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Melanoma: HELP
Articles by Bartosz Chmielowski
Based on 56 articles published since 2010
(Why 56 articles?)
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Between 2010 and 2020, B. Chmielowski wrote the following 56 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Review Direct costs associated with adverse events of systemic therapies for advanced melanoma: Systematic literature review. 2018

Copley-Merriman, Catherine / Stevinson, Kendall / Liu, Frank Xiaoqing / Wang, Jingshu / Mauskopf, Josephine / Zimovetz, Evelina A / Chmielowski, Bartosz. ·Market Access and Outcomes Strategy, RTI Health Solutions, Ann Arbor, MI. · Merck & Co, Inc, Kenilworth, NJ. · Health Economics, RTI Health Solutions, Research Triangle Park, NC. · Market Access and Outcomes Strategy, RTI Health Solutions, Manchester, UK. · Division of Hematology - Medical Oncology, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA. ·Medicine (Baltimore) · Pubmed #30075584.

ABSTRACT: BACKGROUND: Treatments for advanced melanoma are associated with different adverse events (AEs), which may be costly to manage. This study aimed to evaluate direct costs associated with managing treatment-related AEs for advanced melanoma through a systematic literature review. METHODS: Systematic searches were conducted of the PubMed, Embase, Cochrane, BIOSIS, and EconLit medical literature databases to identify studies providing estimates of direct costs and health care resource utilization for the management of AEs of melanoma treatments, published between January 1, 2007, and February 23, 2017. Gray literature searches also were conducted. Studies reporting direct costs for patients with advanced melanoma that were published in English between 2007 and 2017 were eligible. Studies were systematically screened in 2 phases by 2 independent reviewers. Study design details and data on direct costs by country were extracted. RESULTS: Seven studies evaluating the cost of AEs in patients with advanced melanoma were included; most estimated the costs for grade 3 or 4 events. In a United States study, monthly AE costs constituted 36.9% of overall health care costs for dacarbazine, 30.3% for paclitaxel, 9.2% for temozolomide, 6.4% for vemurafenib, and 4.0% for ipilimumab. A multicountry study found the greatest cost per event to be for grade 3 or 4 AEs associated with ipilimumab, including colitis (A$1471 [Australia]-&OV0556;3313 [France]) and diarrhea (£2836 [United Kingdom]), and chemotherapy (neutropenia/leukopenia in Germany [&OV0556;1744] and Italy [&OV0556;804]). Across studies, cost drivers for the most expensive AEs to manage were requiring hospitalization or use of expensive outpatient medications and/or procedures (eg, erythropoietin and blood transfusions for anemia). Some currently available therapies were not available during the research period, and their associated AEs are not reflected. Results may not be comparable across countries. For some studies, resource-use estimates reflect practice patterns from a limited number of centers, limiting generalizability. CONCLUSION: Costs for managing each type of AE associated with the treatment of advanced melanoma are substantial. Effective treatments with improved safety profiles may help reduce total AE management costs.

2 Review Is there a role for single-agent BRAF inhibition in melanoma? 2017

Chmielowski, Bartosz. ·UCLA Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California. ·Clin Adv Hematol Oncol · Pubmed #28398279.

ABSTRACT: -- No abstract --

3 Clinical Trial Selumetinib in Combination With Dacarbazine in Patients With Metastatic Uveal Melanoma: A Phase III, Multicenter, Randomized Trial (SUMIT). 2018

Carvajal, Richard D / Piperno-Neumann, Sophie / Kapiteijn, Ellen / Chapman, Paul B / Frank, Stephen / Joshua, Anthony M / Piulats, Josep M / Wolter, Pascal / Cocquyt, Veronique / Chmielowski, Bartosz / Evans, T R Jeffry / Gastaud, Lauris / Linette, Gerald / Berking, Carola / Schachter, Jacob / Rodrigues, Manuel J / Shoushtari, Alexander N / Clemett, Delyth / Ghiorghiu, Dana / Mariani, Gabriella / Spratt, Shirley / Lovick, Susan / Barker, Peter / Kilgour, Elaine / Lai, Zhongwu / Schwartz, Gary K / Nathan, Paul. ·Richard D. Carvajal and Gary K. Schwartz, Columbia University Medical Center · Paul B. Chapman and Alexander N. Shoushtari, Memorial Sloan Kettering Cancer Center, New York, NY · Sophie Piperno-Neumann and Manuel J. Rodrigues, Institut Curie, Paris · Lauris Gastaud, Centre Antoine-Lacassagne, Nice, France · Ellen Kapiteijn, Leiden University Medical Center, Leiden, the Netherlands · Stephen Frank, Hebrew University Hadassah Medical School - The Sharett Institute of Oncology, Jerusalem · Jacob Schachter, Sheba Medical Center at Tel Hashomer, and Tel-Aviv University Medical School, Tel Aviv, Israel · Anthony M. Joshua, Princess Margaret Cancer Centre, Toronto, ON, Canada · Josep M. Piulats, Institut Catala d'Oncologia L'Hospitalet, L'Hospitalet de Llobregat, Barcelona, Spain · Pascal Wolter, University Hospitals Leuven, Leuven, Belgium · Veronique Cocquyt, Ghent University Hospital, Ghent, Belgium · Bartosz Chmielowski, University of California, Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, CA · T.R. Jeffry Evans, University of Glasgow, Glasgow · Delyth Clemett, Shirley Spratt, Susan Lovick, and Elaine Kilgour, AstraZeneca, Macclesfield · Dana Ghiorghiu and Gabriella Mariani, AstraZeneca, Cambridge · Paul Nathan, Mt Vernon Cancer Centre, Northwood, United Kingdom · Gerald Linette, Washington University School of Medicine, St Louis, MO · Carola Berking, University Hospital of Munich, Munich, Germany · Peter Barker, AstraZeneca, Gaithersburg, MD · and Zhongwu Lai, AstraZeneca, Waltham, MA. ·J Clin Oncol · Pubmed #29528792.

ABSTRACT: Purpose Uveal melanoma is the most common primary intraocular malignancy in adults with no effective systemic treatment option in the metastatic setting. Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective MEK1/2 inhibitor with a short half-life, which demonstrated single-agent activity in patients with metastatic uveal melanoma in a randomized phase II trial. Methods The Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) in Metastatic Uveal Melanoma (SUMIT) study was a phase III, double-blind trial ( ClinicalTrial.gov identifier: NCT01974752) in which patients with metastatic uveal melanoma and no prior systemic therapy were randomly assigned (3:1) to selumetinib (75 mg twice daily) plus dacarbazine (1,000 mg/m

4 Clinical Trial A phase 2 study of ontuxizumab, a monoclonal antibody targeting endosialin, in metastatic melanoma. 2018

D'Angelo, Sandra P / Hamid, Omid A / Tarhini, Ahmad / Schadendorf, Dirk / Chmielowski, Bartosz / Collichio, Frances A / Pavlick, Anna C / Lewis, Karl D / Weil, Susan C / Heyburn, John / Schweizer, Charles / O'Shannessy, Daniel J / Carvajal, Richard D. ·Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Weill Cornell Medical College, New York, NY, USA. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · University of Pittsburgh, Pittsburgh, PA, USA. · Universitätsklinikum Essen, Essen, Germany. · University of California, Los Angeles, CA, USA. · University of North Carolina, Chapel Hill, NC, USA. · New York University, Lake Success, NY, USA. · University of Colorado Cancer Center, Aurora, CO, USA. · Morphotek, Inc., Exton, PA, USA. · Columbia University Medical Center, 177 Ft Washington Avenue, New York, NY, 10032, USA. rdc2150@cumc.columbia.edu. ·Invest New Drugs · Pubmed #29127533.

