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Melanoma: HELP
Articles by David F. McDermott
Based on 40 articles published since 2009
(Why 40 articles?)
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Between 2009 and 2019, D. McDermott wrote the following 40 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. 2013

Kaufman, Howard L / Kirkwood, John M / Hodi, F Stephen / Agarwala, Sanjiv / Amatruda, Thomas / Bines, Steven D / Clark, Joseph I / Curti, Brendan / Ernstoff, Marc S / Gajewski, Thomas / Gonzalez, Rene / Hyde, Laura Jane / Lawson, David / Lotze, Michael / Lutzky, Jose / Margolin, Kim / McDermott, David F / Morton, Donald / Pavlick, Anna / Richards, Jon M / Sharfman, William / Sondak, Vernon K / Sosman, Jeffrey / Steel, Susan / Tarhini, Ahmad / Thompson, John A / Titze, Jill / Urba, Walter / White, Richard / Atkins, Michael B. ·Rush University Cancer Center, 1725 West Harrison Street, Chicago, IL 60612, USA. ·Nat Rev Clin Oncol · Pubmed #23982524.

ABSTRACT: Immunotherapy is associated with durable clinical benefit in patients with melanoma. The goal of this article is to provide evidence-based consensus recommendations for the use of immunotherapy in the clinical management of patients with high-risk and advanced-stage melanoma in the USA. To achieve this goal, the Society for Immunotherapy of Cancer sponsored a panel of melanoma experts--including physicians, nurses, and patient advocates--to develop a consensus for the clinical application of tumour immunotherapy for patients with melanoma. The Institute of Medicine clinical practice guidelines were used as a basis for this consensus development. A systematic literature search was performed for high-impact studies in English between 1992 and 2012 and was supplemented as appropriate by the panel. This consensus report focuses on issues related to patient selection, toxicity management, clinical end points and sequencing or combination of therapy. The literature review and consensus panel voting and discussion were used to generate recommendations for the use of immunotherapy in patients with melanoma, and to assess and rate the strength of the supporting evidence. From the peer-reviewed literature the consensus panel identified a role for interferon-α2b, pegylated-interferon-α2b, interleukin-2 (IL-2) and ipilimumab in the clinical management of melanoma. Expert recommendations for how to incorporate these agents into the therapeutic approach to melanoma are provided in this consensus statement. Tumour immunotherapy is a useful therapeutic strategy in the management of patients with melanoma and evidence-based consensus recommendations for clinical integration are provided and will be updated as warranted.

2 Review Clinical Trial Design and Endpoints for Stage IV Melanoma in the Modern Era. 2017

Izar, Benjamin / Regan, Meredith M / McDermott, David F. ·From the *Beth Israel Deaconess Medical Center; †Dana-Farber Cancer Institute; and ‡Dana-Farber/Harvard Cancer Center, Boston; §Broad Institute of MIT and Harvard, Cambridge; and ∥Harvard Medical School, Boston, MA. ·Cancer J · Pubmed #28114257.

ABSTRACT: Immunotherapies and targeted therapies for the treatment of metastatic or advanced melanoma produce unique patterns of antitumor response. Conventional outcome measures, such as median progression-free and overall survival, may not be ideally suited to identify all patients who derive a benefit from such therapies. Therefore, the introduction of additional endpoint measures, such as milestone comparisons, may be necessary to characterize the potential benefit of such treatment approaches. Immune checkpoint inhibitors induce durable responses in a portion of patients that may continue after treatment cessation. Measuring the associated treatment-free interval, treatment-free survival, and associated patient-reported outcomes could provide important information when implemented in prospective clinical trials. In this article, we discuss the limitations of current endpoint measures and the potential advantage of using novel endpoints and how these might be used in designing clinical trials to address critical unanswered questions for patients with metastatic melanoma.

3 Review The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma. 2015

Mahoney, Kathleen M / Freeman, Gordon J / McDermott, David F. ·Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Department of Medical Oncology, Harvard Medical School, Dana Farber Cancer Institute, Boston, Massachusetts. Electronic address: kmmah5@bidmc.harvard.edu. · Department of Medical Oncology, Harvard Medical School, Dana Farber Cancer Institute, Boston, Massachusetts. · Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. ·Clin Ther · Pubmed #25823918.

ABSTRACT: PURPOSE: Blocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. Therapeutics targeting this pathway are currently in clinical trials. Pembrolizumab and nivolumab are the first of this anti-PD-1 pathway family of checkpoint inhibitors to gain accelerated approval from the US Food and Drug Administration (FDA) for the treatment of ipilimumab-refractory melanoma. Nivolumab has been associated with improved overall survival compared with dacarbazine in patients with previously untreated wild-type serine/threonine-protein kinase B-raf proto-oncogene BRAF melanoma. Although the most mature data are in the treatment of melanoma, the FDA has granted approval of nivolumab for squamous cell lung cancer and the breakthrough therapy designation to immune- checkpoint inhibitors for use in other cancers: nivolumab, an anti-PD-1 monoclonal antibody, for Hodgkin lymphoma, and MPDL-3280A, an anti-PD-L1 monoclonal antibody, for bladder cancer and non-small cell lung cancer. Here we review the literature on PD-1 and PD-L1 blockade and focus on the reported clinical studies that have included patients with melanoma. METHODS: PubMed was searched to identify relevant clinical studies of PD-1/PD-L1-targeted therapies in melanoma. A review of data from the current trials on clinicaltrial.gov was incorporated, as well as data presented in abstracts at the 2014 annual meeting of the American Society of Clinical Oncology, given the limited number of published clinical trials on this topic. FINDINGS: The anti-PD-1 and anti-PD-L1 agents have been reported to have impressive antitumor effects in several malignancies, including melanoma. The greatest clinical activity in unselected patients has been seen in melanoma. Tumor expression of PD-L1 is a suggestive, but inadequate, biomarker predictive of response to immune-checkpoint blockade. However, tumors expressing little or no PD-L1 are less likely to respond to PD-1 pathway blockade. Combination checkpoint blockade with PD-1 plus cytotoxic T-lymphocyte antigen (CTLA)-4 blockade appears to improve response rates in patients who are less likely to respond to single-checkpoint blockade. Toxicity with PD-1 blocking agents is less than the toxicity with previous immunotherapies (eg, interleukin 2, CTLA-4 blockade). Certain adverse events can be severe and potentially life threatening, but most can be prevented or reversed with close monitoring and appropriate management. IMPLICATIONS: This family of immune-checkpoint inhibitors benefits not only patients with metastatic melanoma but also those with historically less responsive tumor types. Although a subset of patients responds to single-agent blockade, the initial trial of checkpoint-inhibitor combinations has reported a potential to improve response rates. Combination therapies appear to be a means of increasing response rates, albeit with increased immune-related adverse events. As these treatments become available to patients, education regarding the recognition and management of immune-related effects of immune-checkpoint blockade will be essential for maximizing clinical benefit.

4 Review Cytotoxic T-lymphocyte antigen-4 blockade in melanoma. 2015

Buchbinder, Elizabeth I / McDermott, David F. ·Division of Oncology, Dana Farber Cancer Institute, Boston, Massachusetts. Electronic address: elizabeth_buchbinder@DFCI.harvard.edu. · Division of Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts. ·Clin Ther · Pubmed #25746738.

