilimumab versus alternative systemic therapies in pretreated unresectable stage III or IV melanoma patients. METHODS: A systematic literature search was performed to identify relevant randomized clinical trials. From these trials, Kaplan-Meier survival curves for each intervention were digitized and combined by means of a Bayesian network meta-analysis (NMA) to compare different drug classes. RESULTS: Of 38 trials identified, 15 formed one interlinked network by drug class to allow for an NMA. Ipilimumab, at a dose of 3 mg/kg, was associated with a greater mean OS time (18.8 months; 95% credible interval [CrI], 15.5-23.0 months) than single-agent chemotherapy (12.3 months; 95% CrI, 6.3-28.0 months), chemotherapy combinations (12.2 months; 95% CrI, 7.1-23.3 months), biochemotherapies (11.9 months; 95% CrI, 7.0-22.0 months), single-agent immunotherapy (11.1 months; 95% CrI, 8.5-16.2 months), and immunotherapy combinations (14.1 months; 95% CrI, 9.0-23.8 months). CONCLUSION: Results of this NMA were in line with previous findings and suggest that OS with ipilimumab is expected to be greater than with alternative systemic therapies, alone or in combination, for the management of pretreated patients with unresectable stage III or IV melanoma.

15 Review Systemic therapy for metastatic malignant melanoma--from deeply disappointing to bright future? 2008

Lorigan, Paul / Eisen, Tim / Hauschild, Axel. ·CRUK Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester, UK. paul.lorigan@manchester.ac.uk ·Exp Dermatol · Pubmed #18312390.

ABSTRACT: The last decade has seen a considerable improvement in the understanding of the biology of melanoma. Advances have come in the understanding of the importance of critical oncogenes and tumour suppressor genes, epigenetic phenomena, signalling pathways, drug resistance mechanisms, the pivotal role of the local immune system, and the importance of cell-cell and cell-matrix interactions. Many of these pathways and interactions include potentially 'drugable' targets. These developments have allowed the identification and/or design of a range of new, targeted therapies. Evaluation of these new drugs has brought a whole new series of challenges. These include identification of appropriate pre-clinical models, overcoming the redundancy in-built in complex biological systems, identification of appropriate molecular and clinical endpoints to show that the drug is hitting the target, how to combine treatments, and new toxicities. For the first time, there is the possibility of personalized treatment for melanoma patients, based on individual host and tumour characteristics. This paper discusses the range of new drugs and targets have been identified, the outcome of clinical trials, and the directions for future advances.

16 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 .).

17 Clinical Trial Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). 2017

Schachter, Jacob / Ribas, Antoni / Long, Georgina V / Arance, Ana / Grob, Jean-Jacques / Mortier, Laurent / Daud, Adil / Carlino, Matteo S / McNeil, Catriona / Lotem, Michal / Larkin, James / Lorigan, Paul / Neyns, Bart / Blank, Christian / Petrella, Teresa M / Hamid, Omid / Zhou, Honghong / Ebbinghaus, Scot / Ibrahim, Nageatte / Robert, Caroline. ·Division of Oncology, Ella Lemelbaum Institute for Melanoma, Sheba Medical Center, Tel Hashomer, Israel. Electronic address: jacob.schachter@sheba.health.gov.il. · Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. · Department of Medical Oncology and Translational Research, Melanoma Institute Australia, The University of Sydney, Mater Hospital and Royal North Shore Hospital, Sydney, Australia. · Department of Medical Oncology, Hospital Clinic de Barcelona, Barcelona, Spain. · Department of Dermatology and Skin Cancer, Aix Marseille University, Hôpital de la Timone, Marseille, France. · Department of Dermatology, Université Lille, INSERM U1189, CHU Lille, F-59000, France. · Department of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA. · Department of Medical Oncology, Westmead and Blacktown Hospitals, Melanoma Institute Australia, and The University of Sydney, Sydney, Australia. · Department of Medical Oncology, Chris O'Brien Lifehouse, Royal Prince Alfred Hospital, and Melanoma Institute Australia, Camperdown, Australia. · Department of Melanoma and Cancer Immunotherapy, Sharett Institute of Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel. · Department of Medical Oncology, Royal Marsden Hospital, London, UK. · Department of Medical Oncology University of Manchester and the Christie NHS Foundation Trust, Manchester, UK. · Department of Medical Oncology, Universitair Ziekenhuis Brussel, Brussels, Belgium. · Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands. · Department of Medicine, Division of Medical Oncology/Hematology, Sunnybrook Health Sciences Center, Toronto, ON, Canada. · Department of Hematology/Oncology, The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Department of BARDS, Merck & Co, Kenilworth, NJ, USA. · Department of Clinical Oncology, Merck & Co, Kenilworth, NJ, USA. · Department of Oncology, Gustave Roussy and Paris-Sud University, Villejuif, France. ·Lancet · Pubmed #28822576.