ABSTRACT: Objectives Ontuxizumab (MORAB-004) is a first-in-class monoclonal antibody that interferes with endosialin function, which is important in tumor stromal cell function, angiogenesis, and tumor growth. This Phase 2 study evaluated the 24-week progression-free survival (PFS) value, pharmacokinetics, and tolerability of 2 doses of ontuxizumab in patients with metastatic melanoma. Patients and methods Patients with metastatic melanoma and disease progression after receiving at least 1 prior systemic treatment were randomized to receive ontuxizumab (2 or 4 mg/kg) weekly, without dose change, until disease progression. Results Seventy-six patients received at least 1 dose of ontuxizumab (40 received 2 mg/kg, 36 received 4 mg/kg). The primary endpoint, 24-week PFS value, was 11.4% (95% Confidence Interval [CI]: 5.3%-19.9%) for all patients (13.5% for 2 mg/kg and 8.9% for 4 mg/kg). The median PFS for all patients was 8.3 weeks (95% CI: 8.1-12.3 weeks). One patient receiving 4 mg/kg had a partial response, as measured by Response Evaluation Criteria in Solid Tumors v1.1. Twenty-seven of 66 response evaluable patients (40.9%) had stable disease. The median overall survival was 31.0 weeks (95% CI: 28.3-44.0 weeks). The most common adverse events overall were headache (55.3%), fatigue (48.7%), chills (42.1%), and nausea (36.8%), mostly grade 1 or 2. Conclusions Ontuxizumab at both doses was well tolerated. The 24-week PFS value was 11.4% among all ontuxizumab-treated patients. The overall response rate was 3.1% at the 4 mg/kg dose, with clinical benefit achieved in 42.4% of response evaluable patients. Efficacy of single-agent ontuxizumab at these doses in melanoma was low.

5 Clinical Trial Overall Survival in Patients With Advanced Melanoma Who Received Nivolumab Versus Investigator's Choice Chemotherapy in CheckMate 037: A Randomized, Controlled, Open-Label Phase III Trial. 2018

Larkin, James / Minor, David / D'Angelo, Sandra / Neyns, Bart / Smylie, Michael / Miller, Wilson H / Gutzmer, Ralf / Linette, Gerald / Chmielowski, Bartosz / Lao, Christopher D / Lorigan, Paul / Grossmann, Kenneth / Hassel, Jessica C / Sznol, Mario / Daud, Adil / Sosman, Jeffrey / Khushalani, Nikhil / Schadendorf, Dirk / Hoeller, Christoph / Walker, Dana / Kong, George / Horak, Christine / Weber, Jeffrey. ·James Larkin, Royal Marsden NHS Foundation Trust, London · Paul Lorigan, The Christie National Health Service Foundation Trust, Manchester, United Kingdom · David Minor, California Pacific Medical Center Research Institute · Adil Daud, University of California San Francisco, San Francisco · Bartosz Chmielowski, University of California, Santa Monica, CA · Sandra D'Angelo, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College · Jeffrey Weber, Perlmutter Cancer Center at New York University-Langone Medical Center, New York · Nikhil Khushalani, Roswell Park Cancer Institute, Buffalo, NY · Gerald Linette, Washington University, St. Louis, MO · Christopher D. Lao, University of Michigan, Ann Arbor, MI · Kenneth Grossmann, Huntsman Cancer Institute, Salt Lake City, UT · Mario Sznol, Yale Comprehensive Cancer Center, New Haven, CT · Jeffrey Sosman, Northwestern University, Chicago, IL · Dana Walker, George Kong, and Christine Horak, Bristol-Myers Squibb, Princeton, NJ · Bart Neyns, University Hospital, Vrije Universiteit Brussel, Brussels, Belgium · Michael Smylie, Cross Cancer Institute, Edmonton, Alberta · Wilson H. Miller Jr, Jewish General Hospital and Segal Cancer Centre, McGill University, Montreal, Quebc, Canada · Ralf Gutzmer, Medizinische Hochschule Hannover, Hannover · Jessica C. Hassel, Nationale Centrum für Tumorerkrankungen Heidelberg, Heidelberg · Dirk Schadendorf, University Hospital Essen, Essen, Germany · and Christoph Hoeller, Medical University of Vienna, Wien, Austria. ·J Clin Oncol · Pubmed #28671856.

ABSTRACT: Purpose Until recently, limited options existed for patients with advanced melanoma who experienced disease progression while receiving treatment with ipilimumab. Here, we report the coprimary overall survival (OS) end point of CheckMate 037, which has previously shown that nivolumab resulted in more patients achieving an objective response compared with chemotherapy regimens in ipilimumab-refractory patients with advanced melanoma. Patients and Methods Patients were stratified by programmed death-ligand 1 expression, BRAF status, and best prior cytotoxic T-lymphocyte antigen-4 therapy response, then randomly assigned 2:1 to nivolumab 3 mg/kg intravenously every 2 weeks or investigator's choice chemotherapy (ICC; dacarbazine 1,000 mg/m

6 Clinical Trial Liver Metastasis and Treatment Outcome with Anti-PD-1 Monoclonal Antibody in Patients with Melanoma and NSCLC. 2017

Tumeh, Paul C / Hellmann, Matthew D / Hamid, Omid / Tsai, Katy K / Loo, Kimberly L / Gubens, Matthew A / Rosenblum, Michael / Harview, Christina L / Taube, Janis M / Handley, Nathan / Khurana, Neharika / Nosrati, Adi / Krummel, Matthew F / Tucker, Andrew / Sosa, Eduardo V / Sanchez, Phillip J / Banayan, Nooriel / Osorio, Juan C / Nguyen-Kim, Dan L / Chang, Jeremy / Shintaku, I Peter / Boasberg, Peter D / Taylor, Emma J / Munster, Pamela N / Algazi, Alain P / Chmielowski, Bartosz / Dummer, Reinhard / Grogan, Tristan R / Elashoff, David / Hwang, Jimmy / Goldinger, Simone M / Garon, Edward B / Pierce, Robert H / Daud, Adil. ·University of California, Los Angeles, Los Angeles, California. · Memorial Sloan Kettering Cancer Center, New York, New York. · Angeles Clinic, Los Angeles, California. · University of California, San Francisco, San Francisco, California. · Johns Hopkins University, Baltimore, Maryland. · OncoSec Inc., San Diego, California. · University of California, San Francisco, San Francisco, California. adil.daud@ucsf.edu. ·Cancer Immunol Res · Pubmed #28411193.