ABSTRACT: PURPOSE: Melanoma is an aggressive malignancy that has a complex relationship with the host immune system. Immunotherapies have long been a mainstay of melanoma therapy, and advanced therapies continue to be effective in treating this disease. Immune checkpoint blockade has proven to be a novel target in melanoma, with the approval of cytotoxic T-lymphocyte antigen-4 (CTLA-4)-targeted therapy. This review evaluates the role of CTLA-4-targeted therapies in the treatment of metastatic melanoma, with a focus on mechanisms, efficacy, toxicity, and future directions of this therapy. METHODS: A search was performed in PubMed to identify relevant clinical studies that explored the clinical experience with CTLA-4-targeted therapy in melanoma. FINDINGS: Signaling through CTLA-4 causes deactivation of T cells after the initial stimulatory signals. Therapies that block CTLA-4 lead to increased T-cell function and an antitumor response in patients with metastatic melanoma. The adverse event profile of these agents is different from that seen with more traditional cancer therapies and consists of dermatitis, colitis, and other autoimmune toxicities. In addition, the pattern of response is different from that seen with traditional cytotoxic therapies, with some patients experiencing initial progression followed by response and some patients having long-term durable responses. IMPLICATIONS: Extensive clinical evidence supports the use of CTLA-4-targeted agents in the treatment of metastatic melanoma. The durability of response seen in patients receiving these agents has changed the landscape for patients with melanoma. Combination therapies and other agents with similar mechanisms warrant further exploration for the treatment of metastatic melanoma.

5 Review Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. 2014

McDermott, David / Lebbé, Celeste / Hodi, F Stephen / Maio, Michele / Weber, Jeffrey S / Wolchok, Jedd D / Thompson, John A / Balch, Charles M. ·Department of Hematology/Oncology, Beth Israel Deaconess Medical Center, 375 Longwood Ave, Mailstop: MASCO 428, Boston, MA 02215, USA. Electronic address: dmcdermo@bidmc.harvard.edu. · APHP Department of Dermatology, CIC, U976 Hôpital Saint-Louis University Paris Diderot, 1 Avenue Claude Vellefaux, Paris 75010, France. Electronic address: celeste.lebbe@sls.aphp.fr. · Center for Immuno-Oncology, Melanoma Center, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA. Electronic address: Stephen_Hodi@dfci.harvard.edu. · Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Siena 53100, Italy. Electronic address: mmaiocro@gmail.com. · Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA. Electronic address: jeffrey.weber@moffitt.org. · Ludwig Center for Cancer Immunotherapy, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA. Electronic address: wolchokj@mskcc.org. · Seattle Cancer Care Alliance, 825 Eastlake Ave E, G4-830, Seattle, WA 98109, USA. Electronic address: jat@uw.edu. · Department of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA. Electronic address: charles.balch@utsouthwestern.edu. ·Cancer Treat Rev · Pubmed #25060490.

ABSTRACT: Historically, the median overall survival for patients with stage IV melanoma was less than 1 year and the 5-year survival rate was ∼10%. Recent advances in therapy have raised 5-year survival expectations to ∼20%. Notably, a subset of melanoma patients who receive immunotherapy with high-dose interleukin-2, and now ipilimumab, can achieve long-term survival of at least 5 years. A major goal in melanoma research is to increase the number of patients who experience this overall survival benefit. In this review, we discuss the attributes of immunotherapy and newer targeted agents, and consider how combination strategies might improve the chances of achieving durable benefit and long-term survival. We also discuss three areas that we believe will be critical to making further advances in melanoma treatment. To better understand the clinical profile of patients who achieve long-term survival with immunotherapy, we first present data from ipilimumab clinical trials in which a subset of patients experienced durable responses. Second, we discuss the limitations of traditional metrics used to evaluate the benefits of immunotherapies. Third, we consider emerging issues that clinicians are currently facing when making treatment decisions regarding immunotherapy. A better understanding of these novel treatments may improve survival outcomes in melanoma, increase the number of patients who experience this overall survival benefit, and inform the future use of these agents in the treatment of other cancer types.

6 Review Interferon, interleukin-2, and other cytokines. 2014

Buchbinder, Elizabeth I / McDermott, David F. ·Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA. Electronic address: ebuchbin@bidmc.harvard.edu. · Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA. ·Hematol Oncol Clin North Am · Pubmed #24880948.

ABSTRACT: Cytokines are a diverse group of signaling molecules with immunomodulatory activity. This article reviews the application of cytokine therapy in melanoma with a focus on interferon-α and interleukin-2. In addition, it addresses the clinical considerations of these therapies including patient selection, reduction in toxicity, and combination regimens.

7 Clinical Trial Results from phase II trial of HSP90 inhibitor, STA-9090 (ganetespib), in metastatic uveal melanoma. 2018

Shah, Shalin / Luke, Jason J / Jacene, Heather A / Chen, Tianqi / Giobbie-Hurder, Anita / Ibrahim, Nageatte / Buchbinder, Elizabeth L / McDermott, David F / Flaherty, Keith T / Sullivan, Ryan J / Lawrence, Donald P / Ott, Patrick A / Hodi, F Stephen. ·Department of Medicine, Medical University of South Carolina, Charleston, South Carolina. · Department of Medicine, University of Chicago, Chicago, Illinois. · Department of Radiology, Brigham and Women's Hospital. · Department of Biostatics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · Department of Medicine, Dana-Farber Cancer Institute. · Department of Medicine, Beth Israel Deaconess Medical Center. · Department of Medicine, Massachusetts General Hospital Cancer Center. ·Melanoma Res · Pubmed #30211813.

ABSTRACT: Uveal melanoma (UM) is a rare form of melanoma without effective therapy. The biology of UM relies on several heat-shock protein 90 (Hsp90)-dependent molecules such as MET, MEK and AKT, making Hsp90 inhibition a rational approach. Patients with stage IV UM, measurable disease, and no previous chemotherapy were eligible. Patients received either ganetespib 200 mg weekly (cohort A) or 150 mg twice a week (cohort B). Primary endpoint response rate (RR) was assessed by RECIST. A total of 17 patients were accrued for this study, with seven in cohort A and 10 in cohort B. Liver metastases were present in 59%. Response outcomes included one partial response, four stable disease, 11 progressive disease, and one withdrawal for ORR: 5.9% and disease control rate of 29.4%. Progression-free survival was 1.6 months (cohort A) and 1.8 months (cohort B). Overall survival was 8.5 months (cohort A) and 4.9 months (cohort B). An overall 31% of adverse events were grade 3-4 and were mostly related to gastrointestinal toxicities. Early on-treatment (1 months) positron emission tomography showed reduction in metabolic activity in 24% of patients, suggesting a pharmacodynamic effect of Hsp90 inhibition. These early metabolic changes did not seem to be durable and/or clinically significant in relation to the 2-month response assessment. Hsp90 inhibition with ganetespib resulted in modest clinical benefit on two dosing schedules and was associated with significant, although manageable, gastrointestinal toxicity. Evidence of pharmacodynamic activity for Hsp90 inhibition was observed via positron emission tomography, which did not translate into clinical benefit, suggesting rapid development of resistance.