ABSTRACT: BACKGROUND: Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis. METHODS: In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of pembrolizumab, or one regimen of ipilimumab, using a centralised, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3, 2015. This study was registered with ClinicalTrials.gov, number NCT01866319. FINDINGS: Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous pembrolizumab every 2 weeks (n=279), intravenous pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either pembrolizumab group and was 16·0 months with ipilimumab (hazard ratio [HR] 0·68, 95% CI 0·53-0·87 for pembrolizumab every 2 weeks vs ipilimumab; p=0·0009 and 0·68, 0·53-0·86 for pembrolizumab every 3 weeks vs ipilimumab; p=0·0008). 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group. INTERPRETATION: Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between pembrolizumab dosing schedules. These conclusions further support the use of pembrolizumab as a standard of care for advanced melanoma. FUNDING: Merck & Co.

18 Clinical Trial Pembrolizumab versus Ipilimumab in Advanced Melanoma. 2015

Robert, Caroline / Schachter, Jacob / Long, Georgina V / Arance, Ana / Grob, Jean Jacques / Mortier, Laurent / Daud, Adil / Carlino, Matteo S / McNeil, Catriona / Lotem, Michal / Larkin, James / Lorigan, Paul / Neyns, Bart / Blank, Christian U / Hamid, Omid / Mateus, Christine / Shapira-Frommer, Ronnie / Kosh, Michele / Zhou, Honghong / Ibrahim, Nageatte / Ebbinghaus, Scot / Ribas, Antoni / Anonymous4340827. ·The authors' affiliations are listed in the Appendix. ·N Engl J Med · Pubmed #25891173.

ABSTRACT: BACKGROUND: The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma. METHODS: In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival. RESULTS: The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%). CONCLUSIONS: The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.).

19 Clinical Trial Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. 2015

Weber, Jeffrey S / D'Angelo, Sandra P / Minor, David / Hodi, F Stephen / Gutzmer, Ralf / Neyns, Bart / Hoeller, Christoph / Khushalani, Nikhil I / Miller, Wilson H / Lao, Christopher D / Linette, Gerald P / Thomas, Luc / Lorigan, Paul / Grossmann, Kenneth F / Hassel, Jessica C / Maio, Michele / Sznol, Mario / Ascierto, Paolo A / Mohr, Peter / Chmielowski, Bartosz / Bryce, Alan / Svane, Inge M / Grob, Jean-Jacques / Krackhardt, Angela M / Horak, Christine / Lambert, Alexandre / Yang, Arvin S / Larkin, James. ·Moffitt Cancer Center, Tampa, FL, USA. Electronic address: jeffrey.weber@moffitt.org. · Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. · California Pacific Center for Melanoma Research, San Francisco, CA, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Medizinische Hochschule Hannover, Hannover, Germany. · Universitair Ziekenhuis Brussel, Brussels, Belgium. · Medical University of Vienna, Vienna, Austria. · Roswell Park Cancer Institute, Buffalo, NY, USA. · Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada. · University of Michigan, Ann Arbor, MI, USA. · Washington University, St Louis, MO, USA. · Centre Hospitalier Universitaire de Lyon, Lyon, France. · Christie Hospital, Manchester, UK. · Huntsman Cancer Institute, Salt Lake City, UT, USA. · German Cancer Research Centre University Hospital, Heidelberg, Germany. · Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. · Yale Cancer Center, New Haven, CT, USA. · Istituto Nazionale Tumori Fondazione G Pascale, Naples, Italy. · Elbe Kliniken Buxtehude, Buxtehude, Germany. · Department of Medicine, University of California, Los Angeles, CA, USA. · Department of Medicine, Mayo Clinic, Scottsdale, AZ, USA. · Department of Oncology, Herlev Hospital, Copenhagen, Denmark. · Aix-Marseille University, Hopital de la Timone, Marseille, France. · Technische Universität München School of Medicine, II Medical Department, Munich, Germany. · Bristol-Myers Squibb, Princeton, NJ, USA. · Bristol-Myers Squibb, Braine-I'Alleud, Belgium. · Royal Marsden Hospital, London, UK. ·Lancet Oncol · Pubmed #25795410.