ABSTRACT: We explored the association between liver metastases, tumor CD8

7 Clinical Trial Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. 2016

Ribas, Antoni / Hamid, Omid / Daud, Adil / Hodi, F Stephen / Wolchok, Jedd D / Kefford, Richard / Joshua, Anthony M / Patnaik, Amita / Hwu, Wen-Jen / Weber, Jeffrey S / Gangadhar, Tara C / Hersey, Peter / Dronca, Roxana / Joseph, Richard W / Zarour, Hassane / Chmielowski, Bartosz / Lawrence, Donald P / Algazi, Alain / Rizvi, Naiyer A / Hoffner, Brianna / Mateus, Christine / Gergich, Kevin / Lindia, Jill A / Giannotti, Maxine / Li, Xiaoyun Nicole / Ebbinghaus, Scot / Kang, S Peter / Robert, Caroline. ·Division of Hematology and Oncology, University of California-Los Angeles, Los Angeles. · Department of Hematology/Oncology, The Angeles Clinic and Research Institute, Los Angeles, California. · Department of Hematology/Oncology, University of California-San Francisco, San Francisco. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital and Melanoma Institute Australia, Sydney, Australia7Department of Clinical Medicine, Macquarie University, Sydney, Australia. · Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · Department of Clinical Research, South Texas Accelerated Research Therapeutics, San Antonio. · Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston. · Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida. · Division of Hematology and Oncology, Abramson Cancer Center at the University of Pennsylvania, Philadelphia. · Department of Medicine, University of Sydney, Sydney, Australia. · Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota. · Department of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida. · Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. · Department of Hematology/Oncology, Massachusetts General Hospital, Boston. · Department of Medical Oncology, Gustave-Roussy Cancer Campus and Paris Sud University, Villejuif Paris-Sud, France. · Department of Clinical Oncology, Merck & Co, Inc, Kenilworth, New Jersey. · BARDS, Merck & Co, Inc, Kenilworth, New Jersey. ·JAMA · Pubmed #27092830.

ABSTRACT: IMPORTANCE: The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab. OBJECTIVE: To characterize the association of pembrolizumab with tumor response and overall survival among patients with advanced melanoma. DESIGN, SETTINGS, AND PARTICIPANTS: Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013). Median duration of follow-up was 21 months. The study was performed in academic medical centers in Australia, Canada, France, and the United States. Eligible patients were aged 18 years and older and had advanced or metastatic melanoma. Data were pooled from 655 enrolled patients (135 from a nonrandomized cohort [n = 87 ipilimumab naive; n = 48 ipilimumab treated] and 520 from randomized cohorts [n = 226 ipilimumab naive; n = 294 ipilimumab treated]). Cutoff dates were April 18, 2014, for safety analyses and October 18, 2014, for efficacy analyses. EXPOSURES: Pembrolizumab 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks continued until disease progression, intolerable toxicity, or investigator decision. MAIN OUTCOMES AND MEASURES: The primary end point was confirmed objective response rate (best overall response of complete response or partial response) in patients with measurable disease at baseline per independent central review. Secondary end points included toxicity, duration of response, progression-free survival, and overall survival. RESULTS: Among the 655 patients (median [range] age, 61 [18-94] years; 405 [62%] men), 581 had measurable disease at baseline. An objective response was reported in 194 of 581 patients (33% [95% CI, 30%-37%]) and in 60 of 133 treatment-naive patients (45% [95% CI, 36% to 54%]). Overall, 74% (152/205) of responses were ongoing at the time of data cutoff; 44% (90/205) of patients had response duration for at least 1 year and 79% (162/205) had response duration for at least 6 months. Twelve-month progression-free survival rates were 35% (95% CI, 31%-39%) in the total population and 52% (95% CI, 43%-60%) among treatment-naive patients. Median overall survival in the total population was 23 months (95% CI, 20-29) with a 12-month survival rate of 66% (95% CI, 62%-69%) and a 24-month survival rate of 49% (95% CI, 44%-53%). In treatment-naive patients, median overall survival was 31 months (95% CI, 24 to not reached) with a 12-month survival rate of 73% (95% CI, 65%-79%) and a 24-month survival rate of 60% (95% CI, 51%-68%). Ninety-two of 655 patients (14%) experienced at least 1 treatment-related grade 3 or 4 adverse event (AE) and 27 of 655 (4%) patients discontinued treatment because of a treatment-related AE. Treatment-related serious AEs were reported in 59 patients (9%). There were no drug-related deaths. CONCLUSIONS AND RELEVANCE: Among patients with advanced melanoma, pembrolizumab administration was associated with an overall objective response rate of 33%, 12-month progression-free survival rate of 35%, and median overall survival of 23 months; grade 3 or 4 treatment-related AEs occurred in 14%. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01295827.

8 Clinical Trial PD-1 Blockade Expands Intratumoral Memory T Cells. 2016

Ribas, Antoni / Shin, Daniel Sanghoon / Zaretsky, Jesse / Frederiksen, Juliet / Cornish, Andrew / Avramis, Earl / Seja, Elizabeth / Kivork, Christine / Siebert, Janet / Kaplan-Lefko, Paula / Wang, Xiaoyan / Chmielowski, Bartosz / Glaspy, John A / Tumeh, Paul C / Chodon, Thinle / Pe'er, Dana / Comin-Anduix, Begoña. ·Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, California. Division of Surgical-Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, California. Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California. Jonsson Comprehensive Cancer Center, Los Angeles, California. bcomin@mednet.ucla.edu aribas@mednet.ucla.edu. · Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, California. · Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark. · Departments of Biological Sciences and Systems Biology, Columbia University, New York, New York. · CytoAnalysis, Denver, Colorado. · Department of General Internal Medicine and Healthy Services Research, University of California Los Angeles, Los Angeles, California. · Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California. Jonsson Comprehensive Cancer Center, Los Angeles, California. Department of Medicine, Division of Dermatology. University of California Los Angeles, Los Angeles, California. · Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, New York. · Division of Surgical-Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, California. Jonsson Comprehensive Cancer Center, Los Angeles, California. bcomin@mednet.ucla.edu aribas@mednet.ucla.edu. ·Cancer Immunol Res · Pubmed #26787823.

ABSTRACT: Tumor responses to programmed cell death protein 1 (PD-1) blockade therapy are mediated by T cells, which we characterized in 102 tumor biopsies obtained from 53 patients treated with pembrolizumab, an antibody to PD-1. Biopsies were dissociated, and single-cell infiltrates were analyzed by multicolor flow cytometry using two computational approaches to resolve the leukocyte phenotypes at the single-cell level. There was a statistically significant increase in the frequency of T cells in patients who responded to therapy. The frequency of intratumoral B cells and monocytic myeloid-derived suppressor cells significantly increased in patients' biopsies taken on treatment. The percentage of cells with a regulatory T-cell phenotype, monocytes, and natural killer cells did not change while on PD-1 blockade therapy. CD8(+) memory T cells were the most prominent phenotype that expanded intratumorally on therapy. However, the frequency of CD4(+) effector memory T cells significantly decreased on treatment, whereas CD4(+) effector T cells significantly increased in nonresponding tumors on therapy. In peripheral blood, an unusual population of blood cells expressing CD56 was detected in two patients with regressing melanoma. In conclusion, PD-1 blockade increases the frequency of T cells, B cells, and myeloid-derived suppressor cells in tumors, with the CD8(+) effector memory T-cell subset being the major T-cell phenotype expanded in patients with a response to therapy.

