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Melanoma: HELP
Articles by Antoni Ribas
Based on 174 articles published since 2008
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Between 2008 and 2019, A. Ribas wrote the following 174 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7
1 Editorial Gauging the Long-Term Benefits of Ipilimumab in Melanoma. 2015

Ribas, Antoni / Flaherty, Keith T. ·University of California, Los Angeles, and the Jonsson Comprehensive Cancer Center, Los Angeles, CA aribas@mednet.ucla.edu. · Massachusetts General Hospital Cancer Center, Boston, MA. ·J Clin Oncol · Pubmed #25667273.

ABSTRACT: -- No abstract --

2 Editorial Interferon alfa in the postsurgical management of high-risk melanoma: is it worth it? 2009

Glaspy, John / Ribas, Antoni / Chmielowski, Bartosz. · ·J Clin Oncol · Pubmed #19433677.

ABSTRACT: -- No abstract --

3 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.

4 Review Targeted agents and immunotherapies: optimizing outcomes in melanoma. 2017

Luke, Jason J / Flaherty, Keith T / Ribas, Antoni / Long, Georgina V. ·Department of Medicine, Division of Hematology/Oncology, University of Chicago Comprehensive Cancer Center, 5841 South Maryland Avenue MC2115, Chicago, Illinois 60637, USA. · Department of Medicine, Harvard Medical School, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA. · Department of Medicine, Division of Hematology/Oncology, University of California Los Angeles Jonsson Comprehensive Cancer Center, 10833 Le Conte Avenue, Los Angeles, California 90024, USA. · Melanoma Institute Australia, The University of Sydney, and The Mater Hospital, Rocklands Road, North Sydney, New South Wales 2060, Australia. · Royal North Shore Hospital, Reserve Road, St Leonards, New South Wales 2065, Australia. ·Nat Rev Clin Oncol · Pubmed #28374786.

ABSTRACT: Treatment options for patients with metastatic melanoma, and especially BRAF-mutant melanoma, have changed dramatically in the past 5 years, with the FDA approval of eight new therapeutic agents. During this period, the treatment paradigm for BRAF-mutant disease has evolved rapidly: the standard-of-care BRAF-targeted approach has shifted from single-agent BRAF inhibition to combination therapy with a BRAF and a MEK inhibitor. Concurrently, immunotherapy has transitioned from cytokine-based treatment to antibody-mediated blockade of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and, now, the programmed cell-death protein 1 (PD-1) immune checkpoints. These changes in the treatment landscape have dramatically improved patient outcomes, with the median overall survival of patients with advanced-stage melanoma increasing from approximately 9 months before 2011 to at least 2 years - and probably longer for those with BRAF-V600-mutant disease. Herein, we review the clinical trial data that established the standard-of-care treatment approaches for advanced-stage melanoma. Mechanisms of resistance and biomarkers of response to BRAF-targeted treatments and immunotherapies are discussed, and the contrasting clinical benefits and limitations of these therapies are explored. We summarize the state of the field and outline a rational approach to frontline-treatment selection for each individual patient with BRAF-mutant melanoma.

5 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.

6 Review Targeted Therapy for Melanoma. 2016

Wong, Deborah J L / Ribas, Antoni. ·Department of Medicine, Division of Hematology/Oncology, University of California Los Angeles (UCLA), Le Conte Avenue, Los Angeles, CA, 10833, USA. · Department of Medicine, Division of Hematology/Oncology, University of California Los Angeles (UCLA), Le Conte Avenue, Los Angeles, CA, 10833, USA. aribas@mednet.ucla.edu. · Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA. aribas@mednet.ucla.edu. ·Cancer Treat Res · Pubmed #26601866.

ABSTRACT: Vemurafenib and dabrafenib, two potent tyrosine kinase inhibitors (TKIs) of the BRAF(V600E) kinase, are highly effective in the treatment of a BRAF (V600) -mutant metastatic melanoma. These are selective type I inhibitors (functional against the active conformation of the kinase) of the RAF kinases, which are key players in the mitogen-activated protein kinase (MAPK) pathway. BRAF (V600) mutations are present in approximately 7 % of all cancers, including high frequencies of mutations reported in 50 % of advanced melanomas and 100 % of hairy cell leukemias. As with most targeted therapies, resistance to BRAF inhibitors is an issue, and mechanisms of resistance are varied. Combining BRAF inhibitors with MEK inhibitors such as trametinib delays the development of resistance. Rationally combining targeted therapies to address the mechanism of resistance or combining BRAF inhibitors with other effective therapies such as immunotherapy may result in further improvement in outcomes for patients.

7 Review Melanoma. 2015

Schadendorf, Dirk / Fisher, David E / Garbe, Claus / Gershenwald, Jeffrey E / Grob, Jean-Jacques / Halpern, Allan / Herlyn, Meenhard / Marchetti, Michael A / McArthur, Grant / Ribas, Antoni / Roesch, Alexander / Hauschild, Axel. ·Department of Dermatology, University Duisburg-Essen, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany. · German Cancer Consortium (DKTK), Heidelberg, Germany. · Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Department of Dermatology, University Tübingen, Tübingen, Germany. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. · Department of Dermatology and Skin Cancers, APHM Timone Hospital Aix-Marseille University, Marseille, France. · Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Melanoma Research Center, Wistar Institute, Philadelphia, Pennsylvania, USA. · Division of Cancer Medicine and Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. · Departments of Medicine, Surgery, and Medical and Molecular Pharmacology, University of California Los Angeles, Los Angeles, California, USA. · Department of Dermatology, University Hospital Schleswig-Holstein (UKSH), Kiel, Germany. ·Nat Rev Dis Primers · Pubmed #27188223.

