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Melanoma: HELP
Articles by Stergios J. Moschos
Based on 34 articles published since 2008
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Between 2008 and 2019, S. Moschos wrote the following 34 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial Resolving "kinks" of chemotherapy in melanoma. 2008

Moschos, Stergios J / Chaudhary, Preet M / Kirkwood, John M. · ·J Natl Cancer Inst · Pubmed #18544737.

ABSTRACT: -- No abstract --

2 Review Melanoma central nervous system metastases: current approaches, challenges, and opportunities. 2016

Cohen, Justine V / Tawbi, Hussain / Margolin, Kim A / Amravadi, Ravi / Bosenberg, Marcus / Brastianos, Priscilla K / Chiang, Veronica L / de Groot, John / Glitza, Isabella C / Herlyn, Meenhard / Holmen, Sheri L / Jilaveanu, Lucia B / Lassman, Andrew / Moschos, Stergios / Postow, Michael A / Thomas, Reena / Tsiouris, John A / Wen, Patrick / White, Richard M / Turnham, Timothy / Davies, Michael A / Kluger, Harriet M. ·Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. · Department of Melanoma, Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Medical Oncology & Therapeutics Research, City of Hope Cancer Center, Duarte, CA, USA. · Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. · Division of Neuro-Oncology, Massachusetts General Hospital, Boston, MA, USA. · Division of Neuro-Oncology, MD Anderson Cancer Center, Houston, TX, USA. · Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA. · Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT, USA. · Department of Neurology & Herbert Irving Comprehensive, Cancer Center, Columbia University Medical Center, New York, NY, USA. · UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. · Department of Oncology, Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, NY, USA. · Division of Neuro-Oncology, Department of Neurology, Stanford University, Stanford, CA, USA. · Department of Radiology, New York-Presbyterian Hospital - Weill Cornell Medicine, New York, NY, USA. · Department of Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. · Department of Cancer Biology & Genetics, Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, NY, USA. · Melanoma Research Foundation, Washington, DC, USA. ·Pigment Cell Melanoma Res · Pubmed #27615400.

ABSTRACT: Melanoma central nervous system metastases are increasing, and the challenges presented by this patient population remain complex. In December 2015, the Melanoma Research Foundation and the Wistar Institute hosted the First Summit on Melanoma Central Nervous System (CNS) Metastases in Philadelphia, Pennsylvania. Here, we provide a review of the current status of the field of melanoma brain metastasis research; identify key challenges and opportunities for improving the outcomes in patients with melanoma brain metastases; and set a framework to optimize future research in this critical area.

3 Review Targeted therapies in melanoma. 2015

Moschos, Stergios J / Pinnamaneni, Ramya. ·Division of Hematology/Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Physicians Office Building, Suite 3116-CB#7305, 170 Manning Drive, Chapel Hill, NC 27599, USA. Electronic address: moschos@med.unc.edu. · Division of Hematology/Oncology, Department of Medicine, East Carolina University, 600 Moye Boulevard, Brody 3E127, Greenville, NC 27834, USA. ·Surg Oncol Clin N Am · Pubmed #25769717.

ABSTRACT: Advances in the biology of melanoma have provided insights about chemoresistance and its genetic heterogeneity in parallel with advances in drug design, culminating in recent major treatment breakthroughs. Although clinical benefit of targeted therapies has been unquestionable, future advances are only possible if we understand the interplay between genetic aberrations and role of other crucial nongenetic changes yet to be identified by such projects as the Cancer Genome Atlas Project in Melanoma. Combination therapies, either among small molecule inhibitors themselves and/or with immunotherapies, may be the optimal strategy to prevent development of drug resistance inherently linked with such targeted therapies.

4 Review Historical review of melanoma treatment and outcomes. 2013

Lee, Carrie / Collichio, Frances / Ollila, David / Moschos, Stergios. ·Department of Medicine, The University of North Carolina School of Medicine, Physician's Office Building, 3rd Floor 170 Manning Drive CB# 7305, Chapel Hill, NC 27599, USA. carrie_lee@med.unc.edu ·Clin Dermatol · Pubmed #23438377.

ABSTRACT: The surgical and medical management of melanoma has changed dramatically since the first description of melanoma as a disease entity more than 200 years ago. Refinement of surgical techniques, including evaluation of optimal surgical margins, utility of elective lymph node dissection, and incorporation of sentinel lymph node mapping as both a prognostic tool and guide for selective lymphadenectomy have lessened surgical morbidity and improved outcomes for early-stage and locally advanced melanoma. Astute clinical observations of the integrated roles of the immune system and oncogenic mutations have more recently led to improvements in survival and quality of life for advanced melanoma. Herein, we provide an overview of the most significant surgical and medical milestones in the treatment of melanoma over the past 2 centuries.

5 Review Next generation of immunotherapy for melanoma. 2008

Kirkwood, John M / Tarhini, Ahmad A / Panelli, Monica C / Moschos, Stergios J / Zarour, Hassane M / Butterfield, Lisa H / Gogas, Helen J. ·Hillman Cancer Center, Research Pavilion, Suite 1.32, 5117 Centre Ave, Pittsburgh, PA 15213-2584, USA. kirkwoodjm@upmc.edu ·J Clin Oncol · Pubmed #18612161.