9 Clinical Trial Long-term outcome in BRAF(V600E) melanoma patients treated with vemurafenib: Patterns of disease progression and clinical management of limited progression. 2015

Puzanov, Igor / Amaravadi, Ravi K / McArthur, Grant A / Flaherty, Keith T / Chapman, Paul B / Sosman, Jeffrey A / Ribas, Antoni / Shackleton, Mark / Hwu, Patrick / Chmielowski, Bartosz / Nolop, Keith B / Lin, Paul S / Kim, Kevin B. ·Vanderbilt-Ingram Cancer Center, Vanderbilt University, 2220 Pierce Avenue #777, Nashville, TN 37232, USA. Electronic address: igor.puzanov@vanderbilt.edu. · Abramson Cancer Center and the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA. Electronic address: Ravi.Amaravadi@uphs.upenn.edu. · Peter MacCallum Cancer Centre, 2 St Andrews Place, East Melbourne, Vic 3002, Australia. Electronic address: grant.mcarthur@petermac.org. · Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114, USA. Electronic address: kflaherty@partners.org. · Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Electronic address: chapmanp@mskcc.org. · Vanderbilt-Ingram Cancer Center, Vanderbilt University, 2220 Pierce Avenue #777, Nashville, TN 37232, USA. Electronic address: jeff.sosman@vanderbilt.edu. · Jonsson Comprehensive Cancer Center, University of California, Los Angeles, 11-934 Factor Bldg., 10833 Le Conte Ave., Los Angeles, CA 90095-1782, USA. Electronic address: aribas@mednet.ucla.edu. · Peter MacCallum Cancer Centre, 2 St Andrews Place, East Melbourne, Vic 3002, Australia. Electronic address: Mark.Shackleton@petermac.org. · The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address: phwu@mdanderson.org. · Jonsson Comprehensive Cancer Center, University of California, Los Angeles, 11-934 Factor Bldg., 10833 Le Conte Ave., Los Angeles, CA 90095-1782, USA. Electronic address: BChmielowski@mednet.ucla.edu. · Plexxikon Inc., 91 Bolivar Drive, Berkeley, CA 94710, USA. Electronic address: easybreathe@msn.com. · Plexxikon Inc., 91 Bolivar Drive, Berkeley, CA 94710, USA. Electronic address: plin@plexxikon.com. · The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address: KimKB@sutterhealth.org. ·Eur J Cancer · Pubmed #25980594.

ABSTRACT: INTRODUCTION: Vemurafenib induces tumour regression in most patients with BRAF(V600E)-mutant melanoma; eventually, most experience progressive disease (PD). Long-term follow-up of patients with BRAF(V600E) melanoma treated in the phase 1 vemurafenib trial is reported. METHODS: Patients received vemurafenib 240-1120 mg (dose escalation cohort) or 960 mg (extension cohort) orally twice daily. Clinical response was evaluated every 8 weeks by Response Evaluation Criteria In Solid Tumors (RECIST). Patients with PD amenable to local therapy (surgery or radiotherapy) were allowed to continue vemurafenib after progression. Overall survival (OS) from time of treatment initiation and from PD was estimated. Sites of PD were recorded. RESULTS: Forty-eight patients (escalation cohort, n = 16; extension cohort, n = 32) received therapeutic doses of vemurafenib (⩾ 240 mg twice daily). Forty-four patients had PD by the time of this analysis and four remained progression free (follow-up time, 1.2-56.1 months). Median OS was 14 months (range, 1.2-56.1); 3- and 4-year melanoma-specific survival rate in the extension cohort was 26% and 19%, respectively. Median OS was 26.0 months (range, 7.7-56.1) among 20 patients who continued vemurafenib after local therapy. Median treatment duration beyond initial PD was 3.8 months (range, 1.1-26.6). In the extension cohort, six and five patients were alive after 3 and 4 years, respectively, on vemurafenib monotherapy. CONCLUSIONS: Some patients with melanoma achieved long-term survival with vemurafenib monotherapy. Continuation of vemurafenib after PD might be beneficial in some patients because remaining disease might continue to respond to BRAF inhibition.

10 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.

11 Clinical Trial A phase 2, multicenter, open-label study of sepantronium bromide (YM155) plus docetaxel in patients with stage III (unresectable) or stage IV melanoma. 2015

Kudchadkar, Ragini / Ernst, Scott / Chmielowski, Bartosz / Redman, Bruce G / Steinberg, Joyce / Keating, Anne / Jie, Fei / Chen, Caroline / Gonzalez, Rene / Weber, Jeffrey. ·Winship Cancer Institute, Emory University, Atlanta, Georgia. · London Regional Cancer Centre, London, Ontario, Canada. · University of California-Los Angeles, Ronald Reagan UCLA Medical Center, Los Angeles, California. · University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. · Astellas Pharmaceuticals Global Development, Northbrook, Illinois. · University of Colorado Denver, Comprehensive Cancer Center, Denver, Colorado. · H. Lee Moffitt Cancer Center, Tampa, Florida. ·Cancer Med · Pubmed #25533314.

ABSTRACT: Survivin is a microtubule-associated protein believed to be involved in preserving cell viability and regulating tumor cell mitosis, and it is overexpressed in many primary tumor types, including melanoma. YM155 is a first-in-class survivin suppressant. The purpose of this Phase 2 study was to evaluate the 6-month progression-free survival (PFS) rate in patients with unresectable Stage III or IV melanoma receiving a combination of YM155 plus docetaxel. The study had two parts: Part 1 established the dose of docetaxel that was tolerable in combination with YM155, and Part 2 evaluated the tolerable docetaxel dose (75 mg/m(2) ) in combination with YM155 (5 mg/m(2) per day continuous infusion over 168 h every 3 weeks). The primary endpoint was 6-month PFS rate. Secondary endpoints were objective response rate (ORR), 1-year overall survival (OS) rate, time from first response to progression, clinical benefit rate (CBR), and safety. Sixty-four patients with metastatic melanoma were treated with docetaxel and YM155. Eight patients received an initial docetaxel dose of 100 mg/m(2) and 56 patients received 75 mg/m(2) of docetaxel. Six-month PFS rate per Independent Review Committee (IRC) was 34.8% (n = 64; 95% CI, 21.3-48.6%), and per Investigator was 31.3% (n = 64; 95% CI, 19.5-43.9%). The best ORR (complete response [CR] + partial response [PR]) per IRC was 12.5% (8/64). The stable disease (SD) rate was 51.6% (33/64), leading to a CBR (CR + PR + SD) of 64.1% (41/64). Estimated probability of 1-year survival was 56.3%. YM155 is a novel agent showing modest activity when combined with docetaxel for treating patients with melanoma. YM155 was generally well tolerated, but the predetermined primary efficacy endpoint (i.e., 6-month PFS rate ≥20%) was not achieved.

12 Clinical Trial PD-1 blockade induces responses by inhibiting adaptive immune resistance. 2014

Tumeh, Paul C / Harview, Christina L / Yearley, Jennifer H / Shintaku, I Peter / Taylor, Emma J M / Robert, Lidia / Chmielowski, Bartosz / Spasic, Marko / Henry, Gina / Ciobanu, Voicu / West, Alisha N / Carmona, Manuel / Kivork, Christine / Seja, Elizabeth / Cherry, Grace / Gutierrez, Antonio J / Grogan, Tristan R / Mateus, Christine / Tomasic, Gorana / Glaspy, John A / Emerson, Ryan O / Robins, Harlan / Pierce, Robert H / Elashoff, David A / Robert, Caroline / Ribas, Antoni. ·1] University of California Los Angeles (UCLA), Los Angeles, California 90095, USA [2] Jonsson Comprehensive Cancer Center, Los Angeles, California 90095, USA. · University of California Los Angeles (UCLA), Los Angeles, California 90095, USA. · Merck &Co, Palo Alto, California 94304, USA. · Gustave Roussy and INSERM U981, Villejuif, Paris Sud, France. · Adaptive Biotechnologies, Seattle, Washington 98102, USA. · 1] Adaptive Biotechnologies, Seattle, Washington 98102, USA [2] Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ·Nature · Pubmed #25428505.