8 Clinical Trial Improved survival and tumor control with Interleukin-2 is associated with the development of immune-related adverse events: data from the PROCLAIM 2017

Curti, Brendan / Daniels, Gregory A / McDermott, David F / Clark, Joseph I / Kaufman, Howard L / Logan, Theodore F / Singh, Jatinder / Kaur, Meenu / Luna, Theresa L / Gregory, Nancy / Morse, Michael A / Wong, Michael K K / Dutcher, Janice P. ·Providence Portland Medical Center, 4805 NE Glisan Street, Portland, OR, 97213, USA. · Moores Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. · Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02215, USA. · Loyola University Medical Center, 2160 S First Avenue, Maywood, IL, 60153, USA. · Rutgers Cancer Center Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08901, USA. · Indiana University Simon Cancer Center, 535 Barnhill Drive, Indianapolis, 46202, USA. · Primary Biostatistical Solutions, 2042 Carnarvon Ct, Victoria, BC, V8R2V3, Canada. · Prometheus Laboratories, 9410 Carroll Park Drive, San Diego, CA, 92121, USA. · Duke University Medical Center, 2301 Erwin Road, Durham, NC, 27705, USA. · MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. · Cancer Research Foundation of NY, 43 Longview Lane, Chappaqua, NY, 10514, USA. jpd4401@aol.com. ·J Immunother Cancer · Pubmed #29254506.

ABSTRACT: BACKGROUND: Immune related adverse events (irAEs) are associated with immunotherapy for cancer and while results suggest improvement in tumor control and overall survival in those experiencing irAEs, the long-term impact is debated. We evaluated irAE reports related to high dose interleukin-2 therapy (IL-2) documented in the PROCLAIM METHODS: Reports on 1535 patients, including 623 with metastatic melanoma (mM) and 919 with metastatic renal cell cancer (mRCC) (7 patients had both diseases), were queried for irAEs. The timing of the event was categorized as occurring before, during or after IL-2 or related to any checkpoint inhibitor (CPI). mM patients and mRCC patients were analyzed separately. Tumor control [complete + partial response + stable disease (CR + PR + SD) was compared between those experiencing no irAE versus those with the development of irAEs. Survival was analyzed by tumor type related to timing of irAE and IL-2, and in those with or without exposure to CPI. RESULTS: Median follow-up was 3.5+ years (range 1-8+ years), 152 irAEs were reported in 130 patients (8.4% of all PROCLAIM CONCLUSIONS: irAEs following IL-2 therapy are associated with improved tumor control and overall survival. IrAEs resulting from IL-2 and from CPIs are qualitatively different, and likely reflect different mechanisms of action of immune activation and response.

9 Clinical Trial A first-in-human phase I, multicenter, open-label, dose-escalation study of the oral RAF/VEGFR-2 inhibitor (RAF265) in locally advanced or metastatic melanoma independent from BRAF mutation status. 2017

Izar, Benjamin / Sharfman, William / Hodi, F Stephen / Lawrence, Donald / Flaherty, Keith T / Amaravadi, Ravi / Kim, Kevin B / Puzanov, Igor / Sosman, Jeffrey / Dummer, Reinhard / Goldinger, Simone M / Lam, Lyhping / Kakar, Shefali / Tang, Zhongwen / Krieter, Oliver / McDermott, David F / Atkins, Michael B. ·Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Center for Cancer Precision Medicine/Dana-Farber Cancer Institute and the Broad Institute, Boston, Massachusetts. · Broad Institute of MIT and Harvard, Cambridge, Massachusetts. · Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. · Dana Farber Cancer Institute, Boston, Massachusetts. · Massachusetts General Hospital, Boston, Massachusetts. · Abramson Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania. · California Pacific Medical Center Research Institute, San Francisco, California. · Vanderbilt-Ingram Cancer Center, Vanderbilt, Tennessee. · University Hospital, Zurich, Switzerland. · Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts. · Novartis Pharmaceuticals Corporation, East Hanover, New Jersey. · Novartis Pharma AG, Basel, Switzerland. · Georgetown-Lombardi Comprehensive Cancer Center, Washington, District of Columbia. ·Cancer Med · Pubmed #28719152.

ABSTRACT: To establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, and anti-tumor efficacy of RAF265. We conducted a multicenter, open-label, phase-I, dose-escalation trial of RAF265, an orally available RAF kinase/VEGFR-2 inhibitor, in patients with advanced or metastatic melanoma. Pharmacokinetic (PK) analysis, pharmacodynamics (PD) and tumor response assessment were conducted. We evaluated metabolic tumor response by 18[F]-fluorodeoxyglucose-positron-emission tomography (FDG-PET), tissue biomarkers using immunohistochemistry (IHC), and modulators of angiogenesis. RAF265 has a serum half-life of approximately 200 h. The MTD was 48 mg once daily given continuously. Among 77 patients, most common treatment-related adverse effects were fatigue (52%), diarrhea (34%), weight loss (31%) and vitreous floaters (27%). Eight of 66 evaluable patients (12.1%) had an objective response, including seven partial and one complete response. Responses occurred in BRAF-mutant and BRAF wild-type (WT) patients. Twelve of 58 (20.7%) evaluable patients had a partial metabolic response. On-treatment versus pretreatment IHC staining in 23 patients showed dose-dependent p-ERK inhibition. We observed a significant temporal increase in placental growth factor levels and decrease in soluble vascular endothelial growth factor receptor 2 (sVEGFR-2) levels in all dose levels. RAF265 is an oral RAF/VEGFR-2 inhibitor that produced antitumor responses, metabolic responses, and modulated angiogenic growth factor levels. Antitumor activity occurred in patients with BRAF-mutant and BRAF-WT disease. Despite low activity at tolerable doses, this study provides a framework for the development of pan-RAF inhibitors and modulators of angiogenesis for the treatment of melanoma.

10 Clinical Trial Combined Anti-VEGF and Anti-CTLA-4 Therapy Elicits Humoral Immunity to Galectin-1 Which Is Associated with Favorable Clinical Outcomes. 2017

Wu, Xinqi / Li, Jingjing / Connolly, Erin M / Liao, Xiaoyun / Ouyang, Jing / Giobbie-Hurder, Anita / Lawrence, Donald / McDermott, David / Murphy, George / Zhou, Jun / Piesche, Matthias / Dranoff, Glenn / Rodig, Scott / Shipp, Margaret / Hodi, F Stephen. ·Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Center for Immuno-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Department of Biostatistics, Dana-Farber Cancer Institute, Boston, Massachusetts. · Massachusetts General Hospital Cancer Center, Boston, Massachusetts. · Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. · Biomedical Research Laboratories, Medicine Faculty, Catholic University of Maule, Talca, Chile. · Novartis Institutes for BioMedical Research, Cambridge, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. stephen_hodi@dfci.harvard.edu. ·Cancer Immunol Res · Pubmed #28473314.