ABSTRACT: PURPOSE: Immunotherapy has a long history with striking but limited success in patients with melanoma. To date, interleukin-2 and interferon-alfa2b are the only approved immunotherapeutic agents for melanoma in the United States. DESIGN: Tumor evasion of host immune responses, and strategies for overcoming tumor-induced immunosuppression are reviewed. Several novel immunotherapies currently in worldwide phase III clinical testing for melanoma are discussed. RESULTS: The limitations of immunotherapy for melanoma stem from tumor-induced mechanisms of immune evasion that render the host tolerant of tumor antigens. For example, melanoma inhibits the maturation of antigen-presenting cells, preventing full T-cell activation and downregulating the effector antitumor immune response. New immunotherapies targeting critical regulatory elements of the immune system may overcome tolerance and promote a more effective antitumor immune response. These include monoclonal antibodies that block the cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and toll-like receptor 9 (TLR9) agonists. Blockade of CTLA4 prevents inhibitory signals that downregulate T-cell activation. TLR9 agonists stimulate dendritic cell maturation and ultimately induce a more effective immune response. These approaches have been shown to stimulate acute immune activation with concomitant appearance of transient adverse events mediated by the immune system. The pattern and duration of immune responses associated with these new modalities differ from those associated with cytokines and cytotoxic agents. In addition, vaccines are being developed that may ultimately target melanoma either alone or in combination with these immunomodulatory therapies. CONCLUSION: The successes of cytokine and interferon therapy of melanoma, coupled with an array of new approaches, are generating new enthusiasm for the immunotherapy of melanoma.

6 Review Focus on FOCIS: interleukin 2 treatment associated autoimmunity. 2008

Moschos, Stergios J / Mandic, Maja / Kirkwood, John M / Storkus, Walter J / Lotze, Michael T. ·University of Pittsburgh Federation of Clinical Immunologic Societies Center of Excellence, Pittsburgh, Pennsylvania 15213-1683, USA. moschossj@upmc.edu ·Clin Immunol · Pubmed #18405863.

ABSTRACT: A patient from the University of Pittsburgh is presented who developed autoimmunity during IL-2 based combination therapy. IL-2 was originally described as a "T cell growth factor" capable of expanding previously activated T cells, enhancing the cytotoxicity of antigen-specific cytotoxic T cells and NK cells. High dose Interleukin 2 (HDIL2) is now FDA-approved for therapy of patients with metastatic melanoma and renal cell carcinoma, based on its ability to induce durable responses in 5-10% of patients. The antitumor effect of HDIL2 is incompletely understood, but it appears that this regimen alters the balance of immigrant T effector cells in relation to T suppressor cells. It promotes a less immunosuppressive tumor microenvironment, inducing tumor regression in a subset of patients that is yet to be defined. The antitumor activity of IL-2, as for other agents that promote durable antitumor activity against melanoma such as interferon alpha and anti-CTLA4 antibody, is frequently associated with development of autoimmunity as observed in this patient. We present studies investigating the mechanisms for the therapeutic benefit of HDIL2 in melanoma.

7 Clinical Trial Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. 2018

Tawbi, Hussein A / Forsyth, Peter A / Algazi, Alain / Hamid, Omid / Hodi, F Stephen / Moschos, Stergios J / Khushalani, Nikhil I / Lewis, Karl / Lao, Christopher D / Postow, Michael A / Atkins, Michael B / Ernstoff, Marc S / Reardon, David A / Puzanov, Igor / Kudchadkar, Ragini R / Thomas, Reena P / Tarhini, Ahmad / Pavlick, Anna C / Jiang, Joel / Avila, Alexandre / Demelo, Sheena / Margolin, Kim. ·From the University of Texas M.D. Anderson Cancer Center, Houston (H.A.T.) · Moffitt Cancer Center and Research Institute, Tampa, FL (P.A.F., N.I.K.) · University of California-San Francisco, San Francisco (A. Algazi), the Angeles Clinic and Research Institute, Los Angeles (O.H.), Stanford University Hospital, Palo Alto (R.P.T.), and the Department of Medical Oncology, City of Hope, Duarte (K.M.) - all in California · Dana-Farber Cancer Institute, Boston (F.S.H., D.A.R.) · University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (S.J.M.) · University of Colorado Comprehensive Cancer Center, Aurora (K.L.) · University of Michigan, Ann Arbor (C.D.L.) · Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (M.A.P.), Roswell Park Cancer Institute, Buffalo (M.S.E., I.P.), and New York University, Lake Success (A.C.P.) - all in New York · Georgetown-Lombardi Comprehensive Cancer Center, Washington DC (M.B.A.) · Winship Cancer Institute of Emory University, Atlanta (R.R.K.) · University of Pittsburgh Medical Center, Pittsburgh (A.T.) · Bristol-Myers Squibb, Princeton, NJ (J.J., A. Avila, S.D.) · and Cleveland Clinic-Taussig Cancer Institute, Cleveland (A.T.). ·N Engl J Med · Pubmed #30134131.

ABSTRACT: BACKGROUND: Brain metastases are a common cause of disabling neurologic complications and death in patients with metastatic melanoma. Previous studies of nivolumab combined with ipilimumab in metastatic melanoma have excluded patients with untreated brain metastases. We evaluated the efficacy and safety of nivolumab plus ipilimumab in patients with melanoma who had untreated brain metastases. METHODS: In this open-label, multicenter, phase 2 study, patients with metastatic melanoma and at least one measurable, nonirradiated brain metastasis (tumor diameter, 0.5 to 3 cm) and no neurologic symptoms received nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for up to four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks until progression or unacceptable toxic effects. The primary end point was the rate of intracranial clinical benefit, defined as the percentage of patients who had stable disease for at least 6 months, complete response, or partial response. RESULTS: Among 94 patients with a median follow-up of 14.0 months, the rate of intracranial clinical benefit was 57% (95% confidence interval [CI], 47 to 68); the rate of complete response was 26%, the rate of partial response was 30%, and the rate of stable disease for at least 6 months was 2%. The rate of extracranial clinical benefit was 56% (95% CI, 46 to 67). Treatment-related grade 3 or 4 adverse events were reported in 55% of patients, including events involving the central nervous system in 7%. One patient died from immune-related myocarditis. The safety profile of the regimen was similar to that reported in patients with melanoma who do not have brain metastases. CONCLUSIONS: Nivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases. (Funded by Bristol-Myers Squibb and the National Cancer Institute; CheckMate 204 ClinicalTrials.gov number, NCT02320058 .).