ABSTRACT: Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8(+) T cells (termed adaptive immune resistance). Here we show that pre-existing CD8(+) T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding to treatment showed proliferation of intratumoral CD8(+) T cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8(+) T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.

13 Clinical Trial Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. 2014

Ribas, Antoni / Gonzalez, Rene / Pavlick, Anna / Hamid, Omid / Gajewski, Thomas F / Daud, Adil / Flaherty, Lawrence / Logan, Theodore / Chmielowski, Bartosz / Lewis, Karl / Kee, Damien / Boasberg, Peter / Yin, Ming / Chan, Iris / Musib, Luna / Choong, Nicholas / Puzanov, Igor / McArthur, Grant A. ·Jonsson Comprehensive Cancer Center at University of California, Los Angeles, CA, USA. · University of Colorado Comprehensive Cancer Center, Aurora, CO, USA. · New York University Medical Center, New York, NY, USA. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · University of Chicago, Chicago, IL, USA. · Hematology/Oncology Division, University of California, San Francisco, CA, USA. · Karmanos Cancer Institute, Detroit, MI, USA. · Indiana University, Indianapolis, IN, USA. · Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. · Genentech, South San Francisco, CA, USA. · Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. · Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Electronic address: grant.mcarthur@petermac.org. ·Lancet Oncol · Pubmed #25037139.

ABSTRACT: BACKGROUND: Addition of a MEK inhibitor to a BRAF inhibitor enhances tumour growth inhibition, delays acquired resistance, and abrogates paradoxical activation of the MAPK pathway in preclinical models of BRAF-mutated melanoma. We assessed the safety and efficacy of combined BRAF inhibition with vemurafenib and MEK inhibition with cobimetinib in patients with advanced BRAF-mutated melanoma. METHODS: We undertook a phase 1b study in patients with advanced BRAF(V600)-mutated melanoma. We included individuals who had either recently progressed on vemurafenib or never received a BRAF inhibitor. In the dose-escalation phase of our study, patients received vemurafenib 720 mg or 960 mg twice a day continuously and cobimetinib 60 mg, 80 mg, or 100 mg once a day for either 14 days on and 14 days off (14/14), 21 days on and 7 days off (21/7), or continuously (28/0). The primary endpoint was safety of the drug combination and to identify dose-limiting toxic effects and the maximum tolerated dose. Efficacy was a key secondary endpoint. All patients treated with vemurafenib and cobimetinib were included in safety and efficacy analyses (intention-to-treat). The study completed accrual and all analyses are final. This study is registered with ClinicalTrials.gov, number NCT01271803. FINDINGS: 129 patients were treated at ten dosing regimens combining vemurafenib and cobimetinib: 66 had recently progressed on vemurafenib and 63 had never received a BRAF inhibitor. Dose-limiting toxic effects arose in four patients. One patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 80 mg once a day 14/14 had grade 3 fatigue for more than 7 days; one patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg once a day 21/7 had a grade 3 prolongation of QTc; and two patients on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg 28/0 had dose-limiting toxic effects-one developed grade 3 stomatitis and fatigue and one developed arthralgia and myalgia. The maximum tolerated dose was established as vemurafenib 960 mg twice a day in combination with cobimetinib 60 mg 21/7. Across all dosing regimens, the most common adverse events were diarrhoea (83 patients, 64%), non-acneiform rash (77 patients, 60%), liver enzyme abnormalities (64 patients, 50%), fatigue (62 patients, 48%), nausea (58 patients, 45%), and photosensitivity (52 patients, 40%). Most adverse events were mild-to-moderate in severity. The most common grade 3 or 4 adverse events were cutaneous squamous-cell carcinoma (12 patients, 9%; all grade 3), raised amounts of alkaline phosphatase (11 patients, 9%]), and anaemia (nine patients, 7%). Confirmed objective responses were recorded in ten (15%) of 66 patients who had recently progressed on vemurafenib, with a median progression-free survival of 2·8 months (95% CI 2·6-3·4). Confirmed objective responses were noted in 55 (87%) of 63 patients who had never received a BRAF inhibitor, including six (10%) who had a complete response; median progression-free survival was 13·7 months (95% CI 10·1-17·5). INTERPRETATION: The combination of vemurafenib and cobimetinib was safe and tolerable when administered at the respective maximum tolerated doses. The combination has promising antitumour activity and further clinical development is warranted in patients with advanced BRAF(V600)-mutated melanoma, particularly in those who have never received a BRAF inhibitor; confirmatory clinical testing is ongoing. FUNDING: F Hoffmann-La Roche/Genentech.

14 Clinical Trial Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. 2014

Robert, Caroline / Ribas, Antoni / Wolchok, Jedd D / Hodi, F Stephen / Hamid, Omid / Kefford, Richard / Weber, Jeffrey S / Joshua, Anthony M / Hwu, Wen-Jen / Gangadhar, Tara C / Patnaik, Amita / Dronca, Roxana / Zarour, Hassane / Joseph, Richard W / Boasberg, Peter / Chmielowski, Bartosz / Mateus, Christine / Postow, Michael A / Gergich, Kevin / Elassaiss-Schaap, Jeroen / Li, Xiaoyun Nicole / Iannone, Robert / Ebbinghaus, Scot W / Kang, S Peter / Daud, Adil. ·Gustave Roussy and INSERM U981, Paris-Sud, France. Electronic address: caroline.robert@gustaveroussy.fr. · University of California Los Angeles, Los Angeles, CA, USA. · Memorial Sloan-Kettering Cancer Center, New York, NY, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Crown Princess Mary Cancer Centre, Westmead Hospital and Melanoma Institute Australia, Westmead, NSW, Australia; University of Sydney, Sydney, NSW, Australia. · H Lee Moffitt Cancer Center, Tampa, FL, USA. · Princess Margaret Cancer Centre, Toronto, ON, Canada. · University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA. · South Texas Accelerated Research Therapeutics, San Antonio, TX, USA. · Mayo Clinic, Rochester, MN, USA. · University of Pittsburgh, Pittsburgh, PA, USA. · Mayo Clinic, Jacksonville, FL, USA. · Gustave Roussy and INSERM U981, Paris-Sud, France. · Merck, Whitehouse Station, NJ, USA. · University of California San Francisco, San Francisco, CA, USA. ·Lancet · Pubmed #25034862.