ABSTRACT: Melanoma is a common cancer in the Western world with an increasing incidence. Sun exposure is still considered to be the major risk factor for melanoma. The prognosis of patients with malignant (advanced-stage) melanoma differs widely between countries, but public campaigns advocating early detection have led to significant reductions in mortality rates. As well as sun exposure, distinct genetic alterations have been identified as associated with melanoma. For example, families with melanoma who have germline mutations in CDKN2A are well known, whereas the vast majority of sporadic melanomas have mutations in the mitogen-activated protein kinase cascade, which is the pathway with the highest oncogenic and therapeutic relevance for this disease. BRAF and NRAS mutations are typically found in cutaneous melanomas, whereas KIT mutations are predominantly observed in mucosal and acral melanomas. GNAQ and GNA11 mutations prevail in uveal melanomas. Additionally, the PI3K-AKT-PTEN pathway and the immune checkpoint pathways are important. The finding that programmed cell death protein 1 ligand 1 (PDL1) and PDL2 are expressed by melanoma cells, T cells, B cells and natural killer cells led to the recent development of programmed cell death protein 1 (PD1)-specific antibodies (for example, nivolumab and pembrolizumab). Alongside other new drugs - namely, BRAF inhibitors (vemurafenib and dabrafenib) and MEK inhibitors (trametinib and cobimetinib) - these agents are very promising and have been shown to significantly improve prognosis for patients with advanced-stage metastatic disease. Early signs are apparent that these new treatment modalities are also improving long-term clinical benefit and the quality of life of patients. This Primer summarizes the current understanding of melanoma, from mechanistic insights to clinical progress. For an illustrated summary of this Primer, visit: http://go.nature.com/vX2N9s.

8 Review Anti-PD-1 therapy in melanoma. 2015

Homet Moreno, Blanca / Parisi, Giulia / Robert, Lidia / Ribas, Antoni. ·Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles (UCLA), CA. · Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles (UCLA), CA; Department of Oncology, Division of Medical Oncology and Immunotherapy, University Hospital of Siena, Italy. · Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles (UCLA), CA; Department of Surgery, University of California Los Angeles (UCLA), Los Angeles, CA; Department of Medical and Molecular Pharmacology, University of California Los Angeles (UCLA), Los Angeles, CA; Jonsson Comprehensive Cancer Center (JCCC) at UCLA, Los Angeles, CA. Electronic address: aribas@mednet.ucla.edu. ·Semin Oncol · Pubmed #25965365.

ABSTRACT: Immune-regulatory mechanisms are used by cancer to hide from the immune system. Advances and in-depth understanding of the biology of melanoma and its interaction with the immune system have led to the development of some of antagonistic antibodies to the programmed death 1 pathway (PD-1) and one of its ligands, programmed death ligand 1 (PD-L1), which are demonstrating high clinical benefit rates and tolerability. Blocking the immune-regulatory checkpoints that limit T-cell responses to melanoma upon PD-1/PD-L1 modulation has provided clinically validated targets for cancer immunotherapy. Combinations with other anti-melanoma agents may result in additional benefits. Nivolumab, pembrolizumab (formerly known as MK-3475 and lambrolizumab), and pidilizumab are anti-PD-1 antibodies in clinical development for melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancers, lymphoma, and several other cancers. Long-term survivors already have been reported with these therapies. In this review, we discuss the current state of anti-PD-1 agents, the evidence in the literature to support the combination of anti-PD-1 antibodies with other anti-cancer agents and discuss the future directions for rational design of clinical trials that keep on increasing the number of long-term survivors.

9 Review Combining targeted therapy with immunotherapy in BRAF-mutant melanoma: promise and challenges. 2014

Hu-Lieskovan, Siwen / Robert, Lidia / Homet Moreno, Blanca / Ribas, Antoni. ·Siwen Hu-Lieskovan, Lidia Robert, Blanca Homet Moreno, and Antoni Ribas, University of California Los Angeles, Los Angeles, CA · and Blanca Homet Moreno, Carlos III Health Institute, Madrid, Spain. ·J Clin Oncol · Pubmed #24958825.

ABSTRACT: Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer. Targeted therapy can successfully block oncogenic signaling in BRAF(V600)-mutant melanoma with high initial clinical responses, but relapse rates are also high. Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma. These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration. Combining BRAF inhibitors and immunotherapy can specifically target the BRAF(V600) driver mutation in the tumor cells and potentially sensitize the immune system to target tumors. However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non-BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities. Here, we present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials.

10 Review Novel insights/translational implication from the emerging biology of melanoma. 2014

Ribas, Antoni. ·Division of Hematology-Oncology, Department of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA. ·Methods Mol Biol · Pubmed #24258970.

ABSTRACT: Melanoma is a main example of how applying advances in basic biology, pharmacology, and molecular diagnostics into the clinic results in unprecedented benefits to patients. After many years of lack of advances in the treatment of patients with metastatic melanoma, the advent of new therapies that block driver oncogenic signaling and modulate immune responses to cancer provided the first studies with a positive impact in overall survival (OS) of patients with advanced melanoma. The pace of progress in the treatment of this disease has been greatly accelerated by these initial breakthroughs, and it continues with new generation agents and combinatorial approaches.

11 Review New drug targets in metastatic melanoma. 2014

Homet, Blanca / Ribas, Antoni. ·Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles (UCLA), CA, USA. ·J Pathol · Pubmed #24027077.