8 Clinical Trial Dabrafenib plus trametinib in patients with BRAF 2017

Davies, Michael A / Saiag, Philippe / Robert, Caroline / Grob, Jean-Jacques / Flaherty, Keith T / Arance, Ana / Chiarion-Sileni, Vanna / Thomas, Luc / Lesimple, Thierry / Mortier, Laurent / Moschos, Stergios J / Hogg, David / Márquez-Rodas, Iván / Del Vecchio, Michele / Lebbé, Céleste / Meyer, Nicolas / Zhang, Ying / Huang, Yingjie / Mookerjee, Bijoyesh / Long, Georgina V. ·Melanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: mdavies@mdanderson.org. · Service de Dermatologie Générale et Oncologique, Hôpital A Paré, Assistance Publique-Hôpitaux de Paris, Boulogne Billancourt, France; EA 4340, Université Versailles Saint-Quentin-en-Yvelines, Boulogne Billancourt, France. · Gustave Roussy, Département de Médecine Oncologique, Service de Dermatologie et Université Paris-Sud, Faculté de Médecine, Villejuif, France. · Service de Dermatologie, Centre Hospitalo-Universitaire Timone, Aix Marseille University, Marseille, France. · Developmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, Boston, MA, USA. · Department of Medical Oncology, Hospital Clinic of Barcelona, Carrer de Villarroel, Barcelona, Spain. · Melanoma and Oesophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Padova, Italy. · Service de Dermatologie, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France. · Oncologie Dermatologique, Centre Eugène Marquis, Rennes, France. · Clinique de Dermatologie, Unité d'Onco-Dermatologie, Le Centre Hospitalier Régional Universitaire de Lille, University Lille 2, Lille, France. · Melanoma Program, Medical Oncology, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA. · Clinical Cancer Research Unit, Princess Margaret Cancer Centre, Toronto, ON, Canada. · Servicio de Oncología Médica; Hospital General Universitario Gregorio Marañon, Madrid, Spain. · Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · APHP Dermatology and CIC Departments, INSERM U976, University Paris Diderot, Hôpital Saint Louis Paris, Paris, France. · Medical Oncology, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France. · Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. · Melanoma Institute Australia, The University of Sydney, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. ·Lancet Oncol · Pubmed #28592387.

ABSTRACT: BACKGROUND: Dabrafenib plus trametinib improves clinical outcomes in BRAF METHODS: This ongoing, multicentre, multicohort, open-label, phase 2 study evaluated oral dabrafenib (150 mg twice per day) plus oral trametinib (2 mg once per day) in four patient cohorts with melanoma brain metastases enrolled from 32 hospitals and institutions in Europe, North America, and Australia: (A) BRAF FINDINGS: Between Feb 28, 2014, and Aug 5, 2016, 125 patients were enrolled in the study: 76 patients in cohort A; 16 patients in cohort B; 16 patients in cohort C; and 17 patients in cohort D. At the data cutoff (Nov 28, 2016) after a median follow-up of 8·5 months (IQR 5·5-14·0), 44 (58%; 95% CI 46-69) of 76 patients in cohort A achieved an intracranial response. Intracranial response by investigator assessment was also achieved in nine (56%; 95% CI 30-80) of 16 patients in cohort B, seven (44%; 20-70) of 16 patients in cohort C, and ten (59%; 33-82) of 17 patients in cohort D. The most common serious adverse events related to study treatment were pyrexia for dabrafenib (eight [6%] of 125 patients) and decreased ejection fraction (five [4%]) for trametinib. The most common grade 3 or worse adverse events, regardless of study drug relationship, were pyrexia (four [3%] of 125) and headache (three [2%]). INTERPRETATION: Dabrafenib plus trametinib was active with a manageable safety profile in this melanoma population that was consistent with previous dabrafenib plus trametinib studies in patients with BRAF FUNDING: Novartis.

9 Clinical Trial Safety and efficacy of the antiganglioside GD3 antibody ecromeximab (KW2871) combined with high-dose interferon-α2b in patients with metastatic melanoma. 2017

Tarhini, Ahmad A / Moschos, Stergios J / Lin, Yan / Lin, Hui-Min / Sander, Cindy / Yin, Yan / Venhaus, Ralph / Gajewski, Thomas F / Kirkwood, John M. ·aDepartment of Medicine, Division of Hematology and Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania bLudwig Institute for Cancer Research Ltd, New York, New York cDepartment of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois, USA. ·Melanoma Res · Pubmed #28489678.