ABSTRACT: The combination of anti-VEGF blockade (bevacizumab) with immune checkpoint anti-CTLA-4 blockade (ipilimumab) in a phase I study showed tumor endothelial activation and immune cell infiltration that were associated with favorable clinical outcomes in patients with metastatic melanoma. To identify potential immune targets responsible for these observations, posttreatment plasma from long-term responding patients were used to screen human protein arrays. We reported that ipilimumab plus bevacizumab therapy elicited humoral immune responses to galectin-1 (Gal-1), which exhibits protumor, proangiogenesis, and immunosuppressive activities in 37.2% of treated patients. Gal-1 antibodies purified from posttreatment plasma suppressed the binding of Gal-1 to CD45, a T-cell surface receptor that transduces apoptotic signals upon binding to extracellular Gal-1. Antibody responses to Gal-1 were found more frequently in the group of patients with therapeutic responses and correlated with improved overall survival. In contrast, another subgroup of treated patients had increased circulating Gal-1 protein instead, and they had reduced overall survival. Our findings suggest that humoral immunity to Gal-1 may contribute to the efficacy of anti-VEGF and anti-CTLA-4 combination therapy. Gal-1 may offer an additional therapeutic target linking anti-angiogenesis and immune checkpoint blockade.

11 Clinical Trial Results from an Integrated Safety Analysis of Urelumab, an Agonist Anti-CD137 Monoclonal Antibody. 2017

Segal, Neil H / Logan, Theodore F / Hodi, F Stephen / McDermott, David / Melero, Ignacio / Hamid, Omid / Schmidt, Henrik / Robert, Caroline / Chiarion-Sileni, Vanna / Ascierto, Paolo A / Maio, Michele / Urba, Walter J / Gangadhar, Tara C / Suryawanshi, Satyendra / Neely, Jaclyn / Jure-Kunkel, Maria / Krishnan, Suba / Kohrt, Holbrook / Sznol, Mario / Levy, Ronald. ·Memorial Sloan Kettering Cancer Center, New York, New York. · Indiana University Simon Cancer Center, Indianapolis, Indiana. · Dana-Farber Cancer Institute, Boston, Massachusetts. · Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Clinica Universidad de Navarra, Pamplona, Spain. · The Angeles Clinic and Research Institute, Los Angeles, California. · Aarhus University Hospital, Aarhus, Denmark. · Gustave Roussy and Paris-Sud University Villejuif, Villejuif, France. · Istituto Oncologico Veneto, Padua, Italy. · Istituto Nazionale Tumori Fondazione "G. Pascale," Naples, Italy. · University Hospital of Siena, Siena, Italy. · Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon. · Abramson Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania. · Bristol-Myers Squibb, Princeton, New Jersey. · Stanford University School of Medicine, Stanford, California. · Yale Comprehensive Cancer Center, New Haven, Connecticut. · Stanford University School of Medicine, Stanford, California. levy@stanford.edu. ·Clin Cancer Res · Pubmed #27756788.

ABSTRACT:

12 Clinical Trial Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. 2016

Hodi, F Stephen / Chesney, Jason / Pavlick, Anna C / Robert, Caroline / Grossmann, Kenneth F / McDermott, David F / Linette, Gerald P / Meyer, Nicolas / Giguere, Jeffrey K / Agarwala, Sanjiv S / Shaheen, Montaser / Ernstoff, Marc S / Minor, David R / Salama, April K / Taylor, Matthew H / Ott, Patrick A / Horak, Christine / Gagnier, Paul / Jiang, Joel / Wolchok, Jedd D / Postow, Michael A. ·Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: stephen_hodi@dfci.harvard.edu. · University of Louisville, Louisville, KY, USA. · New York University, New York, NY, USA. · Gustave Roussy, INSERM U981, Paris, France. · Huntsman Cancer Institute, Salt Lake City, UT, USA. · Beth Israel Deaconess Medical Center, Boston, MA, USA. · Washington University School of Medicine, St Louis, MO, USA. · Institut Universitaire du Cancer, Toulouse, France. · Greenville Health System Cancer Institute, Greenville, SC, USA. · St Luke's Cancer Center and Temple University, Bethlehem, PA, USA. · University of New Mexico, Albuquerque, NM, USA. · Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA. · California Pacific Center for Melanoma Research, San Francisco, CA, USA. · Duke University Medical Center, Durham, NC, USA. · Oregon Health & Science University, Portland, OR, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Bristol-Myers Squibb, Princeton, NJ, USA. · Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. ·Lancet Oncol · Pubmed #27622997.

ABSTRACT: BACKGROUND: Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma. METHODS: In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAF FINDINGS: Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24·5 months (IQR 9·1-25·7), 2-year overall survival was 63·8% (95% CI 53·3-72·6) for those assigned to nivolumab plus ipilimumab and 53·6% (95% CI 38·1-66·8) for those assigned to ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0·74, 95% CI 0·43-1·26; p=0·26). Treatment-related grade 3-4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received ipilimumab alone. The most common treatment-related grade 3-4 adverse events were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten [11%]) in the combination group and diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]) in the ipilimumab alone group. Serious grade 3-4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus ipilimumab (including colitis in ten [11%] of 94 patients, and diarrhoea in five [5%]) compared with four (9%) of 46 patients who received ipilimumab alone (including diarrhoea in two [4%] of 46 patients, colitis in one [2%], and hypophysitis in one [2%]). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis. INTERPRETATION: Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients. FUNDING: Bristol-Myers Squibb.

13 Clinical Trial VEGF Neutralization Plus CTLA-4 Blockade Alters Soluble and Cellular Factors Associated with Enhancing Lymphocyte Infiltration and Humoral Recognition in Melanoma. 2016

Wu, Xinqi / Giobbie-Hurder, Anita / Liao, Xiaoyun / Lawrence, Donald / McDermott, David / Zhou, Jun / Rodig, Scott / Hodi, F Stephen. ·Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Department of Biostatistics, Dana-Farber Cancer Institute, Boston, Massachusetts. · Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. · Massachusetts General Hospital Cancer Center, Boston, Massachusetts. · Beth Israel-Deaconess Medical Center, Boston, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. stephen_hodi@dfci.harvard.edu. ·Cancer Immunol Res · Pubmed #27549123.

ABSTRACT: Immune recognition of tumor targets by specific cytotoxic lymphocytes is essential for the effective rejection of tumors. A phase I clinical trial of ipilimumab (an antibody that blocks CTLA-4 function) in combination with bevacizumab (an antibody that inhibits angiogenesis) in patients with metastatic melanoma found favorable clinical outcomes were associated with increased tumor endothelial activation and lymphocyte infiltration. To better understand the underlying mechanisms, we sought features and factors that changed as a function of treatment in patients. Ipilimumab plus bevacizumab (Ipi-Bev) increased tumor vascular expression of ICAM1 and VCAM1. Treatment also altered concentrations of many circulating cytokines and chemokines, including increases of CXCL10, IL1α, TNFα, CXCL1, IFNα2, and IL8, with decreases in VEGF-A in most patients. IL1α and TNFα induced expression of E-selectin, CXCL1, and VCAM1 on melanoma tumor-associated endothelial cells (TEC) in vitro and promoted adhesion of activated T cells onto TEC. VEGFA inhibited TNFα-induced expression of ICAM1 and VCAM1 and T-cell adhesion, which was blocked by bevacizumab. CXCL10 promoted T-cell migration across TEC in vitro, was frequently expressed by melanoma cells, and was upregulated in a subset of tumors in treated patients. Robust upregulation of CXCL10 in tumors was accompanied by increased T-cell infiltration. Ipi-Bev also augmented humoral immune responses recognizing targets in melanoma, tumor endothelial, and tumor mesenchymal stem cells. Our findings suggest that Ipi-Bev therapy augments immune recognition in the tumor microenvironment through enhancing lymphocyte infiltration and antibody responses. IL1α, TNFα, and CXCL10, together with VEGF neutralization, contribute to Ipi-Bev-induced melanoma immune recognition. Cancer Immunol Res; 4(10); 858-68. ©2016 AACR.