ABSTRACT: BACKGROUND: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries. Eligible patients were 18 years or older, had unresectable or metastatic melanoma, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAF(V 600) mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m(2) every 3 weeks or paclitaxel 175 mg/m(2) combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used permuted blocks (block size of six) within each stratum. Primary endpoints were the proportion of patients who had an objective response and overall survival. Treatment was given open-label, but those doing tumour assessments were masked to treatment assignment. We assessed objective responses per-protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. The trial is closed and this is the first interim analysis, reporting the objective response primary endpoint. This study is registered with ClinicalTrials.gov, number NCT01721746. FINDINGS: Between Dec 21, 2012, and Jan 10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab and 133 to ICC. Confirmed objective responses were reported in 38 (31·7%, 95% CI 23·5-40·8) of the first 120 patients in the nivolumab group versus five (10·6%, 3·5-23·1) of 47 patients in the ICC group. Grade 3-4 adverse events related to nivolumab included increased lipase (three [1%] of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two [1%] each); for ICC, these included neutropenia (14 [14%] of 102), thrombocytopenia (six [6%]), and anaemia (five [5%]). We noted grade 3-4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths occurred. INTERPRETATION: Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need. FUNDING: Bristol-Myers Squibb.

20 Clinical Trial Improved overall survival in melanoma with combined dabrafenib and trametinib. 2015

Robert, Caroline / Karaszewska, Boguslawa / Schachter, Jacob / Rutkowski, Piotr / Mackiewicz, Andrzej / Stroiakovski, Daniil / Lichinitser, Michael / Dummer, Reinhard / Grange, Florent / Mortier, Laurent / Chiarion-Sileni, Vanna / Drucis, Kamil / Krajsova, Ivana / Hauschild, Axel / Lorigan, Paul / Wolter, Pascal / Long, Georgina V / Flaherty, Keith / Nathan, Paul / Ribas, Antoni / Martin, Anne-Marie / Sun, Peng / Crist, Wendy / Legos, Jeff / Rubin, Stephen D / Little, Shonda M / Schadendorf, Dirk. ·The authors' affiliations are listed in the Appendix. ·N Engl J Med · Pubmed #25399551.

ABSTRACT: BACKGROUND: The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients. METHODS: In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival. RESULTS: At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combination-therapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group. CONCLUSIONS: Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01597908.).

21 Clinical Trial Adjuvant bevacizumab in patients with melanoma at high risk of recurrence (AVAST-M): preplanned interim results from a multicentre, open-label, randomised controlled phase 3 study. 2014