ABSTRACT: This study evaluated the safety and clinical benefit of ecromeximab (KW2871) combined with high-dose interferon-α2b (HDI) in patients with metastatic melanoma. We also carried out pharmacokinetic and immune monitoring studies of this combination. This was an open-label, phase 1/2 study of ecromeximab plus HDI in patients with measurable metastatic melanoma. Eligible patients received ecromeximab-HDI combination therapy: ecromeximab administered intravenously once every 2 weeks and HDI at a dose of 20 million units (MU)/m administered intravenously for 5 consecutive days per week for the first 4 weeks (induction phase) and then at 10 MU/m subcutaneously thrice weekly through week 14 (maintenance phase). Patients were treated with combination therapy until disease progression or limiting toxicity. Three dose-escalation cohorts (5, 10, and 20 mg/m) of ecromeximab were planned. Thirty-six evaluable patients were enrolled including six in each of cohorts 1 and 2, and 24 in cohort 3. Median progression-free survival was 2.53 months [95% confidence interval (CI):1.93-3.83] and it was 1.93 months (95% CI: 1.00-3.80) in cohort 3. The median overall survival was 10.28 months (95% CI: 6.93-16.77) and 7.78 months (95% CI: 6.03-13.97) in cohort 3. There was no significant difference in progression-free survival or overall survival by BRAF mutation status. The response rate was 5.6% (95% CI: 0.68-18.7), with two patients showing an objective response (one complete response and one partial response), and the clinical benefit rate was 78% (95% CI: 61-90). Stable disease as best response was observed in 26 (72%) patients including five in each of cohorts 1 and 2, and 16 in cohort 3. Treatment-emergent adverse events considered related to ecromeximab treatment occurred in four (66.7%) patients in cohort 1, five (83.3%) patients in cohort 2, and seven (29.2%) patients in cohort 3. Among TEAEs with a maximum severity of grade 3 or 4, those that occurred only in cohort 3 were related to pain, electrolyte imbalance, blood cell decreases, and allergic reaction. Safety and efficacies considered related to ecromeximab occurred in cohort 3 and included grade 3 hypersensitivity [one (4.2%)] and grade 2 hypotension [one (4.2%)]. Regimen-limiting toxicities occurred in two (8.3%) patients in cohort 3: hypersensitivity (with hypertension, supraventricular tachycardia, bronchospasm, chills, and dyspnea) and hypotension. One patient out of 31 examined showed a low-level transient positivity for human antichimeric antibodies against ecromeximab. Pharmacokinetic measurements by enzyme-linked immunosorbent assay determined that administration of HDI does not influence serum levels of ecromeximab at 5, 10, and 20 mg/m dose levels. Ecromeximab in combination with HDI was generally well tolerated in patients with metastatic melanoma and has shown low immunogenicity. However, the clinical activity was limited, suggesting that future development of this combination should be deprioritized and that other combinations, such as with immune checkpoint inhibitors, should be considered.

10 Clinical Trial Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. 2015

Ribas, Antoni / Puzanov, Igor / Dummer, Reinhard / Schadendorf, Dirk / Hamid, Omid / Robert, Caroline / Hodi, F Stephen / Schachter, Jacob / Pavlick, Anna C / Lewis, Karl D / Cranmer, Lee D / Blank, Christian U / O'Day, Steven J / Ascierto, Paolo A / Salama, April K S / Margolin, Kim A / Loquai, Carmen / Eigentler, Thomas K / Gangadhar, Tara C / Carlino, Matteo S / Agarwala, Sanjiv S / Moschos, Stergios J / Sosman, Jeffrey A / Goldinger, Simone M / Shapira-Frommer, Ronnie / Gonzalez, Rene / Kirkwood, John M / Wolchok, Jedd D / Eggermont, Alexander / Li, Xiaoyun Nicole / Zhou, Wei / Zernhelt, Adriane M / Lis, Joy / Ebbinghaus, Scot / Kang, S Peter / Daud, Adil. ·University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: aribas@mednet.ucla.edu. · Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. · University of Zürich, Zürich, Switzerland. · University Hospital Essen, Essen, Germany. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Gustave Roussy and Paris-Sud University, Villejuif, France. · Dana-Farber Cancer Institute, Boston, MA, USA. · Sheba Medical Center, Tel Hashomer, Israel. · New York University Cancer Institute, New York, NY, USA. · University of Colorado Denver, Aurora, CO, USA. · University of Arizona Cancer Center, Tucson, AZ, USA. · Netherlands Cancer Institute, Amsterdam, Netherlands. · Beverly Hills Cancer Center, Beverly Hills, CA, USA. · Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, Italy. · Duke Cancer Institute, Durham, NC, USA. · Seattle Cancer Care Alliance/University of Washington, Seattle, WA, USA. · University Medical Center, Mainz, Germany. · Universitätsklinikum Tübingen, Tübingen, Germany. · Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA. · Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, and Melanoma Institute Australia, Westmead, NSW, Australia. · St Luke's Cancer Center, Bethlehem, PA, USA; Temple University, Philadelphia, PA, USA. · University of North Carolina, Chapel Hill, NC, USA. · University of Pittsburgh, Pittsburgh, PA, USA. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Merck & Co, Kenilworth, NJ, USA. · University of California, San Francisco, San Francisco, CA, USA. ·Lancet Oncol · Pubmed #26115796.

ABSTRACT: BACKGROUND: Patients with melanoma that progresses on ipilimumab and, if BRAF(V600) mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma. METHODS: We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF(V600) mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0-1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAF(V600) mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients. FINDINGS: Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45-0·73; p<0·0001) and those assigned to pembrolizumab 10 mg/kg (0·50, 0·39-0·64; p<0·0001) compared with those assigned to chemotherapy. 6-month progression-free survival was 34% (95% CI 27-41) in the pembrolizumab 2 mg/kg group, 38% (31-45) in the 10 mg/kg group, and 16% (10-22) in the chemotherapy group. Treatment-related grade 3-4 adverse events occurred in 20 (11%) patients in the pembrolizumab 2 mg/kg group, 25 (14%) in the pembrolizumab 10 mg/kg group, and 45 (26%) in the chemotherapy group. The most common treatment-related grade 3-4 adverse event in the pembrolizumab groups was fatigue (two [1%] of 178 patients in the 2 mg/kg group and one [<1%] of 179 patients in the 10 mg/kg group, compared with eight [5%] of 171 in the chemotherapy group). Other treatment-related grade 3-4 adverse events include generalised oedema and myalgia (each in two [1%] patients) in those given pembrolizumab 2 mg/kg; hypopituitarism, colitis, diarrhoea, decreased appetite, hyponatremia, and pneumonitis (each in two [1%]) in those given pembrolizumab 10 mg/kg; and anaemia (nine [5%]), fatigue (eight [5%]), neutropenia (six [4%]), and leucopenia (six [4%]) in those assigned to chemotherapy. INTERPRETATION: These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma. FUNDING: Merck Sharp & Dohme.