14 Clinical Trial Phase 2 study of sunitinib in patients with metastatic mucosal or acral melanoma. 2015

Buchbinder, Elizabeth I / Sosman, Jeffrey A / Lawrence, Donald P / McDermott, David F / Ramaiya, Nikhil H / Van den Abbeele, Annick D / Linette, Gerald P / Giobbie-Hurder, Anita / Hodi, F Stephen. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Hematology-Oncology, Vanderbilt University, Nashville, Tennessee. · Hematology-Oncology, Massachusetts General Hospital, Boston, Massachusetts. · Hematology-Oncology, Beth Israel-Deaconess Medical Center, Boston, Massachusetts. · Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Imaging, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts. · Hematology-Oncology, Washington University in St. Louis, St. Louis, Missouri. · Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. ·Cancer · Pubmed #26264378.

ABSTRACT: BACKGROUND: Patients with mucosal and acral melanomas have limited treatment options and a poor prognosis. Mutations of the KIT oncogene in these melanoma subtypes provide a potential therapeutic target. METHODS: A multicenter phase 2 trial of sunitinib was conducted in patients with unresectable stage III or IV melanoma of a mucosal or acral primary origin. Patients were treated in 2 cohorts: cohort A received sunitinib at a dose of 50 mg daily for 4 weeks of a 6-week cycle, and cohort B received sunitinib at a dose of 37.5 mg daily on a continuous basis. Dose reductions were permitted for treatment-related toxicities, and tumor assessments were performed every 2 months. RESULTS: Fifty-two patients were enrolled: 21 in cohort A and 31 in cohort B. Four patients had confirmed partial responses, which lasted 5 to 10 months (1 with a KIT mutation). In both cohorts, the proportion of patients alive and progression-free at 2 months was 52% (95% confidence interval, 38%-66%); this was significantly larger than the hypothesized null of 5%. There was no significant difference in response or overall survival between the 25% of patients with a KIT mutation and those without one (response rate, 7.7% vs 9.7%; overall survival, 6.4 vs 8.6 months). The overall disease control rate was 44%, and a high rate of toxicity was associated with the treatment. CONCLUSIONS: Sunitinib showed activity in the treatment of mucosal and acral melanoma that was not dependent on the presence of a KIT mutation. However, the medication was poorly tolerated, and there were no prolonged responses. Cancer 2015;121:4007-4015. © 2015 American Cancer Society.

15 Clinical Trial A Phase I Trial of Bortezomib and Sorafenib in Advanced Malignant Melanoma. 2015

Sullivan, Ryan J / Ibrahim, Nageatte / Lawrence, Donald P / Aldridge, Julie / Giobbie-Hurder, Anita / Hodi, F Stephen / Flaherty, Keith T / Conley, Christine / Mier, James W / Atkins, Michael B / McDermott, David F. ·Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA; rsullivan7@partners.org. · Dana-Farber Cancer Institute, Boston, Massachusetts, USA; · Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA; · Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; · Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., USA. ·Oncologist · Pubmed #25986244.

ABSTRACT: LESSONS LEARNED: This study is a rare example of effective doses of both targeted agents being both administered and tolerated.This combination should not be used in melanoma. BACKGROUND: Sorafenib and bortezomib affect BCL family member expression. We previously demonstrated that bortezomib augmented sorafenib-mediated cytotoxicity in melanoma cell lines in vitro. We aimed to combine sorafenib 400 mg b.i.d. with increasing doses of weekly bortezomib. METHODS: Patients with metastatic melanoma were enrolled in dose-escalation cohorts to determine the maximum tolerated dose (MTD) of sorafenib (twice daily) in combination with bortezomib (weekly for 3 of 4 weeks). The MTD was defined as the highest dose level at which less than 33% of patients exhibited a dose-limiting toxicity (DLT). Efficacy, as measured by 6-month progression-free survival and response rate per RECIST, was documented. RESULTS: Eleven patients were enrolled at three dose levels. DLTs (fatigue and rash) were seen in two of three patients at the highest dose level. Five patients were enrolled for sorafenib 400 mg b.i.d. and bortezomib 1.0 mg/m(2) weekly for 3 of every 4 weeks; none had DLTs, and this dose level was defined as the MTD. Of 10 evaluable patients, no responses were seen. Two of 11 patients (18%) remained progression free for longer than 6 months. CONCLUSION: The combination of sorafenib and bortezomib is safe but not active in patients with melanoma.

16 Clinical Trial Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. 2014

Hodi, F Stephen / Lee, Sandra / McDermott, David F / Rao, Uma N / Butterfield, Lisa H / Tarhini, Ahmad A / Leming, Philip / Puzanov, Igor / Shin, Donghoon / Kirkwood, John M. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts3Harvard Medical School, Harvard University, Boston, Massachusetts. · Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts5Harvard Medical School, Boston, Massachusetts. · University of Pittsburgh Department of Pathology, Pittsburgh, Pennsylvania. · University of Pittsburgh Department of Medicine, Pittsburgh, Pennsylvania. · Hematology and Oncology, The Christ Hospital Cancer Center, Cincinnati, Ohio9University of Cincinnati Department of Medicine, Cincinnati, Ohio. · Department of Medicine, Division of Hematology and Oncology, Vanderbilt University, Nashville, Tennessee. ·JAMA · Pubmed #25369488.

ABSTRACT: IMPORTANCE: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade with ipilimumab prolongs survival in patients with metastatic melanoma. CTLA-4 blockade and granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccine combinations demonstrate therapeutic synergy in preclinical models. A key unanswered question is whether systemic GM-CSF (sargramostim) enhances CTLA-4 blockade. OBJECTIVE: To compare the effect of ipilimumab plus sargramostim vs ipilimumab alone on overall survival (OS) in patients with metastatic melanoma. DESIGN, SETTING, AND PARTICIPANTS: The Eastern Cooperative Oncology Group (ECOG) conducted a US-based phase 2 randomized clinical trial from December 28, 2010, until July 28, 2011, of patients (N = 245) with unresectable stage III or IV melanoma, at least 1 prior therapy, no central nervous system metastases, and ECOG performance status of 0 or 1. INTERVENTIONS: Patients were randomized to receive ipilimumab, 10 mg/kg, intravenously on day 1 plus sargramostim, 250 μg subcutaneously, on days 1 to 14 of a 21-day cycle (n = 123) vs ipilimumab alone (n = 122). Ipilimumab treatment included induction for 4 cycles followed by maintenance every fourth cycle. MAIN OUTCOMES AND MEASURES: Primary end point: comparison of length of OS. Secondary end point: progression-free survival (PFS), response rate, safety, and tolerability. RESULTS: Median follow-up was 13.3 months (range, 0.03-19.9). Median OS as of December 2012 for ipilimumab plus sargramostim was 17.5 months (95% CI, 14.9-not reached) vs 12.7 months (95% CI, 10.0-not reached) for ipilimumab. The 1-year survival rate for ipilimumab plus sargramostim was 68.9% (95% CI, 60.6%-85.5%) compared to 52.9% (95% CI, 43.6%-62.2%) for ipilimumab alone (stratified log-rank 1-sided P = .01; mortality hazard ratio 0.64 [1-sided 90% repeated CI, not applicable-0.90]). A planned interim analysis was conducted at 69.8% of expected events (104 observed with 149 expected deaths). Planned interim analysis using the O'Brien-Fleming boundary was crossed for improvement in OS. There was no difference in PFS. Median PFS for ipilimumab plus sargramostim was 3.1 months (95% CI, 2.9-4.6) vs 3.1 months (95% CI, 2.9-4.0) for ipilimumab alone. Grade 3 to 5 adverse events occurred in 44.9% (95% CI; 35.8%-54.4%) of patients in the ipilimumab plus sargramostim group vs 58.3% (95% CI, 49.0%-67.2%) of patients in the ipilimumab-alone group (2-sided P = .04). CONCLUSION AND RELEVANCE: Among patients with unresectable stage III or IV melanoma, treatment with ipilimumab plus sargramostim vs ipilimumab alone resulted in longer OS and lower toxicity, but no difference in PFS. These findings require confirmation in larger studies with longer follow-up. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01134614.