Corrie, Pippa G / Marshall, Andrea / Dunn, Janet A / Middleton, Mark R / Nathan, Paul D / Gore, Martin / Davidson, Neville / Nicholson, Steve / Kelly, Charles G / Marples, Maria / Danson, Sarah J / Marshall, Ernest / Houston, Stephen J / Board, Ruth E / Waterston, Ashita M / Nobes, Jenny P / Harries, Mark / Kumar, Satish / Young, Gemma / Lorigan, Paul. ·Cambridge Cancer Trials Centre, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, UK. Electronic address: pippa.corrie@addenbrookes.nhs.uk. · Warwick Clinical Trials Unit, University of Warwick, Coventry, UK. · Oxford National Institute for Health Research Biomedical Research Centre, Oxford, UK. · Medical Oncology, Mount Vernon Hospital, Northwood, Middlesex, UK. · Royal Marsden Hospital NHS Trust, London, UK. · Oncology Research, Broomfield Hospital, Chelmsford, UK. · Oncology Department, Leicester Royal Infirmary, Leicester, UK. · Sir Bobby Robson Cancer Trials Research Centre, Freeman Hospital, Newcastle upon Tyne, UK. · Cancer Research, St James's University Hospital, Leeds, UK. · Academic Unit of Clinical Oncology, Weston Park Hospital, Sheffield, UK. · Cancer and Palliative Care, St Helen's Hospital, St Helens, UK. · Oncology Department, Royal Surrey County Hospital, Surrey, UK. · Oncology Department, Royal Preston Hospital, Preston, UK. · Clinical Trials Unit, Beatson West of Scotland Cancer Centre, Glasgow, UK. · Clinical Oncology, Norfolk and Norwich University Hospital, Norwich, UK. · Guy's and St Thomas' Hospital, London, UK. · Velindre Cancer Centre, Cardiff, UK. · Cambridge Cancer Trials Centre/Cambridge Clinical Trials Unit-Cancer Theme, Addenbrooke's Hospital, Cambridge, UK. · Deptartment of Medical Oncology, Christie Hospital, Manchester, UK. ·Lancet Oncol · Pubmed #24745696.

ABSTRACT: BACKGROUND: Bevacizumab, a monoclonal antibody that targets VEGF, has shown restricted activity in patients with advanced melanoma. We aimed to assess the role of bevacizumab as adjuvant treatment for patients with resected melanoma at high risk of recurrence. We report results from the preplanned interim analysis. METHODS: We did a multicentre, open-label, randomised controlled phase 3 trial at 48 centres in the UK between July 18, 2007, and March 29, 2012. Patients aged 16 years or older with American Joint Committee on Cancer stage (AJCC) stage IIB, IIC, and III cutaneous melanoma were randomly allocated (1:1), via a central, computer-based minimisation procedure, to receive intravenous bevacizumab 7.5 mg/kg, every 3 weeks for 1 year, or to observation. Randomisation was stratified by Breslow thickness of the primary tumour, N stage according to AJCC staging criteria, ulceration of the primary tumour, and patient sex. The primary endpoint was overall survival; secondary endpoints included disease-free interval, distant-metastases interval and quality of life. Analysis was by intention-to-treat. This trial is registered as an International Standardised Randomised Controlled Trial, number ISRCTN81261306. FINDINGS: 1343 patients were randomised to either the bevacizumab group (n=671) or the observation group (n=672). Median follow-up was 25 months (IQR 16-37) in the bevacizumab group and 25 months (17-37) in the observation group. At the time of interim analysis, 286 (21%) of 1343 enrolled patients had died: 140 (21%) of 671 patients in the bevacizumab group, and 146 (22%) of 672 patients in the observation group. 134 (96%) of patients in the bevacizumab group died because of melanoma versus 139 (95%) in the observation group. We noted no significant difference in overall survival between treatment groups (hazard ratio [HR] 0.97, 95% CI 0.78-1.22; p=0.76); this finding persisted after adjustment for stratification variables (HR 1.03; 95% CI 0.81-1.29; p=0.83). Median duration of treatment with bevacizumab was 51 weeks (IQR 21-52) and dose intensity was 86% (41-96), showing good tolerability. 180 grade 3 or 4 adverse events were recorded in 101 (15%) of 671 patients in the bevacizumab group, and 36 (5%) of 672 patients in the observation group. Bevacizumab resulted in a higher incidence of grade 3 hypertension than did observation (41 [6%] vs one [<1%]). There was an improvement in disease-free interval for patients in the bevacizumab group compared with those in the observation group (HR 0.83, 95% CI 0.70-0.98, p=0.03), but no significant difference between groups for distant-metastasis-free interval (HR 0.88, 95% CI 0.73-1.06, p=0.18). No significant differences were noted between treatment groups in the standardised area under the curve for any of the quality-of-life scales over 36 months. Three adverse drug reactions were regarded as both serious and unexpected: one patient had optic neuritis after the first bevacizumab infusion, a second patient had persistent erectile dysfunction, and a third patient died of a haemopericardium after receiving two bevacizumab infusions and was later identified to have had significant predisposing cardiovascular risk factors. INTERPRETATION: Bevacizumab has promising tolerability. Longer follow-up is needed to identify an effect on the primary endpoint of overall survival at 5 years.