ABSTRACT: Over the past 30 years, and despite extensive clinical research, the treatment options for metastatic melanoma have been limited. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimes have failed to show significant improvement in overall survival. Recent advances and in-depth understanding of the biology of melanoma have contributed in the development of new agents and to a change in the consideration of melanoma as one of the most therapy-resistant malignancies. Since the discovery of activating mutations in the BRAF oncogene, there has been remarkable progress in the development of targeted therapies for unresectable and metastatic melanoma, with unprecedentedly high response rates. Inactivation of immune regulatory checkpoints that limit T cell responses to melanoma has provided clinically validated targets for cancer immunotherapy, resulting in durable tumour responses. The combination of both approaches may result in additional benefits. Here we discuss current molecular targeted treatment options, immunotherapy and promising ongoing research to develop new strategies to treat melanoma.

12 Review Clinical development of the anti-CTLA-4 antibody tremelimumab. 2010

Ribas, Antoni. ·Department of Medicine, Division of Hematology/Oncology, University of California, Los Angeles (UCLA), Los Angeles, CA 90095–1782, USA. aribas@mednet.ucla.edu ·Semin Oncol · Pubmed #21074059.

ABSTRACT: Tremelimumab (formerly CP-675,206) is a fully human IgG2 monoclonal antibody tested in patients with cancer, of whom the majority have had metastatic melanoma. Clinical trials using tremelimumab demonstrate that this antibody can induce durable tumor regressions (up to 8 years at this time) in 7% to 10% of patients with metastatic melanoma. These tumor responses are mediated by the intratumoral infiltration of cytotoxic T lymphocytes (CTLs) as demonstrated in patient-derived tumor biopsies. Grade 3 or 4 toxicities in the range of 20% to 25% are mainly inflammatory or autoimmune in nature, which are on-target effects after inhibiting CTLA-4-mediated self-tolerance. The lack of survival advantage in the early analysis of a phase III clinical trial comparing tremelimumab with standard chemotherapy for metastatic melanoma highlights the importance of gaining a better understanding of how this antibody modulates the human immune system and how to better select patients for this mode of therapy.

13 Review Obstacles to and opportunities for more effective peptide-based therapeutic immunization in human melanoma. 2009

Ray, Swagatam / Chhabra, Arvind / Mehrotra, Shikhar / Chakraborty, Nitya G / Ribas, Antoni / Economou, James / Mukherji, Bijay. ·Department of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, L-3080, Farmington, CT 06030, USA. ·Clin Dermatol · Pubmed #19880048.

ABSTRACT: Melanoma cells can play a number of tricks to evade the host immune response. They can make themselves invisible to cells of the immune system poised to attack them, elaborate molecules that are frankly immunosuppressive, and can create a microenvironment that is hostile to cells of the immune system. Efforts are underway to institute measures that would make tumor cells more susceptible to immune attack, but these efforts have not been all that successful so far. This contribution reviews the history and the rationale of cancer vaccines, the major obstacles to peptide-based immunization, and a discussion on how to surmount them. Also included are the roles played by peripheral tolerance, low-affinity T-cell receptors, T-cell ignorance, activation-induced cell death, exhaustion of T cells and regulation of the immune response, helpless cytolytic T lymphocytes, and evasion by tumor cells.

14 Review Overcoming immunologic tolerance to melanoma: targeting CTLA-4 with tremelimumab (CP-675,206). 2008

Ribas, Antoni. ·Division of Hematology-Oncology, 11-934 Factor Building. UCLA Medical Center, 10833 Le Conte Avenue, Los Angeles, California 90095-1782, USA. aribas@mednet.ucla.edu ·Oncologist · Pubmed #19001146.

ABSTRACT: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade therapies have been evaluated in clinical trials and have shown promise as possible options for treating patients with cancer. One agent under investigation is tremelimumab (CP-675,206), a monoclonal antibody that has been demonstrated to be a safe and efficacious treatment in patients with malignant melanoma. Results of a phase I clinical trial suggested that a dose of 15 mg/kg of tremelimumab would be the maximum-tolerated dose, with the most common grade 3-4 toxicities being diarrhea and rash. Pharmacokinetic studies showed that the postinfusion plasma concentration and area under the plasma disposition curve both increased in an approximately proportional manner with dose. Studies also showed that tremelimumab has a low clearance (0.132 ml/h x kg), a small volume of distribution (81.2 ml/kg), and a long terminal-phase half-life (22.1 days). A pivotal phase II clinical trial assessing single-agent tremelimumab as second-line therapy in metastatic melanoma has completed accrual, with response rate as the primary endpoint. A pivotal phase III trial has also completed accrual; that study compared the overall survival of previously untreated patients receiving single-agent tremelimumab versus dacarbazine or temozolomide.

15 Clinical Trial Outcomes by line of therapy and programmed death ligand 1 expression in patients with advanced melanoma treated with pembrolizumab or ipilimumab in KEYNOTE-006: A randomised clinical trial. 2018