11 Clinical Trial Targeted next generation sequencing identifies clinically actionable mutations in patients with melanoma. 2014

Jeck, William R / Parker, Joel / Carson, Craig C / Shields, Janiel M / Sambade, Maria J / Peters, Eldon C / Burd, Christin E / Thomas, Nancy E / Chiang, Derek Y / Liu, Wenjin / Eberhard, David A / Ollila, David / Grilley-Olson, Juneko / Moschos, Stergios / Neil Hayes, D / Sharpless, Norman E. ·Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC, USA. ·Pigment Cell Melanoma Res · Pubmed #24628946.

ABSTRACT: Somatic sequencing of cancers has produced new insight into tumorigenesis, tumor heterogeneity, and disease progression, but the vast majority of genetic events identified are of indeterminate clinical significance. Here, we describe a NextGen sequencing approach to fully analyzing 248 genes, including all those of known clinical significance in melanoma. This strategy features solution capture of DNA followed by multiplexed, high-throughput sequencing and was evaluated in 31 melanoma cell lines and 18 tumor tissues from patients with metastatic melanoma. Mutations in melanoma cell lines correlated with their sensitivity to corresponding small molecule inhibitors, confirming, for example, lapatinib sensitivity in ERBB4 mutant lines and identifying a novel activating mutation of BRAF. The latter event would not have been identified by clinical sequencing and was associated with responsiveness to a BRAF kinase inhibitor. This approach identified focal copy number changes of PTEN not found by standard methods, such as comparative genomic hybridization (CGH). Actionable mutations were found in 89% of the tumor tissues analyzed, 56% of which would not be identified by standard-of-care approaches. This work shows that targeted sequencing is an attractive approach for clinical use in melanoma.

12 Clinical Trial PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8⁺ T cells induced by melanoma vaccines. 2014

Fourcade, Julien / Sun, Zhaojun / Pagliano, Ornella / Chauvin, Joe-Marc / Sander, Cindy / Janjic, Bratislav / Tarhini, Ahmad A / Tawbi, Hussein A / Kirkwood, John M / Moschos, Stergios / Wang, Hong / Guillaume, Philippe / Luescher, Immanuel F / Krieg, Arthur / Anderson, Ana C / Kuchroo, Vijay K / Zarour, Hassane M. ·Authors' Affiliations: Division of Hematology/Oncology, Department of Medicine; Departments of Immunology and Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Pfizer, Cambridge; and Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland. ·Cancer Res · Pubmed #24343228.

ABSTRACT: Although melanoma vaccines stimulate tumor antigen-specific CD8(+) T cells, objective clinical responses are rarely observed. To investigate this discrepancy, we evaluated the character of vaccine-induced CD8(+) T cells with regard to the inhibitory T-cell coreceptors PD-1 and Tim-3 in patients with metastatic melanoma who were administered tumor vaccines. The vaccines included incomplete Freund's adjuvant, CpG oligodeoxynucleotide (CpG), and the HLA-A2-restricted analog peptide NY-ESO-1 157-165V, either by itself or in combination with the pan-DR epitope NY-ESO-1 119-143. Both vaccines stimulated rapid tumor antigen-specific CD8(+) T-cell responses detected ex vivo, however, tumor antigen-specific CD8(+) T cells produced more IFN-γ and exhibited higher lytic function upon immunization with MHC class I and class II epitopes. Notably, the vast majority of vaccine-induced CD8(+) T cells upregulated PD-1 and a minority also upregulated Tim-3. Levels of PD-1 and Tim-3 expression by vaccine-induced CD8(+) T cells at the time of vaccine administration correlated inversely with their expansion in vivo. Dual blockade of PD-1 and Tim-3 enhanced the expansion and cytokine production of vaccine-induced CD8(+) T cells in vitro. Collectively, our findings support the use of PD-1 and Tim-3 blockades with cancer vaccines to stimulate potent antitumor T-cell responses and increase the likelihood of clinical responses in patients with advanced melanoma.

13 Clinical Trial Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. 2013

Trunzer, Kerstin / Pavlick, Anna C / Schuchter, Lynn / Gonzalez, Rene / McArthur, Grant A / Hutson, Thomas E / Moschos, Stergios J / Flaherty, Keith T / Kim, Kevin B / Weber, Jeffrey S / Hersey, Peter / Long, Georgina V / Lawrence, Donald / Ott, Patrick A / Amaravadi, Ravi K / Lewis, Karl D / Puzanov, Igor / Lo, Roger S / Koehler, Astrid / Kockx, Mark / Spleiss, Olivia / Schell-Steven, Annette / Gilbert, Houston N / Cockey, Louise / Bollag, Gideon / Lee, Richard J / Joe, Andrew K / Sosman, Jeffrey A / Ribas, Antoni. ·Vanderbilt-Ingram Cancer Center, 777 Preston Research Building, Nashville, TN 37232-6307, USA. jeff.sosman@vanderbilt.edu ·J Clin Oncol · Pubmed #23569304.

ABSTRACT: PURPOSE To assess pharmacodynamic effects and intrinsic and acquired resistance mechanisms of the BRAF inhibitor vemurafenib in BRAF(V600)-mutant melanoma, leading to an understanding of the mechanism of action of vemurafenib and ultimately to optimization of metastatic melanoma therapy. METHODS In the phase II clinical study NP22657 (BRIM-2), patients received oral doses of vemurafenib (960 mg twice per day). Serial biopsies were collected to study changes in mitogen-activated protein kinase (MAPK) signaling, cell-cycle progression, and factors causing intrinsic or acquired resistance by immunohistochemistry, DNA sequencing, or somatic mutation profiling. Results Vemurafenib inhibited MAPK signaling and cell-cycle progression. An association between the decrease in extracellular signal-related kinase (ERK) phosphorylation and objective response was observed in paired biopsies (n = 22; P = .013). Low expression of phosphatase and tensin homolog showed a modest association with lower response. Baseline mutations in MEK1(P124) coexisting with BRAF(V600) were noted in seven of 92 samples; their presence did not preclude objective tumor responses. Acquired resistance to vemurafenib associated with reactivation of MAPK signaling as observed by elevated ERK1/2 phosphorylation levels in progressive lesions and the appearance of secondary NRAS(Q61) mutations or MEK1(Q56P) or MEK1(E203K) mutations. These two activating MEK1 mutations had not previously been observed in vivo in biopsies of progressive melanoma tumors. CONCLUSION Vemurafenib inhibits tumor proliferation and oncogenic BRAF signaling through the MAPK pathway. Acquired resistance results primarily from MAPK reactivation driven by the appearance of secondary mutations in NRAS and MEK1 in subsets of patients. The data suggest that inhibition downstream of BRAF should help to overcome acquired resistance.