22 Clinical Trial A randomized, open-label clinical trial of tasisulam sodium versus paclitaxel as second-line treatment in patients with metastatic melanoma. 2014

Hamid, Omid / Ilaria, Robert / Garbe, Claus / Wolter, Pascal / Maio, Michele / Hutson, Thomas E / Arance, Ana / Lorigan, Paul / Lee, Jeeyun / Hauschild, Axel / Mohr, Peter / Hahka-Kemppinen, Marjo / Kaiser, Christopher / Turner, P Kellie / Conti, Ilaria / Grob, Jean-Jacques. ·The Angeles Clinic and Research Institute, Los Angeles, California. ·Cancer · Pubmed #24676877.

ABSTRACT: BACKGROUND: Tasisulam sodium (hereafter referred to as tasisulam) is a novel, highly albumin-bound agent that demonstrated activity in a phase 2 melanoma study. METHODS: In this open-label phase 3 study, patients with AJCC stage IV melanoma received tasisulam (targeting an albumin-corrected exposure of 1200-6400 h (hour).μg/mL on day 1) or paclitaxel (80 mg/m(2) on days 1, 8, and 15) every 28 days as second-line treatment. RESULTS: The study was placed on clinical hold after randomization of 336 patients when a safety review indicated an imbalance of possibly drug-related deaths in the tasisulam arm. Efficacy results for tasisulam versus paclitaxel revealed a response rate of 3.0% versus 4.8%, a median progression-free survival of 1.94 months versus 2.14 months (P = .048), and a median overall survival of 6.77 months versus 9.36 months (P = .121). The most common drug-related grade ≥3 laboratory toxicities (graded according to Common Terminology for Adverse Events [version 3.0]) were thrombocytopenia (18.9%) for patients treated with tasisulam and neutropenia/leukopenia (8.7%) among those receiving paclitaxel. There were 13 possibly related deaths reported to occur on the study, with the majority occurring during cycle 2 in the setting of grade 4 myelosuppression, all in the tasisulam arm. Investigation of the unexpectedly high rate of hematologic toxicity revealed a subset of patients with low tasisulam clearance, leading to drug accumulation and high albumin-corrected exposure in cycle 2. CONCLUSIONS: Although the study was stopped early because of safety issues in the tasisulam arm, tasisulam was considered unlikely to be superior to paclitaxel, and paclitaxel activity in the second-line treatment of melanoma was much lower than expected. The toxicity imbalance was attributed to an unexpectedly low tasisulam clearance in a subset of patients, underscoring the importance of pharmacokinetic monitoring of compounds with complex dosing, even in late-phase studies.

23 Clinical Trial Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. 2014

Kelderman, Sander / Heemskerk, Bianca / van Tinteren, Harm / van den Brom, Rob R H / Hospers, Geke A P / van den Eertwegh, Alfonsus J M / Kapiteijn, Ellen W / de Groot, Jan Willem B / Soetekouw, Patricia / Jansen, Rob L / Fiets, Edward / Furness, Andrew J S / Renn, Alexandra / Krzystanek, Marcin / Szallasi, Zoltan / Lorigan, Paul / Gore, Martin E / Schumacher, Ton N M / Haanen, John B A G / Larkin, James M G / Blank, Christian U. ·Netherlands Cancer Institute NKI-AVL, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands, s.kelderman@nki.nl. ·Cancer Immunol Immunother · Pubmed #24609989.