Carlino, Matteo S / Long, Georgina V / Schadendorf, Dirk / Robert, Caroline / Ribas, Antoni / Richtig, Erika / Nyakas, Marta / Caglevic, Christian / Tarhini, Ahmed / Blank, Christian / Hoeller, Christoph / Bar-Sela, Gil / Barrow, Catherine / Wolter, Pascal / Zhou, Honghong / Emancipator, Kenneth / Jensen, Erin H / Ebbinghaus, Scot / Ibrahim, Nageatte / Daud, Adil. ·Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, NSW, Australia; Blacktown Hospital, Blacktown, NSW, Australia; Melanoma Institute Australia, Sydney, NSW, Australia; School of Medicine, University of Sydney, Sydney, NSW, Australia. Electronic address: Matteo.carlino@sydney.edu.au. · Melanoma Institute Australia, Sydney, NSW, Australia; Department of Medical Oncology and Translational Research, University of Sydney, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia; Mater Hospital, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au. · Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. Electronic address: Dirk.Schadendorf@uk-essen.de. · Department of Oncology, Gustave Roussy, Villejuif, France; Paris-Sud University, Orsay, France. Electronic address: Caroline.Robert@igr.fr. · Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: aribas@mednet.ucla.edu. · Department of Dermatology, Medical University of Graz, Graz, Austria. Electronic address: erika.richtig@medunigraz.at. · Department of Clinical Cancer Research, Oslo University Hospital, Oslo, Norway. Electronic address: marnya@ous-hf.no. · Unit of Investigational Cancer Drugs, Instituto Oncologico Fundación Arturo López Pérez, Santiago, Chile. Electronic address: oncodemia@yahoo.com. · Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: tarhiniaa@upmc.edu. · Division of Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands. Electronic address: c.blank@nki.nl. · Department of Dermatology, Medical University of Vienna, Vienna, Austria. Electronic address: christoph.hoeller@meduniwien.ac.at. · Division of Oncology, Rambam Health Care Campus, Haifa, Israel. Electronic address: g_barsela@rambam.health.gov.il. · Wellington Blood and Cancer Centre, Wellington Hospital, Wellington, New Zealand. Electronic address: Catherine.Barrow@ccdhb.org.nz. · Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium. Electronic address: pascalwolter@hotmail.com. · Department of BARDS, Merck & Co., Inc., Kenilworth, NJ, USA. Electronic address: honghongz@gmail.com. · Companion Diagnostics, Merck & Co., Inc., Kenilworth, NJ, USA. Electronic address: kenneth.emancipator@merck.com. · LDS - Medical Communications, Merck & Co., Inc., North Wales, PA, USA. Electronic address: erin_jensen2@merck.com. · Department of Clinical Oncology, Merck & Co., Inc., North Wales, PA, USA. Electronic address: scot_ebbinghaus@merck.com. · Department of Clinical Oncology, Merck & Co., Inc., North Wales, PA, USA. Electronic address: nageatte.ibrahim@merck.com. · University of California, San Francisco, San Francisco, CA, USA. Electronic address: adaud@medicine.ucsf.edu. ·Eur J Cancer · Pubmed #30096704.

ABSTRACT: BACKGROUND: Predictive biomarkers of patients likely to benefit from anti-programmed death 1 inhibitor therapy have clinical relevance. We examined whether line of therapy or tumour programmed death ligand 1 (PD-L1) expression affects the efficacy and safety of pembrolizumab, compared with ipilimumab, in advanced melanoma. METHODS: Of 834 patients enrolled in the randomised, open-label phase III KEYNOTE-006 study, 833 were included in this analysis. Patients were randomly assigned 1:1:1 to receive pembrolizumab 10 mg/kg every 2 or 3 weeks (for 24 months) or ipilimumab 3 mg/kg every 3 weeks (for four doses) until disease progression/intolerable toxicity. This analysis evaluated progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). Data cut-off: 03 November 2016. RESULTS: Of the patients, 60.3% were male, 65.9% were treatment naive and 80.6% had PD-L1-positive tumours (median follow-up was 33.9 months). Twenty-four-month survival rates were higher with pembrolizumab than with ipilimumab in treatment-naive (PFS 31.0% versus 14.6%; OS 58.0% versus 44.7%) and previously treated patients (PFS 25.7% versus 11.3%; OS 49.2% versus 37.9%). Twenty-four-month survival rates were higher with pembrolizumab than with ipilimumab in patients with PD-L1-positive tumours (PFS 33.2% versus 13.1%; OS 58.4% versus 45.0%) and similar in PD-L1-negative tumours (PFS 14.9% versus NR [no data at 24 months for a PFS estimate]; OS 43.6% versus 31.8%). Safety of pembrolizumab by subgroup was consistent with previous reports. CONCLUSIONS: Findings support pembrolizumab monotherapy as standard of care in patients with advanced melanoma, regardless of first- or second-line therapy or PD-L1 status. CLINICALTRIALS. GOV IDENTIFIER: NCT01866319.

16 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

17 Clinical Trial Association of programmed death ligand-1 (PD-L1) expression with treatment outcomes in patients with BRAF mutation-positive melanoma treated with vemurafenib or cobimetinib combined with vemurafenib. 2018

Wongchenko, Matthew J / Ribas, Antoni / Dréno, Brigitte / Ascierto, Paolo A / McArthur, Grant A / Gallo, Jorge D / Rooney, Isabelle A / Hsu, Jessie / Koeppen, Hartmut / Yan, Yibing / Larkin, James. ·Genentech, Inc., South San Francisco, CA, USA. · Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA. · Nantes University, Nantes, France. · Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy. · Peter MacCallum Cancer Centre, East Melbourne, VIC., Australia. · University of Melbourne, Parkville, VIC., Australia. · F. Hoffmann-La Roche Ltd, Basel, Switzerland. · The Royal Marsden NHS Foundation Trust, London, UK. ·Pigment Cell Melanoma Res · Pubmed #29156488.

ABSTRACT: The prognostic significance of programmed death ligand-1 (PD-L1) on treatment outcomes in patients receiving BRAF with or without MEK inhibitors is not well understood. This retrospective exploratory analysis evaluated the association of tumour PD-L1 expression with progression-free survival (PFS) and overall survival (OS) among 210 patients in the coBRIM trial treated with cobimetinib plus vemurafenib or placebo plus vemurafenib. In the vemurafenib cohort, there was a trend of increased PFS and OS in those with PD-L1

18 Clinical Trial Vemurafenib treatment for patients with locally advanced, unresectable stage IIIC or metastatic melanoma and activating exon 15 BRAF mutations other than V600E. 2017