ABSTRACT: BACKGROUND: The anti-programmed-death-receptor-1 (PD-1) antibody pembrolizumab has shown potent antitumour activity at different doses and schedules in patients with melanoma. We compared the efficacy and safety of pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced melanoma. METHODS: In an open-label, international, multicentre expansion cohort of a phase 1 trial, patients (aged ≥18 years) with advanced melanoma whose disease had progressed after at least two ipilimumab doses were randomly assigned with a computer-generated allocation schedule (1:1 final ratio) to intravenous pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks until disease progression, intolerable toxicity, or consent withdrawal. Primary endpoint was overall response rate (ORR) assessed with the Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) by independent central review. Analysis was done on the full-analysis set (all treated patients with measurable disease at baseline). This study is registered with ClinicalTrials.gov, number NCT01295827. FINDINGS: 173 patients received pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84). Median follow-up duration was 8 months. ORR was 26% at both doses--21 of 81 patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group (difference 0%, 95% CI -14 to 13; p=0·96). Treatment was well tolerated, with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths. The most common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg groups were fatigue (29 [33%] vs 31 [37%]), pruritus (23 [26%] vs 16 [19%]), and rash (16 [18%] vs 15 [18%]). Grade 3 fatigue, reported in five (3%) patients in the 2 mg/kg pembrolizumab group, was the only drug-related grade 3 to 4 adverse event reported in more than one patient. INTERPRETATION: The results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options. FUNDING: Merck Sharp and Dohme.

15 Clinical Trial Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma. 2014

Chodon, Thinle / Comin-Anduix, Begoña / Chmielowski, Bartosz / Koya, Richard C / Wu, Zhongqi / Auerbach, Martin / Ng, Charles / Avramis, Earl / Seja, Elizabeth / Villanueva, Arturo / McCannel, Tara A / Ishiyama, Akira / Czernin, Johannes / Radu, Caius G / Wang, Xiaoyan / Gjertson, David W / Cochran, Alistair J / Cornetta, Kenneth / Wong, Deborah J L / Kaplan-Lefko, Paula / Hamid, Omid / Samlowski, Wolfram / Cohen, Peter A / Daniels, Gregory A / Mukherji, Bijay / Yang, Lili / Zack, Jerome A / Kohn, Donald B / Heath, James R / Glaspy, John A / Witte, Owen N / Baltimore, David / Economou, James S / Ribas, Antoni. ·Authors' Affiliations: Departments of Medicine, Surgery, Pathology and Laboratory Medicine, Microbiology, Immunology and Molecular Genetics, and Molecular and Medical Pharmacology; Jonsson Comprehensive Cancer Center; Department of Ophthalmology, Jules Stein Eye Institute; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research; Howard Hughes Medical Institute, University of California, Los Angeles (UCLA); The Angeles Clinic Research Institute, Los Angeles; Department of Medicine, University of California San Diego (UCSD) Moores Cancer Center, La Jolla; Divisions of Chemistry and Biology, California Institute of Technology, Pasadena, California; Department of Medical and Molecular Genetics, Indiana University, and the Indiana University Viral Production Facility (IU VPF), Indianapolis, Indiana; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada; Mayo Clinic Scottsdale, Scottsdale, Arizona; Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut; and Center for Immunology, Roswell Park Cancer Institute, Buffalo, New York. ·Clin Cancer Res · Pubmed #24634374.

ABSTRACT: PURPOSE: It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short 1-week manufacture protocol to determine the feasibility, safety, and antitumor efficacy of this double cell therapy. EXPERIMENTAL DESIGN: A clinical trial (NCT00910650) adoptively transferring MART-1 T-cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide-pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and reinfused with (n = 10) or without (n = 3) prior cryopreservation. RESULTS: A total of 14 patients with metastatic melanoma were enrolled and 9 of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1-specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1-specific T cells in the blood as compared with cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using noncryopreserved T cells. CONCLUSION: Double cell therapy with ACT of TCR-engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses.

16 Clinical Trial Natural killer T cells in advanced melanoma patients treated with tremelimumab. 2013

Ibarrondo, F Javier / Yang, Otto O / Chodon, Thinle / Avramis, Earl / Lee, Yohan / Sazegar, Hooman / Jalil, Jason / Chmielowski, Bartosz / Koya, Richard C / Schmid, Ingrid / Gomez-Navarro, Jesus / Jamieson, Beth D / Ribas, Antoni / Comin-Anduix, Begoña. ·Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America ; UCLA AIDS Institute, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America. ·PLoS One · Pubmed #24167550.

ABSTRACT: A significant barrier to effective immune clearance of cancer is loss of antitumor cytotoxic T cell activity. Antibodies to block pro-apoptotic/downmodulatory signals to T cells are currently being tested. Because invariant natural killer T cells (iNKT) can regulate the balance of Th1/Th2 cellular immune responses, we characterized the frequencies of circulating iNKT cell subsets in 21 patients with melanoma who received the anti-CTLA4 monoclonal antibody tremelimumab alone and 8 patients who received the antibody in combination with MART-126-35 peptide-pulsed dendritic cells (MART-1/DC). Blood T cell phenotypes and functionality were characterized by flow cytometry before and after treatment. iNKT cells exhibited the central memory phenotype and showed polyfunctional cytokine production. In the combination treatment group, high frequencies of pro-inflammatory Th1 iNKT CD8(+) cells correlated with positive clinical responses. These results indicate that iNKT cells play a critical role in regulating effective antitumor T cell activity.

17 Clinical Trial Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. 2013

Hamid, Omid / Robert, Caroline / Daud, Adil / Hodi, F Stephen / Hwu, Wen-Jen / Kefford, Richard / Wolchok, Jedd D / Hersey, Peter / Joseph, Richard W / Weber, Jeffrey S / Dronca, Roxana / Gangadhar, Tara C / Patnaik, Amita / Zarour, Hassane / Joshua, Anthony M / Gergich, Kevin / Elassaiss-Schaap, Jeroen / Algazi, Alain / Mateus, Christine / Boasberg, Peter / Tumeh, Paul C / Chmielowski, Bartosz / Ebbinghaus, Scot W / Li, Xiaoyun Nicole / Kang, S Peter / Ribas, Antoni. ·Angeles Clinic and Research Institute, Los Angeles, CA, USA. ·N Engl J Med · Pubmed #23724846.

ABSTRACT: BACKGROUND: The programmed death 1 (PD-1) receptor is a negative regulator of T-cell effector mechanisms that limits immune responses against cancer. We tested the anti-PD-1 antibody lambrolizumab (previously known as MK-3475) in patients with advanced melanoma. METHODS: We administered lambrolizumab intravenously at a dose of 10 mg per kilogram of body weight every 2 or 3 weeks or 2 mg per kilogram every 3 weeks in patients with advanced melanoma, both those who had received prior treatment with the immune checkpoint inhibitor ipilimumab and those who had not. Tumor responses were assessed every 12 weeks. RESULTS: A total of 135 patients with advanced melanoma were treated. Common adverse events attributed to treatment were fatigue, rash, pruritus, and diarrhea; most of the adverse events were low grade. The confirmed response rate across all dose cohorts, evaluated by central radiologic review according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was 38% (95% confidence interval [CI], 25 to 44), with the highest confirmed response rate observed in the cohort that received 10 mg per kilogram every 2 weeks (52%; 95% CI, 38 to 66). The response rate did not differ significantly between patients who had received prior ipilimumab treatment and those who had not (confirmed response rate, 38% [95% CI, 23 to 55] and 37% [95% CI, 26 to 49], respectively). Responses were durable in the majority of patients (median follow-up, 11 months among patients who had a response); 81% of the patients who had a response (42 of 52) were still receiving treatment at the time of analysis in March 2013. The overall median progression-free survival among the 135 patients was longer than 7 months. CONCLUSIONS: In patients with advanced melanoma, including those who had had disease progression while they had been receiving ipilimumab, treatment with lambrolizumab resulted in a high rate of sustained tumor regression, with mainly grade 1 or 2 toxic effects. (Funded by Merck Sharp and Dohme; ClinicalTrials.gov number, NCT01295827.).