14 Clinical Trial Safety and efficacy of decitabine in combination with temozolomide in metastatic melanoma: a phase I/II study and pharmacokinetic analysis. 2013

Tawbi, H A / Beumer, J H / Tarhini, A A / Moschos, S / Buch, S C / Egorin, M J / Lin, Y / Christner, S / Kirkwood, J M. ·Department of Medicine/Division of Hematology/Oncology, School of Medicine, University of Pittsburgh, Pittsburgh 15232, USA. tawbih@upmc.edu ·Ann Oncol · Pubmed #23172636.

ABSTRACT: BACKGROUND: Temozolomide (TMZ) is widely used for chemotherapy of metastatic melanoma. We hypothesized that epigenetic modulators will reverse chemotherapy resistance, and in this article, we report studies that sought to determine the recommended phase 2 dose (RP2D), safety, and efficacy of decitabine (DAC) combined with TMZ. PATIENTS AND METHODS: In phase I, DAC was given at two dose levels: 0.075 and 0.15 mg/kg intravenously daily × 5 days/week for 2 weeks, TMZ orally 75 mg/m(2) qd for weeks 2-5 of a 6-week cycle. The phase II portion used a two-stage Simon design with a primary end point of objective response rate (ORR). RESULTS: The RP2D is DAC 0.15 mg/kg and TMZ 75 mg/m(2). The phase II portion enrolled 35 patients, 88% had M1c disease; 42% had history of brain metastases. The best responses were 2 complete response (CR), 4 partial response (PR), 14 stable disease (SD), and 13 progressive disease (PD); 18% ORR and 61% clinical benefit rate (CR + PR + SD). The median overall survival (OS) was 12.4 months; the 1-year OS rate was 56%. Grade 3/4 neutropenia was common but lasted >7 days in six patients. CONCLUSIONS: The combination of DAC and TMZ is safe, leads to 18% ORR and 12.4-month median OS, suggesting possible superiority over the historical 1-year OS rate, and warrants further evaluation in a randomized setting.

15 Clinical Trial Safety and immunogenicity of vaccination with MART-1 (26-35, 27L), gp100 (209-217, 210M), and tyrosinase (368-376, 370D) in adjuvant with PF-3512676 and GM-CSF in metastatic melanoma. 2012

Tarhini, Ahmad A / Leng, Siyang / Moschos, Stergios J / Yin, Yan / Sander, Cindy / Lin, Yan / Gooding, William E / Kirkwood, John M. ·Department of Medicine, Division of Hematology and Oncology, University of Pittsburgh, Pittsburgh, PA 15232, USA. tarhiniaa@upmc.edu ·J Immunother · Pubmed #22495394.

ABSTRACT: The effectivenes of cancer vaccines in inducing CD8(+) T-cell responses remains a challenge, resulting in a need for testing more potent adjuvants. Our objective was to determine the safety and immunogenicity of vaccination against melanoma-related antigens employing MART-1, gp100, and tysosinase paptides combined with the TLR9 agonist PF-3512676 and local granulocyte macrophage-colony stimulating factor in oil emulsion. Using continuous monitoring of safety and a 2-stage design for immunologic efficacy, 20 immune response evaluable patients were targetted. Vaccinations were given subcutaneously on days 1 and 15 per cycle (1cycle=28 d) for up to 13 cycles. Interferon-γ enzyme-linked immunosorbent spot was used as the primary assay measuring the frequency of peripheral antigen-specific CD8(+) T cells at days 50 and 90 compared with baseline (target ≥ 9/20 immunologic responses). Clinical responses were measured by Response Evaluation Criteria In Solid Tumors every 8 weeks. Twenty-two (including 20 immune response evaluable) melanoma patients were enrolled. All had American Joint Committe on Cancer stage IV (5M1a, 6M1b, 11M1c) and most had previously received therapy. Eight had previously treated brain metastases. An average of 3.5 cycles of vaccination per patient was administered. Clinical response data were available for 21 patients. There were 2 partial response and 8 stable disease lasting 2-7 months. One patient with ongoing partial response continued on treatment. At a median follow-up of 7.39 months (range, 3.22-20.47 mo), median progression-free survival was 1.9 months (90% confidence interval, 1.84-3.68) and median overall survival was 13.4 months (90% confidence interval,11.3-∞). No regimen-related grade 3/4/5 toxicities were observed. There were 9/20 patients with positive enzyme-linked immunosorbent spot at day 50 and/or day 90. Our adjuvant regimen combining PF-3512676 and granulocyte macrophage-colony stimulating factor was safe and is worthy of further testing with these or alternative peptides, potentially in combination with antibodies that target immunoregulatory checkpoints.

16 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.).

17 Clinical Trial Safety and efficacy of combination immunotherapy with interferon alfa-2b and tremelimumab in patients with stage IV melanoma. 2012

Tarhini, Ahmad A / Cherian, John / Moschos, Stergios J / Tawbi, Hussein A / Shuai, Yongli / Gooding, William E / Sander, Cindy / Kirkwood, John M. ·University of Pittsburgh Cancer Institute, University of Pittsburgh Medical Center Cancer Pavilion, 5150 Centre Ave, Fifth Fl, Pittsburgh, PA 15232, USA. tarhiniaa@upmc.edu ·J Clin Oncol · Pubmed #22184371.