Hallmeyer, Sigrun / Gonzalez, Rene / Lawson, David H / Cranmer, Lee D / Linette, Gerald P / Puzanov, Igor / Taback, Bret / Cowey, C Lance / Ribas, Antoni / Daniels, Gregory A / Moore, Timothy / Gibney, Geoffrey T / Tawbi, Hussein / Whitman, Eric / Lee, Geraldine / Mun, Yong / Liu, Shiyao / Hamid, Omid. ·aDepartment of Internal Medicine, Advocate Medical Group - Oncology North, Park Ridge, Illinois bMelanoma Research Clinic, University of Colorado Cancer Center, Aurora, Colorado cDepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia dDepartment of Hematology and Oncology, The University of Arizona Cancer Center, Tucson, Arizona eDepartment of Medicine, Washington University School of Medicine, St Louis, Missouri fDepartment of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee gDepartment of Surgery, Columbia University Medical Center, New York, New York hDepartment of Medical Oncology, Texas Oncology, Dallas, Texas iDepartment of Medicine, Jonsson Comprehensive Cancer Center at University of California jDepartment of Immuno-Oncology, The Angeles Clinic and Research Institute, Los Angeles kDepartment of Oncology, Moores Cancer Center, University of California, San Diego, La Jolla lGenentech Inc., South San Francisco, California mMid Ohio Oncology and Hematology Inc., Columbus, Ohio nDepartment of Melanoma, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC oDepartment of Pathology, University of Pittsburgh Cancer Institute and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania pDepartment of Melanoma, Carol G. Simon Cancer Center, Atlantic Health System, Morristown, New Jersey, USA. ·Melanoma Res · Pubmed #29076950.

ABSTRACT: BRAF mutations are found in ~50% of metastatic melanomas, most commonly in codon V600. Vemurafenib improves progression-free survival and overall survival in patients with advanced BRAF-mutated melanoma. The results of a descriptive study evaluating vemurafenib in patients with advanced melanoma harbouring BRAF mutations other than V600E are reported. Eligible patients with stage IIIC or IV melanoma and non-V600E BRAF mutations received vemurafenib (960 mg, twice daily). End points included investigator-assessed best overall response rate (primary), time to response, duration of response, progression-free survival, overall survival and safety. Planned (V600K vs. non-V600K mutations) subgroup analyses were carried out. Thirty-one patients were enrolled; 13 (42%) had V600K mutations and 18 (58%) had other mutations. Investigator-assessed confirmed that the best overall response rate was 23% (95% confidence interval=10-41%) in the overall population, and was similar between patients with V600K mutations (23%; 95% confidence interval=5-54%) versus other mutations (22%; 95% confidence interval=6-48%). Responses were observed in patients with V600K (n=3), V600E2 (n=1), V600R (n=1), L597S (n=1) and D594G (n=1) mutations. No new safety signals were reported. Vemurafenib showed activity in patients with advanced melanoma with rarer BRAF mutations.

19 Clinical Trial Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. 2017

Hamid, Omid / Puzanov, Igor / Dummer, Reinhard / Schachter, Jacob / Daud, Adil / Schadendorf, Dirk / Blank, Christian / Cranmer, Lee D / Robert, Caroline / Pavlick, Anna C / Gonzalez, Rene / Hodi, F Stephen / Ascierto, Paolo A / Salama, April K S / Margolin, Kim A / Gangadhar, Tara C / Wei, Ziwen / Ebbinghaus, Scot / Ibrahim, Nageatte / Ribas, Antoni. ·The Angeles Clinic and Research Institute, Los Angeles, CA, USA. Electronic address: ohamid@theangelesclinic.org. · Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. · University of Zürich, Zürich, Switzerland. · Ella Lemelbaum Institute of Melanoma, Sheba Medical Center, Tel Hashomer, Israel. · University of California, San Francisco, San Francisco, CA, USA. · University Hospital Essen, Essen, Germany. · Netherlands Cancer Institute, Amsterdam, The Netherlands. · University of Arizona Cancer Center, Tucson, AZ, USA. · Gustave Roussy and Paris-Sud University, Villejuif, France. · New York University Cancer Institute, New York, NY, USA. · University of Colorado Denver, Aurora, CO, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, Italy. · Duke Cancer Institute, Durham, NC, USA. · City of Hope, Duarte, CA, USA. · Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA. · Merck & Co., Inc., Kenilworth, NJ, USA. · University of California Los Angeles, Los Angeles, CA, USA. ·Eur J Cancer · Pubmed #28961465.

ABSTRACT: AIM: To evaluate the protocol-specified final analysis of overall survival (OS) in the KEYNOTE-002 study (NCT01704287) of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory, advanced melanoma. METHODS: In this randomised, phase II study, eligible patients had advanced melanoma with documented progression after two or more ipilimumab doses, previous BRAF or MEK inhibitor or both, if BRAF RESULTS: A total of 180 patients were randomised to pembrolizumab 2 mg/kg, 181 to pembrolizumab 10 mg/kg and 179 to chemotherapy. At a median follow-up of 28 months (range 24.1-35.5), 368 patients died and 98 (55%) crossed over to pembrolizumab. Pembrolizumab 2 mg/kg (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.67-1.10, p = 0.117) and 10 mg/kg (0.74, 0.57-0.96, p = 0.011) resulted in a non-statistically significant improvement in OS versus chemotherapy; median OS was 13.4 (95% CI 11.0-16.4) and 14.7 (95% CI 11.3-19.5), respectively, versus 11.0 months (95% CI 8.9-13.8), with limited improvement after censoring for crossover. Two-year survival rates were 36% and 38%, versus 30%. Progression-free survival, objective response rate and duration of response improved with pembrolizumab versus chemotherapy, regardless of dose. Grade III-V treatment-related adverse events occurred in 24 (13.5%), 30 (16.8%) and 45 (26.3%) patients, respectively. CONCLUSION: Improvement in OS with pembrolizumab was not statistically significant at either dose versus chemotherapy.