17 Clinical Trial Bevacizumab plus ipilimumab in patients with metastatic melanoma. 2014

Hodi, F Stephen / Lawrence, Donald / Lezcano, Cecilia / Wu, Xinqi / Zhou, Jun / Sasada, Tetsuro / Zeng, Wanyong / Giobbie-Hurder, Anita / Atkins, Michael B / Ibrahim, Nageatte / Friedlander, Philip / Flaherty, Keith T / Murphy, George F / Rodig, Scott / Velazquez, Elsa F / Mihm, Martin C / Russell, Sara / DiPiro, Pamela J / Yap, Jeffrey T / Ramaiya, Nikhil / Van den Abbeele, Annick D / Gargano, Maria / McDermott, David. ·Authors' Affiliations: Departments of Medical Oncology, Stephen_Hodi@dfci.harvard.edu. · Massachusetts General Hospital Cancer Center; Departments of. · University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; · Authors' Affiliations: Departments of Medical Oncology. · Biostatistics, and. · Lombardi Cancer Center Georgetown University, Washington, District of Columbia; and. · Mount Sinai Medical Center, New York, New York. · Pathology and. · Tufts University; Miraca Life Sciences, Newton, Massachusetts; · Surgery, Brigham and Women's Hospital; · Imaging, Dana-Farber Cancer Institute; · Beth Israel-Deaconess Medical Center, Boston; ·Cancer Immunol Res · Pubmed #24838938.

ABSTRACT: Ipilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopathy. Besides promoting angiogenesis, vascular endothelial growth factor (VEGF) suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. This study investigated the combination of CTLA4 blockade with ipilimumab and VEGF inhibition with bevacizumab. Patients with metastatic melanoma were treated in four dosing cohorts of ipilimumab (3 or 10 mg/kg) with four doses at 3-week intervals and then every 12 weeks, and bevacizumab (7.5 or 15 mg/kg) every 3 weeks. Forty-six patients were treated. Inflammatory events included giant cell arteritis (n = 1), hepatitis (n = 2), and uveitis (n = 2). On-treatment tumor biopsies revealed activated vessel endothelium with extensive CD8(+) and macrophage cell infiltration. Peripheral blood analyses demonstrated increases in CCR7(+/-)/CD45RO(+) cells and anti-galectin antibodies. Best overall response included 8 partial responses, 22 instances of stable disease, and a disease-control rate of 67.4%. Median survival was 25.1 months. Bevacizumab influences changes in tumor vasculature and immune responses with ipilimumab administration. The combination of bevacizumab and ipilimumab can be safely administered and reveals VEGF-A blockade influences on inflammation, lymphocyte trafficking, and immune regulation. These findings provide a basis for further investigating the dual roles of angiogenic factors in blood vessel formation and immune regulation, as well as future combinations of antiangiogenesis agents and immune checkpoint blockade.

18 Clinical Trial Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. 2014

Topalian, Suzanne L / Sznol, Mario / McDermott, David F / Kluger, Harriet M / Carvajal, Richard D / Sharfman, William H / Brahmer, Julie R / Lawrence, Donald P / Atkins, Michael B / Powderly, John D / Leming, Philip D / Lipson, Evan J / Puzanov, Igor / Smith, David C / Taube, Janis M / Wigginton, Jon M / Kollia, Georgia D / Gupta, Ashok / Pardoll, Drew M / Sosman, Jeffrey A / Hodi, F Stephen. ·Suzanne L. Topalian, William H. Sharfman, Julie R. Brahmer, Evan J. Lipson, Janis M. Taube, and Drew M. Pardoll, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD · Mario Sznol and Harriet M. Kluger, Yale University School of Medicine and Smilow Cancer Center, Yale-New Haven Hospital, New Haven, CT · David F. McDermott, Beth Israel Deaconess Medical Center · Donald P. Lawrence, Massachusetts General Hospital Cancer Center · F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA · Richard D. Carvajal, Memorial Sloan-Kettering Cancer Center, New York, NY · Michael B. Atkins, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC · John D. Powderly, Carolina BioOncology Institute, Huntersville, NC · Philip D. Leming, The Christ Hospital Cancer Center, Cincinnati, OH · Igor Puzanov and Jeffrey A. Sosman, Vanderbilt University Medical Center, Nashville, TN · David C. Smith, University of Michigan, Ann Arbor, MI · and Jon M. Wigginton, Georgia D. Kollia, and Ashok Gupta, Bristol-Myers Squibb, Princeton, NJ. ·J Clin Oncol · Pubmed #24590637.

ABSTRACT: PURPOSE: Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued. PATIENTS AND METHODS: Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation. RESULTS: Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative. CONCLUSION: Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.

19 Clinical Trial A single-arm, open-label, expanded access study of vemurafenib in patients with metastatic melanoma in the United States. 2014

Flaherty, Lawrence / Hamid, Omid / Linette, Gerald / Schuchter, Lynn / Hallmeyer, Sigrun / Gonzalez, Rene / Cowey, C Lance / Pavlick, Anna / Kudrik, Fred / Curti, Brendan / Lawson, David / Chapman, Paul B / Margolin, Kim / Ribas, Antoni / McDermott, David / Flaherty, Keith / Cranmer, Lee / Hodi, F Stephen / Day, Bann-Mo / Linke, Rolf / Hainsworth, John. ·From the *Karmanos Cancer Center, Wayne State University, Detroit, MI; †The Angeles Clinic and Research Institute, Los Angeles, CA; ‡Washington University, St Louis, MO; §University of Pennsylvania, Philadelphia, PA; ∥Oncology Specialists S.C., Park Ridge, IL; ¶University of Colorado Cancer Center, Aurora, CO; #Baylor Sammons Cancer Center, Texas Oncology, PA, Dallas, TX; **NYU Medical Center, New York, NY; ††South Carolina Oncology Associates, Columbia, SC; ‡‡Providence Portland Medical Center, Portland, OR; §§Winship Cancer Institute, Emory University, Atlanta, GA; ∥∥Memorial Sloan Kettering Cancer Center, New York, NY; ¶¶Seattle Cancer Care Alliance, Seattle, WA; ##UCLA School of Medicine, Los Angeles, CA; ***Beth Israel Deaconess Medical Center and †††Massachusetts General Hospital, Boston, MA; ‡‡‡University of Arizona Cancer Center, Tucson, AZ; §§§Dana Farber Cancer Institute, Boston, MA; ∥∥∥Genentech, San Francisco, CA; ¶¶¶The SFJ Pharma Group, Pleasanton, CA; and ###Sarah Cannon Research Institute, Nashville, TN. ·Cancer J · Pubmed #24445759.