18 Clinical Trial Multifunctional T-cell analyses to study response and progression in adoptive cell transfer immunotherapy. 2013

Ma, Chao / Cheung, Ann F / Chodon, Thinle / Koya, Richard C / Wu, Zhongqi / Ng, Charles / Avramis, Earl / Cochran, Alistair J / Witte, Owen N / Baltimore, David / Chmielowski, Bartosz / Economou, James S / Comin-Anduix, Begonya / Ribas, Antoni / Heath, James R. ·NanoSystems Biology Cancer Center, Division of Physics, California Institute of Technology, Pasadena, CA 91125, USA. ·Cancer Discov · Pubmed #23519018.

ABSTRACT: SIGNIFICANCE: A longitudinal functional study of adoptively transferred TCR–engineered lymphocytes yielded revealing snapshots for understanding the changes of antitumor responses over time in ACT immunotherapy of patients with advanced melanoma.

19 Clinical Trial Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. 2012

Sosman, Jeffrey A / Kim, Kevin B / Schuchter, Lynn / Gonzalez, Rene / Pavlick, Anna C / Weber, Jeffrey S / McArthur, Grant A / Hutson, Thomas E / Moschos, Stergios J / Flaherty, Keith T / Hersey, Peter / Kefford, Richard / Lawrence, Donald / Puzanov, Igor / Lewis, Karl D / Amaravadi, Ravi K / Chmielowski, Bartosz / Lawrence, H Jeffrey / Shyr, Yu / Ye, Fei / Li, Jiang / Nolop, Keith B / Lee, Richard J / Joe, Andrew K / Ribas, Antoni. ·Vanderbilt-Ingram Cancer Center, Nashville, TN 37232-6307, USA. jeff.sosman@vanderbilt.edu ·N Engl J Med · Pubmed #22356324.

ABSTRACT: BACKGROUND: Approximately 50% of melanomas harbor activating (V600) mutations in the serine-threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600-mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial. METHODS: We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600-mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point. RESULTS: A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients. CONCLUSIONS: Vemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600-mutant metastatic melanoma. In this study with a long follow-up, the median overall survival was approximately 16 months. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00949702.).

20 Clinical Trial KIT as a therapeutic target in metastatic melanoma. 2011

Carvajal, Richard D / Antonescu, Cristina R / Wolchok, Jedd D / Chapman, Paul B / Roman, Ruth-Ann / Teitcher, Jerrold / Panageas, Katherine S / Busam, Klaus J / Chmielowski, Bartosz / Lutzky, Jose / Pavlick, Anna C / Fusco, Anne / Cane, Lauren / Takebe, Naoko / Vemula, Swapna / Bouvier, Nancy / Bastian, Boris C / Schwartz, Gary K. ·Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA. carvajar@mskcc.org ·JAMA · Pubmed #21642685.

ABSTRACT: CONTEXT: Some melanomas arising from acral, mucosal, and chronically sun-damaged sites harbor activating mutations and amplification of the type III transmembrane receptor tyrosine kinase KIT. We explored the effects of KIT inhibition using imatinib mesylate in this molecular subset of disease. OBJECTIVE: To assess clinical effects of imatinib mesylate in patients with melanoma harboring KIT alterations. DESIGN, SETTING, AND PATIENTS: A single-group, open-label, phase 2 trial at 1 community and 5 academic oncology centers in the United States of 295 patients with melanoma screened for the presence of KIT mutations and amplification between April 23, 2007, and April 16, 2010. A total of 51 cases with such alterations were identified and 28 of these patients were treated who had advanced unresectable melanoma arising from acral, mucosal, and chronically sun-damaged sites. INTERVENTION: Imatinib mesylate, 400 mg orally twice daily. MAIN OUTCOME MEASURES: Radiographic response, with secondary end points including time to progression, overall survival, and correlation of molecular alterations and clinical response. RESULTS: Two complete responses lasting 94 (ongoing) and 95 weeks, 2 durable partial responses lasting 53 and 89 (ongoing) weeks, and 2 transient partial responses lasting 12 and 18 weeks among the 25 evaluable patients were observed. The overall durable response rate was 16% (95% confidence interval [CI], 2%-30%), with a median time to progression of 12 weeks (interquartile range [IQR], 6-18 weeks; 95% CI, 11-18 weeks), and a median overall survival of 46.3 weeks (IQR, 28 weeks-not achieved; 95% CI, 28 weeks-not achieved). Response rate was better in cases with mutations affecting recurrent hotspots or with a mutant to wild-type allelic ratio of more than 1 (40% vs 0%, P = .05), indicating positive selection for the mutated allele. CONCLUSIONS: Among patients with advanced melanoma harboring KIT alterations, treatment with imatinib mesylate results in significant clinical responses in a subset of patients. Responses may be limited to tumors harboring KIT alterations of proven functional relevance. Trial Registration clinicaltrials.gov Identifier: NCT00470470.

21 Clinical Trial CTLA4 blockade induces frequent tumor infiltration by activated lymphocytes regardless of clinical responses in humans. 2011

Huang, Rong Rong / Jalil, Jason / Economou, James S / Chmielowski, Bartosz / Koya, Richard C / Mok, Stephen / Sazegar, Hooman / Seja, Elizabeth / Villanueva, Arturo / Gomez-Navarro, Jesus / Glaspy, John A / Cochran, Alistair J / Ribas, Antoni. ·Division of Hematology-Oncology, 11-934 Factor Building, UCLA Medical Center, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA. ·Clin Cancer Res · Pubmed #21558401.

ABSTRACT: BACKGROUND: CTLA4 blocking monoclonal antibodies provide durable clinical benefit in a subset of patients with advanced melanoma mediated by intratumoral lymphocytic infiltrates. A key question is defining whether the intratumoral infiltration (ITI) is a differentiating factor between patients with and without tumor responses. METHODS: Paired baseline and postdosing tumor biopsy specimens were prospectively collected from 19 patients with metastatic melanoma, including 3 patients with an objective tumor response, receiving the anti-CTLA4 antibody tremelimumab within a clinical trial with primary endpoint of quantitating CD8(+) cytotoxic T-lymphocyte (CTL) infiltration in tumors. Samples were analyzed for cell density by automated imaging capture and further characterized for functional lymphocyte properties by assessing the cell activation markers HLA-DR and CD45RO, the cell proliferation marker Ki67, and the regulatory T-cell marker FOXP3. RESULTS: There was a highly significant increase in ITI by CD8(+) cells in biopsy samples taken after tremelimumab treatment. This included increases between 1-fold and 100-fold changes in 14 of 18 evaluable cases regardless of clinical tumor response or progression. There was no difference between the absolute number, location, or cell density of infiltrating cells between clinical responders and patients with nonresponding lesions that showed acquired intratumoral infiltrates. There were similar levels of expression of T-cell activation markers (CD45RO, HLA-DR) in both groups and no difference in markers for cell replication (Ki67) or the suppressor cell marker FOXP3. CONCLUSION: CTLA4 blockade induces frequent increases in ITI by T cells despite which only a minority of patients have objective tumor responses.