ABSTRACT: INTRODUCTION: Ipilimumab, a cytotoxic T lymphocyte-associated antigen-4 blocking antibody, has improved overall survival (OS) in metastatic melanoma in phase III trials. However, about 80 % of patients fail to respond, and no predictive markers for benefit from therapy have been identified. We analysed a 'real world' population of patients treated with ipilimumab to identify markers for treatment benefit. METHODS: Patients with advanced cutaneous melanoma were treated in the Netherlands (NL) and the United Kingdom (UK) with ipilimumab at 3 mg/kg. Baseline characteristics and peripheral blood parameters were assessed, and patients were monitored for the occurrence of adverse events and outcomes. RESULTS: A total of 166 patients were treated in the Netherlands. Best overall response and disease control rates were 17 and 35 %, respectively. Median follow-up was 17.9 months, with a median progression-free survival of 2.9 months. Median OS was 7.5 months, and OS at 1 year was 37.8 % and at 2 years was 22.9 %. In a multivariate model, baseline serum lactate dehydrogenase (LDH) was demonstrated to be the strongest predictive factor for OS. These findings were validated in an independent cohort of 64 patients from the UK. CONCLUSION: In both the NL and UK cohorts, long-term benefit of ipilimumab treatment was unlikely for patients with baseline serum LDH greater than twice the upper limit of normal. In the absence of prospective data, clinicians treating melanoma may wish to consider the data presented here to guide patient selection for ipilimumab therapy.

24 Clinical Trial DOC-MEK: a double-blind randomized phase II trial of docetaxel with or without selumetinib in wild-type BRAF advanced melanoma. 2014

Gupta, A / Love, S / Schuh, A / Shanyinde, M / Larkin, J M / Plummer, R / Nathan, P D / Danson, S / Ottensmeier, C H / Lorigan, P / Collins, L / Wise, A / Asher, R / Lisle, R / Middleton, M R. ·Department of Oncology, Oxford University Hospitals NHS Trust, Oxford. ·Ann Oncol · Pubmed #24567366.

ABSTRACT: BACKGROUND: Treatment options for wild-type BRAF melanoma patients remain limited. Selumetinib, a MEK 1/2 inhibitor, suppresses pERK levels independent of BRAF and NRAS mutation status, and combination with docetaxel has demonstrated synergy in xenograft models. The aim of this study was to assess the efficacy and safety of selumetinib plus docetaxel as first-line treatment in patients with wild-type BRAF advanced melanoma. PATIENTS AND METHODS: In this double-blind multicentre phase II trial patients with wild-type BRAF melanoma were randomized (1:1) to docetaxel with selumetinib or placebo. Docetaxel 75 mg/m(2) was administered intravenously every 3 weeks up to six cycles. Selumetinib 75 mg or placebo was given orally twice daily until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Tumour NRAS mutation status was analysed retrospectively and correlated with treatment outcomes. RESULTS: Eighty-three patients were randomized to docetaxel plus selumetinib (n = 41) or docetaxel plus placebo (n = 42). The PFS hazard ratio (HR) (selumetinib:placebo) was 0.75 [90% confidence interval (CI) 0.50-1.14; P = 0.130], with a median PFS of 4.23 months (90% CI 3.63-6.90) for docetaxel plus selumetinib and 3.93 months (90% CI 2.07-4.16) for docetaxel alone. There was no significant difference in overall survival. The objective response rate was 32% with selumetinib versus 14% with placebo (P = 0.059). In a retrospective subset analysis, NRAS mutation status did not affect significantly upon clinical outcomes in either arm. The combination of docetaxel and selumetinib could be administered effectively to patients with metastatic melanoma, although the combination was less well tolerated than docetaxel alone. CONCLUSIONS: The combination of docetaxel with selumetinib showed no significant improvement in PFS compared with docetaxel alone, although more patients showed a response to combination therapy. We found no evidence to support using tumour NRAS mutation as a basis for selecting patients for combined MEK inhibitor and chemotherapy. CLINICAL TRIAL: DOC-MEK (EudraCT no: 2009-018153-23).