ABSTRACT: PURPOSE: This open-label, multicenter study was designed to allow access to vemurafenib for patients with metastatic melanoma, bridging the time between end of enrollment in the phase III registration trial (December 2010) and commercial availability following US Food and Drug Administration approval of vemurafenib for the treatment of unresectable or metastatic BRAF-mutated melanoma (August 2011). PATIENTS AND METHODS: Eligible patients had metastatic melanoma with a BRAF mutation (detected by the cobas 4800 BRAF V600 Mutation Test). Unlike previous vemurafenib trials, patients with poor performance status (PS) and treated brain metastases were permitted. Enrolled patients received oral vemurafenib 960 mg twice daily. RESULTS: Of 374 patients enrolled at 29 US sites (December 2010 to October 2011), 371 patients received vemurafenib and were followed up for a median of 2.8 months (the study had a prespecified end upon vemurafenib approval and commercial availability). At baseline, most patients (75%) had stage M1c disease, and 19% had an Eastern Cooperative Oncology Group PS of 2 or 3; 72% of patients had received prior systemic therapy for metastatic melanoma, 27% received prior ipilimumab, and 29% radiotherapy for prior brain metastases. Because reassessment data to confirm response were not available for most patients, point estimates of objective response rate (ORR) are reported. Among 241 efficacy-evaluable patients, the ORR was 54% (median time to response, 1.9 months). The ORR in non-central nervous system sites in patients with previously treated brain metastases (n = 68) was 53%. The ORR in prior ipilimumab-treated patients (n = 68) was 52%. For patients with PS of 0 or 1 (n = 210) and 2 or 3 (n = 31), the ORRs were 55%, and 42%, respectively. The safety profile observed was consistent with that reported in previous studies. The number of patients with grade 3 or 4 treatment-related adverse events was higher in patients with PS 2 or 3 than in those with PS 0 or 1 (10% vs. 5%, respectively). Adverse events requiring a dose reduction (at least 1 level) occurred in 11% of patients, and 9 patients (2%) experienced events leading to vemurafenib withdrawal, including 2 with repeated QT interval prolongation. DISCUSSION: This study confirmed the established rapid and high tumor response rate achievable with vemurafenib in BRAF mutation-positive metastatic melanoma. Several groups not included in previous studies, including patients with previously treated brain metastases, Eastern Cooperative Oncology Group PS 2 to 3, or previous ipilimumab treatment had benefitted from vemurafenib similar to the overall population. No new safety signals were detected.

20 Clinical Trial Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). 2013

McDermott, D / Haanen, J / Chen, T-T / Lorigan, P / O'Day, S / Anonymous5350766. ·Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, USA. ·Ann Oncol · Pubmed #23942774.

ABSTRACT: BACKGROUND: In a phase III trial (ClinicalTrials.gov registration ID: NCT00094653), ipilimumab significantly improved survival versus a vaccine control in pretreated patients with metastatic melanoma. Here, we characterize outcomes of those patients who survived ≥ 2 years. METHODS: Patients were randomized (3 : 1 : 1) to receive ipilimumab 3 mg/kg + gp100 vaccine, ipilimumab 3 mg/kg + placebo, or gp100 vaccine alone. Baseline demographic data, duration of survival, responses, and safety among patients with ≥ 2 years' survival were analyzed. RESULTS: Among 676 randomized patients, 474 and 259 patients had at least 2 or 3 years of potential follow-up, respectively, and were eligible for analysis. Among these, 94 (20%) and 42 (16%) survived ≥ 2 and ≥ 3 years, respectively. Survival rates at 2 and 3 years were 25% (24 of 95) and 25% (13 of 53) with ipilimumab alone and 19% (54 of 284) and 15% (24 of 156) with ipilimumab plus gp100. Safety among patients with ≥ 2 years' survival was comparable with the overall study population, with the onset of new ipilimumab-related toxic effect (all grades) reported in 6 of 78 (8%) patients. CONCLUSIONS: Ipilimumab results in survival of ≥ 2 years in one-fifth of pretreated patients with 2 years potential follow-up in a phase III trial. New onset, low-grade events starting after administration of the last dose were infrequent. TRIAL REGISTRATION ID: NCT00094653.

21 Clinical Trial Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. 2012

Topalian, Suzanne L / Hodi, F Stephen / Brahmer, Julie R / Gettinger, Scott N / Smith, David C / McDermott, David F / Powderly, John D / Carvajal, Richard D / Sosman, Jeffrey A / Atkins, Michael B / Leming, Philip D / Spigel, David R / Antonia, Scott J / Horn, Leora / Drake, Charles G / Pardoll, Drew M / Chen, Lieping / Sharfman, William H / Anders, Robert A / Taube, Janis M / McMiller, Tracee L / Xu, Haiying / Korman, Alan J / Jure-Kunkel, Maria / Agrawal, Shruti / McDonald, Daniel / Kollia, Georgia D / Gupta, Ashok / Wigginton, Jon M / Sznol, Mario. ·Department of Surgery, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA. stopali1@jhmi.edu ·N Engl J Med · Pubmed #22658127.

ABSTRACT: BACKGROUND: Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1. METHODS: We enrolled patients with advanced melanoma, non-small-cell lung cancer, castration-resistant prostate cancer, or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred. RESULTS: A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non-small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non-small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1-PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1-negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1-positive tumors had an objective response (P=0.006). CONCLUSIONS: Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.).

22 Clinical Trial Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. 2012

Margolin, Kim / Ernstoff, Marc S / Hamid, Omid / Lawrence, Donald / McDermott, David / Puzanov, Igor / Wolchok, Jedd D / Clark, Joseph I / Sznol, Mario / Logan, Theodore F / Richards, Jon / Michener, Tracy / Balogh, Agnes / Heller, Kevin N / Hodi, F Stephen. ·University of Washington, Seattle, WA 98109, USA. kmargoli@seattlecca.org ·Lancet Oncol · Pubmed #22456429.