22 Clinical Trial Intra-lymph node prime-boost vaccination against Melan A and tyrosinase for the treatment of metastatic melanoma: results of a phase 1 clinical trial. 2011

Ribas, Antoni / Weber, Jeffrey S / Chmielowski, Bartosz / Comin-Anduix, Begonya / Lu, David / Douek, Michael / Ragavendra, Nagesh / Raman, Steve / Seja, Elizabeth / Rosario, Darlene / Miles, Sabrina / Diamond, David C / Qiu, Zhiyong / Obrocea, Mihail / Bot, Adrian. ·Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA. aribas@mednet.ucla.edu ·Clin Cancer Res · Pubmed #21385924.

ABSTRACT: PURPOSE: The goal of this study was to test the safety and activity of a therapeutic vaccine, MKC1106-MT, in patients with metastatic melanoma. EXPERIMENTAL DESIGN: MKC1106-MT comprises a plasmid (pMEL-TYR) and two peptides (E-MEL and E-TYR), corresponding to Melan A and tyrosinase, administered by intra-lymph node injection in a prime-boost sequence. All 18 patients were HLA-A*0201 positive and received a fixed priming dose of plasmid and a low or a high peptide dose. Enumeration of antigen-specific T cells was done prior to and throughout the treatment. Patients who did not exhibit disease progression remained on study and could receive up to eight cycles of treatment. RESULTS: The MKC1106-MT regimen was well tolerated and resulted in an overall immune response rate of 50%. The treatment showed disease control, defined as stable disease that lasted for 8 weeks or more in 6 of 18 (33%) of the patients: 14% and 46% in the low and high peptide dose, respectively. Interestingly, four patients, all with tumor burden largely confined to lymph nodes and Melan A-specific T cells at baseline, showed durable disease control associated with radiologic evidence of tumor regression. There was no noticeable correlation between the expansion of antigen-specific T cells in blood and the clinical outcome; yet, there was evidence of active tumor-infiltrating lymphocytes (TIL) in two regressing lesions. CONCLUSIONS: MKC1106-MT showed immunogenicity and evidence of disease control in a defined patient population. These findings support further development of this investigational agent and the concept of therapeutic vaccination in metastatic melanoma.

23 Clinical Trial Multicenter phase II study of matured dendritic cells pulsed with melanoma cell line lysates in patients with advanced melanoma. 2010

Ribas, Antoni / Camacho, Luis H / Lee, Sun Min / Hersh, Evan M / Brown, Charles K / Richards, Jon M / Rodriguez, Maria Jovie / Prieto, Victor G / Glaspy, John A / Oseguera, Denise K / Hernandez, Jackie / Villanueva, Arturo / Chmielowski, Bartosz / Mitsky, Peggie / Bercovici, Nadège / Wasserman, Ernesto / Landais, Didier / Ross, Merrick I. ·University of California Los Angeles (UCLA), CA, USA. aribas@mednet.ucla.edu ·J Transl Med · Pubmed #20875102.

ABSTRACT: BACKGROUND: Several single center studies have provided evidence of immune activation and antitumor activity of therapeutic vaccination with dendritic cells (DC) in patients with metastatic melanoma. The efficacy of this approach in patients with favorable prognosis metastatic melanoma limited to the skin, subcutaneous tissues and lung (stages IIIc, M1a, M1b) was tested in a multicenter two stage phase 2 study with centralized DC manufacturing. METHODS: The vaccine (IDD-3) consisted 8 doses of autologous monocyte-derived matured DC generated in serum-free medium with granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin-13 (IL-13), pulsed with lysates of three allogeneic melanoma cell lines, and matured with interferon gamma. The primary endpoint was antitumor activity. RESULTS: Among 33 patients who received IDD-3 there was one complete response (CR), two partial responses (PR), and six patients had stable disease (SD) lasting more than eight weeks. The overall prospectively defined tumor growth control rate was 27% (90% confidence interval of 13-46%). IDD-3 administration had minimal toxicity and it resulted in a high frequency of immune activation to immunizing melanoma antigens as assessed by in vitro immune monitoring assays. CONCLUSIONS: The administration of matured DC loaded with tumor lysates has significant immunogenicity and antitumor activity in patients with limited metastatic melanoma. CLINICAL TRIAL REGISTRATION: NCT00107159.

24 Clinical Trial Modulation of cell signaling networks after CTLA4 blockade in patients with metastatic melanoma. 2010

Comin-Anduix, Begoña / Sazegar, Hooman / Chodon, Thinle / Matsunaga, Douglas / Jalil, Jason / von Euw, Erika / Escuin-Ordinas, Helena / Balderas, Robert / Chmielowski, Bartosz / Gomez-Navarro, Jesus / Koya, Richard C / Ribas, Antoni. ·Division of Surgical Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, California, United States of America. bcomin@mednet.ucla.edu ·PLoS One · Pubmed #20856802.

ABSTRACT: BACKGROUND: The effects on cell signalling networks upon blockade of cytotoxic T lymphocyte-associated antigen-4 (CTLA4) using the monoclonal antibody tremelimumab were studied in peripheral blood mononuclear cell (PBMC) samples from patients with metastatic melanoma. METHODOLOGY/PRINCIPAL: Findings Intracellular flow cytometry was used to detect phosphorylated (p) signaling molecules downstream of the T cell receptor (TCR) and cytokine receptors. PBMC from tremelimumab-treated patients were characterized by increase in pp38, pSTAT1 and pSTAT3, and decrease in pLck, pERK1/2 and pSTAT5 levels. These changes were noted in CD4 and CD8 T lymphocytes but also in CD14 monocytes. A divergent pattern of phosphorylation of Zap70, LAT, Akt and STAT6 was noted in patients with or without an objective tumor response. CONCLUSIONS/SIGNIFICANCE: The administration of the CTLA4-blocking antibody tremelimumab to patients with metastatic melanoma influences signaling networks downstream of the TCR and cytokine receptors both in T cells and monocytes. The strong modulation of signaling networks in monocytes suggests that this cell subset may be involved in clinical responses to CTLA4 blockade. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov; Registration numbers NCT00090896 and NCT00471887.

25 Clinical Trial Imaging of CTLA4 blockade-induced cell replication with (18)F-FLT PET in patients with advanced melanoma treated with tremelimumab. 2010

Ribas, Antoni / Benz, Matthias R / Allen-Auerbach, Martin S / Radu, Caius / Chmielowski, Bartosz / Seja, Elizabeth / Williams, John L / Gomez-Navarro, Jesus / McCarthy, Timothy / Czernin, Johannes. ·Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, California, USA. aribas@mednet.ucla.edu ·J Nucl Med · Pubmed #20150263.

ABSTRACT: METHODS: We tested the role of whole-body molecular imaging in patients with advanced melanoma receiving the CTLA4-blocking antibody tremelimumab, allowing the analysis of changes in glucose metabolism using the PET probe (18)F-FDG and cell replication with the PET probe 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT). RESULTS: PET/CT scans obtained at a median of 2 mo after initial dosing did not demonstrate significant changes in lesion size or (18)F-FDG or (18)F-FLT uptake when focusing on metastatic lesions. Similarly, there was no difference in (18)F-FDG uptake in the non-melanoma-involved spleen. However, there were significant increases in standardized uptake values for (18)F-FLT in the spleen using post- and pretremelimumab treatment scans. CONCLUSION: Molecular imaging with the PET probe (18)F-FLT allows mapping and noninvasive imaging of cell proliferation in secondary lymphoid organs after CTLA4 blockade in patients with metastatic melanoma.

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