ABSTRACT: PURPOSE: We tested the hypothesis that the combination of tremelimumab and interferon alfa-2b acting via different and possibly synergistic mechanisms would overcome tumor immune tolerance and lead to significant and durable clinical responses. PATIENTS AND METHODS: We conducted a phase II study in which patients were administered tremelimumab 15 mg/kg/course (three cycles [one cycle = 4 weeks]) intravenously every 12 weeks. High-dose interferon alfa-2b (HDI) was administered concurrently, including intravenous induction at 20 MU/m2/d for 5 d/wk for 4 weeks followed by maintenance at 10 MU/m2/d subcutaneously three times a week for 8 weeks per course. From course 2 onward, HDI maintenance was administered subcutaneously. RESULTS: Thirty-seven patients with American Joint Committee on Cancer stage IV (9M1a, 6M1b, and 22M1c) were enrolled. Two patients had previously treated brain metastases. Grades 3 and 4 toxicities included neutropenia (six patients; 17%), diarrhea/colitis (four patients; 11%), liver enzyme increase (four patients; 11%), rash (four patients; 11%), fatigue (15 patients; 40%), and anxiety/depression (five patients; 14%). Response data were available for 35 patients. The best objective response rate (RR; Response Evaluation Criteria in Solid Tumors) by intention to treat was 24% (90% CI, 13% to 36%; four complete responses [CRs] and five partial responses [PRs] that lasted 6, 6, > 12, > 14, > 18, 20, > 28, 30, and > 37 months, respectively). Fourteen patients (38%) had stable disease (SD) that lasted 1.5 to 21 months. The median progression-free survival was 6.4 months (95% CI, 3.3 to 12.1 months). The median overall survival (OS) was 21 months (95% CI, 9.5 to not reached). There was a weak association between therapy-induced autoimmunity and clinical benefits (CR/PR/SD; P = .0059), baseline C-reactive protein (CRP) less than or equal to 2.7× the upper limit of normal and clinical benefits (P = .0494) and improved probability of survival (P = .0032), and baseline lymphocyte count of at least 1,000/μL and response (CR/PR; P = .0183) and clinical benefits (CR/PR/SD; P = .0255). Biomarker associations were not significant after adjustment for multiple comparisons. CONCLUSION: HDI can be administered combined with tremelimumab with acceptable toxicity and promising durable antitumor efficacy that warrant further testing in a randomized trial.

18 Clinical Trial Inhibition of DNA repair with MGMT pseudosubstrates: phase I study of lomeguatrib in combination with dacarbazine in patients with advanced melanoma and other solid tumours. 2011

Tawbi, H A / Villaruz, L / Tarhini, A / Moschos, S / Sulecki, M / Viverette, F / Shipe-Spotloe, J / Radkowski, R / Kirkwood, J M. ·Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. tawbih@upmc.edu ·Br J Cancer · Pubmed #21811257.

ABSTRACT: BACKGROUND: The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) reverses the O6-methylguanine (O6-meG) lesion induced by dacarbazine. Depletion of MGMT can be achieved using O6-meG pseudosubstrates. Herein, we report the first phase I experience of the novel O6-meG pseudosubstrate lomeguatrib, combined with dacarbazine. METHODS: This is a phase I dose-escalation study to determine the maximum tolerated dose and recommended phase II dose (RP2D) of lomeguatrib combined with a single dose of dacarbazine on a 21-day schedule. RESULTS: The vast majority of the 41 patients enrolled had metastatic melanoma (36/41) and most had no previous chemotherapy (30/41). The most frequent non-hematological adverse events (AEs) were nausea (52%), and fatigue (42%). The most frequent AEs of grade 3-4 severity were neutropaenia (42%), leukopaenia (17%), and thrombocytopaenia (12%). Only 1 patient had a partial response and 10 patients had stable disease. CONCLUSION: The RP2D of lomeguatrib was 40 mg orally twice daily for 10 days combined with 400 mg m(-2) of dacarbazine IV on day 2. Oral administration of lomeguatrib substantially increases the haematological toxicity of dacarbazine consistent with experience with other O6-meG pseudosubstrates.

19 Clinical Trial Pharmacodynamic (phase 0) study using etaracizumab in advanced melanoma. 2010

Moschos, Stergios J / Sander, Cindy A / Wang, Wenjun / Reppert, Shelley L / Drogowski, Laura M / Jukic, Drazen M / Rao, Uma N M / Athanassiou, Charalambos / Buzoianu, Manuela / Mandic, Maja / Richman, Laura / McKinney, LuAnn / Leininger, Joel / Tice, David A / Hammershaimb, Luz / Kirkwood, John M. ·University of Pittsburgh Cancer Institute, PA, USA. ·J Immunother · Pubmed #20445352.

ABSTRACT: AlphaVbeta3 (alphavbeta3) is an important molecule for tumor-induced angiogenesis and is upregulated in metastatic melanoma (MM). We proposed to study the mechanism of action of etaracizumab, a monoclonal antibody targeting alphavbeta3, in MM. Patients with MM and biopsiable tumor were treated with etaracizumab in 3 dose cohorts starting from 8 mg/kg. Tumor saturation by etaracizumab using LM609 immunohistochemical staining of tumor sections was the primary endpoint. Subsequent dose cohorts were defined based on the tumor saturation by etaracizumab. Secondary end points were analysis of clinical benefit and changes from baseline of several tumor and peripheral blood biomarkers. Eighteen patients were enrolled at 3 dose levels. Etaracizumab showed better melanoma cell saturation at the 8mg/kg and 1 mg/kg dose compared with the 4 mg/kg dose and better vascular endothelial cell saturation at 8 mg/kg compared with lower dose groups. Etaracizumab demonstrated an acceptable safety profile. The optimal biologic dose out of those selected for investigation was 8 mg/kg. Patients treated at the highest dose may have had better clinical benefit secondary to suppression of the activated immediate downstream effector of alphavbeta3 signaling, FAK, in melanoma cells, but this alone did not ultimately affect melanoma cell proliferation or apoptosis. No apparent antiangiogenic or immunomodulatory effects of etaracizumab were noted.