ABSTRACT: BACKGROUND: Brain metastases commonly develop in patients with melanoma and are a frequent cause of death of patients with this disease. Ipilimumab improves survival in patients with advanced melanoma. We aimed to investigate the safety and activity of this drug specifically in patients with brain metastases. METHODS: Between July 31, 2008, and June 3, 2009, we enrolled patients with melanoma and brain metastases from ten US centres who were older than 16 years into two parallel cohorts. Patients in cohort A were neurologically asymptomatic and were not receiving corticosteroid treatment at study entry; those in cohort B were symptomatic and on a stable dose of corticosteroids. Patients were to receive four doses of 10 mg/kg intravenous ipilimumab, one every 3 weeks. Individuals who were clinically stable at week 24 were eligible to receive 10 mg/kg intravenous ipilimumab every 12 weeks. The primary endpoint was the proportion of patients with disease control, defined as complete response, partial response, or stable disease after 12 weeks, assessed with modified WHO criteria. Analyses of safety and efficacy included all treated patients. This trial is registered with ClinicalTrials.gov, number NCT00623766. FINDINGS: We enrolled 72 patients: 51 into cohort A and 21 into cohort B. After 12 weeks, nine patients in cohort A exhibited disease control (18%, 95% CI 8-31), as did one patient in cohort B (5%, 0·1-24). When the brain alone was assessed, 12 patients in cohort A (24%, 13-38) and two in cohort B (10%, 1-30) achieved disease control. We noted disease control outside of the brain in 14 patients (27%, 16-42) in cohort A and in one individual (5%, 0·1-24) in cohort B. The most common grade 3 adverse events in cohort A were diarrhoea (six patients [12%]) and fatigue (six [12%]); in cohort B, they were dehydration (two individuals [10%]), hyperglycaemia (two [10%]), and increased concentrations of serum aspartate aminotransferase (two [10%]). One patient in each cohort had grade 4 confusion. The most common grade 3 immune-related adverse events were diarrhoea (six patients [12%]) and rash (one [2%]) in cohort A, and rash (one individual [5%]) and increased concentrations of serum aspartate aminotransferase (two [10%]) in cohort B. One patient in cohort A died of drug-related complications of immune-related colitis. INTERPRETATION: Ipilimumab has activity in some patients with advanced melanoma and brain metastases, particularly when metastases are small and asymptomatic. The drug has no unexpected toxic effects in this population. FUNDING: Bristol-Myers Squibb.

23 Clinical Trial BEAM: a randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced melanoma. 2012

Kim, Kevin B / Sosman, Jeffrey A / Fruehauf, John P / Linette, Gerald P / Markovic, Svetomir N / McDermott, David F / Weber, Jeffrey S / Nguyen, Hoa / Cheverton, Peter / Chen, Daniel / Peterson, Amy C / Carson, William E / O'Day, Steven J. ·The University of Texas MD Anderson Cancer Center, Houston, TX, USA. ·J Clin Oncol · Pubmed #22124101.

ABSTRACT: PURPOSE: Metastatic melanoma, a highly vascularized tumor with strong expression of vascular endothelial growth factor, has an overall poor prognosis. We conducted a placebo-controlled, double-blind phase II study of carboplatin plus paclitaxel with or without bevacizumab in patients with previously untreated metastatic melanoma. PATIENTS AND METHODS: Patients were randomly assigned in a two-to-one ratio to carboplatin (area under the curve, 5) plus paclitaxel (175 mg/m(2)) and bevacizumab (15 mg/kg; CPB) or placebo (CP) administered intravenously once every 3 weeks. Progression-free survival (PFS) was the primary end point. Secondary end points included overall survival (OS) and safety. RESULTS: Two hundred fourteen patients (73% with M1c disease) were randomly assigned. With a median follow-up of 13 months, median PFS was 4.2 months for the CP arm (n = 71) and 5.6 months for the CPB arm (n = 143; hazard ratio [HR], 0.78; P = .1414). Overall response rates were 16.4% and 25.5%, respectively (P = .1577). With 13-month follow-up, median OS was 8.6 months in the CP arm versus 12.3 months in the CPB arm (HR, 0.67; P = .0366), whereas in an evaluation 4 months later, it was 9.2 versus 12.3 months, respectively (HR, 0.79; P = .1916). In patients with elevated serum lactate dehydrogenase (n = 84), median PFS and OS were longer in the CPB arm (PFS: 4.4 v 2.7 months; HR, 0.62; OS: 8.5 v 7.5 months; HR, 0.52). No new safety signals were observed. CONCLUSION: The study did not meet the primary objective of statistically significant improvement in PFS with the addition of bevacizumab to carboplatin plus paclitaxel. A larger phase III study will be necessary to determine whether there is benefit to the addition of bevacizumab to carboplatin plus paclitaxel in this disease setting.

24 Clinical Trial Multicenter, phase II study of axitinib, a selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, in patients with metastatic melanoma. 2011

Fruehauf, John / Lutzky, Jose / McDermott, David / Brown, Charles K / Meric, Jean-Baptiste / Rosbrook, Brad / Shalinsky, David R / Liau, Katherine F / Niethammer, Andreas G / Kim, Sinil / Rixe, Olivier. ·University of California, Irvine, Orange, 92868, USA. johnfruehauf@msn.com ·Clin Cancer Res · Pubmed #21976544.

ABSTRACT: PURPOSE: This multicenter, open-label, phase II study evaluated the safety and clinical activity of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, 2, and 3, in patients with metastatic melanoma. EXPERIMENTAL DESIGN: Thirty-two patients with a maximum of one prior systemic therapy received axitinib at a starting dose of 5 mg twice daily. The primary endpoint was objective response rate. RESULTS: Objective response rate was 18.8% [95% confidence interval (CI), 7.2-36.4], comprising one complete and five partial responses with a median response duration of 5.9 months (95% CI, 5.0-17.0). Stable disease at 16 weeks was noted in six patients (18.8%), with an overall clinical benefit rate of 37.5%. Six-month progression-free survival rate was 33.9%, 1-year overall survival rate was 28.1%, and median overall survival was 6.6 months (95% CI, 5.2-9.0). The most frequently (>15%) reported nonhematologic, treatment-related adverse events were fatigue, hypertension, hoarseness, and diarrhea. Treatment-related fatal bowel perforation, a known class effect, occurred in one patient. Axitinib selectively decreased plasma concentrations of soluble VEGFR (sVEGFR)-2 and sVEGFR-3 compared with soluble stem cell factor receptor (sKIT). No significant association was noted between plasma levels of axitinib and response. However, post hoc analyses indicated potential relationships between efficacy endpoints and diastolic blood pressure of 90 mm Hg or higher as well as baseline serum lactate dehydrogenase levels. CONCLUSIONS: Axitinib was well tolerated, showed a selective VEGFR-inhibitory profile, and showed single-agent activity in metastatic melanoma. Further evaluations of axitinib, alone and combined with chemotherapy, are ongoing.

25 Clinical Trial Improved survival with ipilimumab in patients with metastatic melanoma. 2010

Hodi, F Stephen / O'Day, Steven J / McDermott, David F / Weber, Robert W / Sosman, Jeffrey A / Haanen, John B / Gonzalez, Rene / Robert, Caroline / Schadendorf, Dirk / Hassel, Jessica C / Akerley, Wallace / van den Eertwegh, Alfons J M / Lutzky, Jose / Lorigan, Paul / Vaubel, Julia M / Linette, Gerald P / Hogg, David / Ottensmeier, Christian H / Lebbé, Celeste / Peschel, Christian / Quirt, Ian / Clark, Joseph I / Wolchok, Jedd D / Weber, Jeffrey S / Tian, Jason / Yellin, Michael J / Nichol, Geoffrey M / Hoos, Axel / Urba, Walter J. ·Dana-Farber Cancer Institute, Boston, MA 02115, USA. stephen_hodi@dfci.harvard.edu ·N Engl J Med · Pubmed #20525992.

ABSTRACT: BACKGROUND: An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. METHODS: A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. RESULTS: The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. CONCLUSIONS: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

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