20 Clinical Trial Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. 2017

Ribas, Antoni / Dummer, Reinhard / Puzanov, Igor / VanderWalde, Ari / Andtbacka, Robert H I / Michielin, Olivier / Olszanski, Anthony J / Malvehy, Josep / Cebon, Jonathan / Fernandez, Eugenio / Kirkwood, John M / Gajewski, Thomas F / Chen, Lisa / Gorski, Kevin S / Anderson, Abraham A / Diede, Scott J / Lassman, Michael E / Gansert, Jennifer / Hodi, F Stephen / Long, Georgina V. ·University of California at Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. Electronic address: aribas@mednet.ucla.edu. · University Hospital of Zurich, Zurich, Switzerland. · Roswell Park Cancer Institute, Buffalo, NY, USA. · The West Clinic, Memphis, TN, USA. · University of Utah Huntsman Cancer Institute, Salt Lake City, UT, USA. · Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. · Fox Chase Cancer Center, Philadelphia, PA, USA. · Hospital Clinic i Provincial de Barcelona, Barcelona, Spain. · Olivia Newton-John Cancer Research Institute, Austin Health, School of Cancer Medicine, LaTrobe University, Heidelberg, VIC, Australia. · Hopitaux Universitaires de Genève, Geneva, Switzerland. · University of Pittsburgh Cancer Institute and Hillman UPMC Cancer Center, Pittsburgh, PA, USA. · The University of Chicago School of Medicine, Chicago, IL, USA. · Amgen Inc., Thousand Oaks, CA, USA. · Amgen Inc., South San Francisco, CA, USA. · Merck & Co., Inc., Kenilworth, NJ, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Melanoma Institute Australia, The University of Sydney and Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. ·Cell · Pubmed #28886381.

ABSTRACT: Here we report a phase 1b clinical trial testing the impact of oncolytic virotherapy with talimogene laherparepvec on cytotoxic T cell infiltration and therapeutic efficacy of the anti-PD-1 antibody pembrolizumab. Twenty-one patients with advanced melanoma were treated with talimogene laherparepvec followed by combination therapy with pembrolizumab. Therapy was generally well tolerated, with fatigue, fevers, and chills as the most common adverse events. No dose-limiting toxicities occurred. Confirmed objective response rate was 62%, with a complete response rate of 33% per immune-related response criteria. Patients who responded to combination therapy had increased CD8

21 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.

22 Clinical Trial Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. 2017

Long, Georgina V / Atkinson, Victoria / Cebon, Jonathan S / Jameson, Michael B / Fitzharris, Bernie M / McNeil, Catriona M / Hill, Andrew G / Ribas, Antoni / Atkins, Michael B / Thompson, John A / Hwu, Wen-Jen / Hodi, F Stephen / Menzies, Alexander M / Guminski, Alexander D / Kefford, Richard / Kong, Benjamin Y / Tamjid, Babak / Srivastava, Archana / Lomax, Anna J / Islam, Mohammed / Shu, Xinxin / Ebbinghaus, Scot / Ibrahim, Nageatte / Carlino, Matteo S. ·Melanoma Institute Australia, University of Sydney, Mater Hospital, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au. · Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, QLD, Australia; University of Queensland, Brisbane, QLD, Australia. · Olivia Newton-John Cancer Research Institute, Austin Health, School of Cancer Medicine, LaTrobe University, Heidelberg, VIC, Australia. · Regional Cancer Centre, Waikato Hospital, Hamilton, New Zealand. · Canterbury District Health Board, Christchurch Hospital, Christchurch, New Zealand. · Royal Prince Alfred Hospital, Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Chris O'Brien Lifehouse, Camperdown, NSW, Australia. · Tasman Oncology Research, Southport Gold Coast, QLD, Australia. · Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. · Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA. · Department of Medicine, University of Washington, Seattle, WA, USA. · University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Melanoma Institute Australia, University of Sydney, Mater Hospital, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia. · Westmead Hospital, Melanoma Institute Australia, Macquarie University, Sydney, NSW, Australia. · Westmead Hospital, Westmead, NSW, Australia; Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Blacktown Hospital, Blacktown, NSW, Australia. · Merck & Co, Kenilworth, NJ, USA. ·Lancet Oncol · Pubmed #28729151.