25 Clinical Trial Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. 2014

McArthur, Grant A / Chapman, Paul B / Robert, Caroline / Larkin, James / Haanen, John B / Dummer, Reinhard / Ribas, Antoni / Hogg, David / Hamid, Omid / Ascierto, Paolo A / Garbe, Claus / Testori, Alessandro / Maio, Michele / Lorigan, Paul / Lebbé, Celeste / Jouary, Thomas / Schadendorf, Dirk / O'Day, Stephen J / Kirkwood, John M / Eggermont, Alexander M / Dréno, Brigitte / Sosman, Jeffrey A / Flaherty, Keith T / Yin, Ming / Caro, Ivor / Cheng, Suzanne / Trunzer, Kerstin / Hauschild, Axel. ·Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia. Electronic address: grant.mcarthur@petermac.org. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Institut Gustave Roussy, Paris, France. · Royal Marsden Hospital, London, UK. · The Netherlands Cancer Institute, Amsterdam, Netherlands. · University of Zurich, Zurich, Switzerland. · Jonsson Comprehensive Cancer Center at University of California, Los Angeles, CA, USA. · Princess Margaret Hospital and University Health Network, Toronto, ON, Canada. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. · The University of Tübingen, Tübingen, Germany. · Istituto Europeo di Oncologia, Milan, Italy. · University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. · University of Manchester, Manchester, UK. · APHP Oncodermatology, Hôpital Saint Louis University, Paris, France. · Saint André Hospital, Bordeaux, France. · University Hospital Essen, Essen, Germany. · Beverly Hills Cancer Center, Beverly Hills, CA, USA. · University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. · Gustave-Roussy Cancer Center and University Paris-Sud, Villejuif/Paris Sud, France. · Nantes University Hospital, Nantes, France. · Vanderbilt University School of Medicine, Nashville, TN, USA. · Massachusetts General Hospital, Boston, MA, USA. · Genentech Inc, San Francisco, CA, USA. · Roche Molecular Systems Inc, Pleasanton, CA, USA. · F Hoffmann-La Roche, Basel, Switzerland. · University of Kiel, Kiel, Germany. ·Lancet Oncol · Pubmed #24508103.

ABSTRACT: BACKGROUND: In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAF(V600) mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAF(V600E) and BRAF(V600K) mutation subgroups. METHODS: Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAF(V600) mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m(2) of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980. FINDINGS: 675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5 months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI 0·57-0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI 0·32-0·46]; p<0·0001). For the 598 (91%) patients with BRAF(V600E) disease, median overall survival in the vemurafenib group was 13·3 months (95% CI 11·9-14·9) compared with 10·0 months (8·0-14·0) in the dacarbazine group (HR 0·75 [95% CI 0·60-0·93]; p=0·0085); median progression-free survival was 6·9 months (95% CI 6·2-7·0) and 1·6 months (1·6-2·1), respectively (HR 0·39 [95% CI 0·33-0·47]; p<0·0001). For the 57 (9%) patients with BRAF(V600K) disease, median overall survival in the vemurafenib group was 14·5 months (95% CI 11·2-not estimable) compared with 7·6 months (6·1-16·6) in the dacarbazine group (HR 0·43 [95% CI 0·21-0·90]; p=0·024); median progression-free survival was 5·9 months (95% CI 4·4-9·0) and 1·7 months (1·4-2·9), respectively (HR 0·30 [95% CI 0·16-0·56]; p<0·0001). The most frequent grade 3-4 events were cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of 287 patients) in the dacarbazine group. Eight (2%) patients in the vemurafenib group and seven (2%) in the dacarbazine group had grade 5 events. INTERPRETATION: Inhibition of BRAF with vemurafenib improves survival in patients with the most common BRAF(V600E) mutation and in patients with the less common BRAF(V600K) mutation. FUNDING: F Hoffmann-La Roche-Genentech.

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