ABSTRACT: BACKGROUND: Reduced-dose nivolumab in combination with standard-dose ipilimumab improves objective response and progression-free survival compared with standard-dose ipilimumab alone, but increases toxicity. We assessed the safety and anti-tumour activity of standard-dose pembrolizumab in combination with reduced-dose ipilimumab. METHODS: In this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA. Eligible patients were aged at least 18 years, had advanced melanoma, had an Eastern Coooperative Oncology Group performance status of 0 or 1, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, had adequate organ function, had resolution of toxic effects of the most recent previous chemotherapy to grade 1 or less, had no active autoimmune disease requiring systemic steroids or immunosuppressive agents, had no active non-infectious pneumonitis, had no uncontrolled thyroid dysfunction or diabetes, had no active brain metastases, and had not received previous immune checkpoint inhibitor therapy. Patients received intravenous pembrolizumab 2 mg/kg plus intravenous ipilimumab 1 mg/kg every 3 weeks for four doses, followed by intravenous pembrolizumab 2 mg/kg every 3 weeks for up to 2 years or disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was safety and tolerability. The proportion of patients achieving an objective response assessed per RECIST version 1.1 by independent central review and overall survival were secondary endpoints. We also assessed progression-free survival. The primary endpoint was assessed in all patients who received at least one dose of combination therapy. Activity was assessed in all enrolled patients. This trial is registered with ClinicalTrials.gov, number NCT02089685. Enrolment into this cohort is closed, but patients are still being monitored for safety and anti-tumour activity. FINDINGS: Between Jan 13, 2015, and Sept 17, 2015, we enrolled and treated 153 patients. As of the Oct 17, 2016, cutoff date, median follow-up was 17·0 months (IQR 14·8-18·8). 110 (72%) of 153 patients received all four pembrolizumab plus ipilimumab doses; 64 (42%) remained on pembrolizumab monotherapy. 110 grade 3-4 treatment-related adverse events occurred in 69 (45%) patients. No treatment-related deaths occurred. Treatment-related adverse events led to discontinuation of pembrolizumab and ipilimumab in 22 (14%) patients, including 17 (11%) who discontinued both treatments for the same event and five (3%) who discontinued ipilimumab for one event and later discontinued pembrolizumab for another. 12 (8%) patients discontinued ipilimumab only and 14 (9%) discontinued pembrolizumab only because of treatment-related adverse events. 158 immune-mediated adverse events of any grade occurred in 92 (60%) patients, and 50 immune-mediated adverse events of grade 3-4 occurred in 42 (27%) patients; the most common immune-mediated adverse events were hypothyroidism (25 [16%]) and hyperthyroidism (17 [11%]). 93 (61% [95% CI 53-69]) patients achieved an objective response. Estimated 1 year progression-free survival was 69% (95% CI 60-75), and estimated 1 year overall survival was 89% (95% CI 83-93). INTERPRETATION: Standard-dose pembrolizumab given in combination with four doses of reduced-dose ipilimumab followed by standard-dose pembrolizumab has a manageable toxicity profile and provides robust anti-tumour activity in patients with advanced melanoma. These data suggest that standard-dose pembrolizumab plus reduced-dose ipilimumab might be a tolerable, efficacious treatment option for patients with advanced melanoma. A randomised phase 2 trial of alternative dosing strategies of this combination is underway. FUNDING: Merck & Co, Inc.

23 Clinical Trial IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. 2017

Ayers, Mark / Lunceford, Jared / Nebozhyn, Michael / Murphy, Erin / Loboda, Andrey / Kaufman, David R / Albright, Andrew / Cheng, Jonathan D / Kang, S Peter / Shankaran, Veena / Piha-Paul, Sarina A / Yearley, Jennifer / Seiwert, Tanguy Y / Ribas, Antoni / McClanahan, Terrill K. ·Merck & Co. Inc., Kenilworth, New Jersey, USA. · University of Washington, Seattle, Washington, USA. · University of Texas MD Anderson Cancer Center, Houston, Texas, USA. · University of Chicago, Chicago, Illinois, USA. · UCLA, Los Angeles, California, USA. ·J Clin Invest · Pubmed #28650338.

ABSTRACT: Programmed death-1-directed (PD-1-directed) immune checkpoint blockade results in durable antitumor activity in many advanced malignancies. Recent studies suggest that IFN-γ is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to anti-PD-1 therapies, including pembrolizumab. However, whether quantifying T cell-inflamed microenvironment is a useful pan-tumor determinant of PD-1-directed therapy response has not been rigorously evaluated. Here, we analyzed gene expression profiles (GEPs) using RNA from baseline tumor samples of pembrolizumab-treated patients. We identified immune-related signatures correlating with clinical benefit using a learn-and-confirm paradigm based on data from different clinical studies of pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually defining a pan-tumor T cell-inflamed GEP in 220 patients with 9 cancers. Predictive value was independently confirmed and compared with that of PD-L1 immunohistochemistry in 96 patients with head and neck squamous cell carcinoma. The T cell-inflamed GEP contained IFN-γ-responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance, and these features were necessary, but not always sufficient, for clinical benefit. The T cell-inflamed GEP has been developed into a clinical-grade assay that is currently being evaluated in ongoing pembrolizumab trials.

24 Clinical Trial Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials. 2017

Schadendorf, Dirk / Long, Georgina V / Stroiakovski, Daniil / Karaszewska, Boguslawa / Hauschild, Axel / Levchenko, Evgeny / Chiarion-Sileni, Vanna / Schachter, Jacob / Garbe, Claus / Dutriaux, Caroline / Gogas, Helen / Mandalà, Mario / Haanen, John B A G / Lebbé, Céleste / Mackiewicz, Andrzej / Rutkowski, Piotr / Grob, Jean-Jacques / Nathan, Paul / Ribas, Antoni / Davies, Michael A / Zhang, Ying / Kaper, Mathilde / Mookerjee, Bijoyesh / Legos, Jeffrey J / Flaherty, Keith T / Robert, Caroline. ·Department of Dermatology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany; German Cancer Consortium, 69117 Heidelberg, Germany. Electronic address: Dirk.Schadendorf@uk-essen.de. · Melanoma Institute Australia, The University of Sydney, NSW, Australia; Mater Hospital, North Sydney, NSW, Australia; Royal North Shore Hospital, St Leonards, NSW, Australia. · Moscow City Oncology Hospital No 62, Moscow 143423, Russia. · Przychodnia Lekarska KOMED, Wojska Polskiego 6, 62-500 Konin, Poland. · Department of Dermatology, University Medical Center Schleswig-Holstein, Arnold-Heller-Straße 3, 24105 Kiel, Germany. · Petrov Research Institute of Oncology, 68 Leningradskaya Street, Saint Petersburg 197758, Russia. · Melanoma and Esophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Via Gattamelata 64, 35128 Padova, Italy. · Oncology Division, Sheba Medical Center, Tel HaShomer, Emek HaEla St 1, Ramat Gan, Israel. · Department of Dermatology, University of Tübingen, Geschwister-Scholl-Platz, 72074 Tübingen, Germany. · Service de Dermatologie et Dermatologie Pédiatrique, Hôpital Saint-André, 1 Rue Jean Burguet, 33000 Bordeaux, France. · First Department of Medicine, "Laiko" General Hospital, National and Kapodistrian University of Athens, Athens 157 72, Greece. · Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. · Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. · APHP Dermatology and CIC Departments, INSERM U976, University Paris Diderot, Paris, France. · Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary Street, 61-866 Poznań, Poland. · Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Wawelska 15B, 02-034 Warsaw, Poland. · Department of Dermatology, University Hospital Center, Timone Hospital, Aix Marseille University, 264 Rue St Pierre, 13885 Marseille Cedex 05, France. · Mount Vernon Cancer Centre, Rickmansworth Road, HA6 2RN Northwood, UK. · Department of Medicine, Hematology/Oncology, UCLA Medical Center, 100 UCLA Medical Plaza, Suite 550, Los Angeles, CA, USA. · Melanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, TX, USA. · Novartis Pharmaceuticals Corporation, 1 Health Plaza, East Hanover 07936, NJ, USA. · Developmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston 02114, MA, USA. · Department of Medical Oncology, Dermatology Service, Gustave Roussy Comprehensive Cancer Center and Faculty of Medicine, University Paris-South, F-94805, Villejuif, France. ·Eur J Cancer · Pubmed #28648698.

ABSTRACT: AIM: Understanding predictors of long-term benefit with currently available melanoma therapies is the key for optimising individualised treatments. A prior pooled analysis of dabrafenib plus trametinib (D + T)-randomised trials (median follow-up, 20.0 months) identified baseline lactate dehydrogenase (LDH) and number of organ sites with metastasis as predictive factors for progression-free (PFS) and overall (OS) survival. However, longer-term follow-up analyses are needed to confirm which patients treated with D + T can achieve maximum benefit. METHODS: Three-year landmark data were retrospectively pooled for D + T patients in phase 3 trials (COMBI-d [NCT01584648]; COMBI-v [NCT01597908]). Univariate and multivariate analyses assessed prognostic values of predefined baseline factors; regression tree analysis determined hierarchy and interactions between variables. RESULTS: Long-term pooled outcomes were consistent with individual trial results (N = 563; 3-year PFS, 23%; 3-year OS, 44%). Baseline LDH level and number of organ sites remained strongly associated with and/or predictive of PFS and OS. In addition, baseline sum of lesion diameters (SLD) was identified as a predictor for progression. In the most favourable prognostic group (normal LDH, SLD <66 mm, <3 organ sites; n = 183/563 [33%]), 3-year PFS was 42%. Baseline number of organ sites was also predictive of outcomes in patients with PFS ≥ 6 months. CONCLUSION: Using the largest phase 3 data set available for BRAF/MEK inhibitor combination therapy in melanoma, these results demonstrate that durable responses lasting ≥3 years are possible in subsets of patients with BRAF-mutant melanoma receiving D + T. Although the best predictive model evolved with longer follow-up, factors predicting clinical outcomes with the combination remained consistent with previous analyses.

25 Clinical Trial Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. 2017

Long, G V / Flaherty, K T / Stroyakovskiy, D / Gogas, H / Levchenko, E / de Braud, F / Larkin, J / Garbe, C / Jouary, T / Hauschild, A / Chiarion-Sileni, V / Lebbe, C / Mandalà, M / Millward, M / Arance, A / Bondarenko, I / Haanen, J B A G / Hansson, J / Utikal, J / Ferraresi, V / Mohr, P / Probachai, V / Schadendorf, D / Nathan, P / Robert, C / Ribas, A / Davies, M A / Lane, S R / Legos, J J / Mookerjee, B / Grob, J-J. ·Melanoma Institute Australia, The University of Sydney, and Royal North Shore and Mater Hospitals, North Sydney, Australia. · Developmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, Boston, USA. · Moscow City Oncology Hospital #62, Moscow, Russia. · First Department of Medicine, "Laiko" General Hospital, National and Kapodistrian University of Athens, Athens, Greece. · Petrov Research Institute of Oncology, Saint Petersburg, Russia. · Dipartimento di Medicina Oncologica, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · Royal Marsden NHS Foundation Trust, London, UK. · Department of Dermatology, University of Tübingen, Tübingen, Germany. · Service D'oncologie Médicale, Hopital Francois Mitterrand, Pau, France. · Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany. · Melanoma and Oesophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Padova, Italy. · APHP Dermatology and CIC Departments, INSERM U976, University Paris Diderot, Paris, France. · Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. · Medical Oncology Department, Sir Charles Gairdner Hospital, Perth, Australia. · Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain. · Dnipropetrovsk State Medical Academy, Clinical Hospital #4, Dnipropetrovsk, Ukraine. · Netherlands Cancer Institute, Amsterdam, The Netherlands. · Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. · Skin Cancer Unit, German Cancer Research Center (DKFZ) and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim and Heidelberg, Germany. · Department of Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy. · Dermatologisches Zentrum Buxtehude, Elbe Kliniken Buxtehude, Buxtehude, Germany. · Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council, Dnipropetrovsk, Ukraine. · Department of Dermatology, University Hospital Essen, Essen, Germany. · German Cancer Consortium, Heidelberg, Germany. · Mount Vernon Cancer Centre, Northwood, UK. · Gustave Roussy, Département de Médecine Oncologique, Service de Dermatologie et Université Paris-Sud, Faculté de Médecine, Villejuif, France. · Department of Medicine, Hematology/Oncology, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, USA. · Melanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Novartis Pharmaceuticals Corporation, East Hanover, USA. · Service de Dermatologie, Centre Hospitalo-Universitaire Timone, Aix-Marseille Université, Marseille, France. ·Ann Oncol · Pubmed #28475671.

ABSTRACT: Background: Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients. Patients and methods: This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics. Results: Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and <3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use. Conclusions: These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.

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