20 Clinical Trial Immunogenicity and antitumor effects of vaccination with peptide vaccine+/-granulocyte-monocyte colony-stimulating factor and/or IFN-alpha2b in advanced metastatic melanoma: Eastern Cooperative Oncology Group Phase II Trial E1696. 2009

Kirkwood, John M / Lee, Sandra / Moschos, Stergios J / Albertini, Mark R / Michalak, John C / Sander, Cindy / Whiteside, Theresa / Butterfield, Lisa H / Weiner, Louis. ·Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213-2584, USA. KirkwoodJM@upmc.edu ·Clin Cancer Res · Pubmed #19228745.

ABSTRACT: PURPOSE: No therapy has ever shown prolongation of survival in stage IV metastatic melanoma. The association of cytokine-induced autoimmunity with improved prognosis led us to investigate the effect of multi-epitope melanoma vaccines alone and in combination with cytokines in this Eastern Cooperative Oncology Group multicenter phase II trial. EXPERIMENTAL DESIGN: Eligible patients were required to have failed prior therapies and to be HLA-A2 positive. Three HLA class I-restricted lineage antigen epitopes were administered in a factorial 2x2 design. Peptide vaccine alone (arm A), or combined with granulocyte-monocyte colony-stimulating factor (GM-CSF; Immunex) 250 microg/d subcutaneously for 14 of 28 days each month (arm B), or combined with IFN-alpha2b (Intron A; Schering-Plough) 10 million units/m2 three times a week (arm C), or combined with both IFN-alpha2b and GM-CSF (arm D). The primary endpoint was immune response measured by enzyme-linked immunospot assay; secondary endpoints were clinical antitumor response, disease-free survival, and overall survival. RESULTS: One hundred twenty patients enrolled and 115 patients were analyzed. Immune responses to at least one melanoma antigen were observed in 26 of 75 (35%) patients with serial samples. Neither IFN-alpha2b nor GM-CSF significantly improved immune responses. Six objective clinical responses were documented. At a median follow-up of 25.4 months, the median overall survival of patients with vaccine immune response was significantly longer than that of patients with no immune response (21.3 versus 13.4 months; P=0.046). CONCLUSION: Immune response to vaccination correlates with prolonged survival in patients with metastatic melanoma and is not enhanced by immunomodulatory cytokines as tested in this trial.

21 Clinical Trial A phase 2 trial of sequential temozolomide chemotherapy followed by high-dose interleukin 2 immunotherapy for metastatic melanoma. 2008

Tarhini, Ahmad A / Kirkwood, John M / Gooding, William E / Moschos, Stergios / Agarwala, Sanjiv S. ·Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. ·Cancer · Pubmed #18720480.

ABSTRACT: BACKGROUND: Previous biochemotherapy regimens for metastatic melanoma have required attenuated dosages of interleukin 2 (IL-2) that may have compromised efficacy. METHODS: In a phase 2 study, the authors tested sequential temozolomide (75 mg/m2 per day orally for 3 weeks) followed by high-dose, IL-2 (600,000 U/kg per dose intravenously; maximum, 14 doses over 5 days). RESULTS: Thirty-eight patients with treatment-naive American Joint Committee on Cancer stage IV melanoma (8 patients with M1a disease, 6 patients with M1b disease, and 24 patients with M1c disease) were enrolled. Ten patients had a history of treated brain metastases. Thirty-one patients who received at least 2 cycles of IL-2 were evaluable for response. Grade 3 toxicities included hyperbilirubinemia (9 patients), hematologic toxicities (leukopenia in 5 patients, thrombocytopenia in 3 patients), diarrhea (2 patients), and oliguria (1 patient). One patient had grade 4 nausea. The overall response rate (ORR) was 16% and included 3 complete responses that lasted 10.8 months, > or =32 months, and > or =36 months and 2 partial responses that lasted 13 months and 14 months. Responses were observed in patients with M1a disease and in patients with M1c disease. Sixteen patients had stable disease (15 patients progressed). The median progression-free survival (PFS) was 5.3 months (95% confidence interval [CI], 3.7-7.5 months). The probability of PFS at 6 months was 0.52 (95% CI, 0.33-0.67). Among 38 enrolled patients, 16 patients remained alive at a median follow-up of 6.7 months (range, 1.9-36.1 months). The median overall survival (OS) was 12.1 months (95% CI, 9.1-16.4 months), and the probability of 12-month OS was 0.54 (95% CI, 0.34-0.70 months). CONCLUSIONS: The current results indicated that it is safe to administer HD IL-2 sequentially with temozolomide and that this combination has lower toxicity than previously used concurrent biochemotherapy regimens. However, The ORR and the durability of responses with this combination did not exceed those of single-agent HD IL-2.

22 Article The incidence of radiation necrosis following stereotactic radiotherapy for melanoma brain metastases: the potential impact of immunotherapy. 2017

Kaidar-Person, Orit / Zagar, Timothy M / Deal, Allison / Moschos, Stergios J / Ewend, Matthew G / Sasaki-Adams, Deanna / Lee, Carrie B / Collichio, Frances A / Fried, David / Marks, Lawrence B / Chera, Bhishamjit S. ·aUNC Lineberger Comprehensive Cancer Center Departments of bRadiation Oncology cMedicine dNeurosurgery, University of North Carolina, Chapel Hill, North Carolina, USA. ·Anticancer Drugs · Pubmed #28368903.

ABSTRACT: Stereotactic radiotherapy (SRT) is the standard treatment for patients with limited number of brain metastases. In the past few years, newer immunotherapies (immune checkpoint inhibitors) have been proven to prolong survival in patients with metastatic melanoma. The safety of the combination of SRT and immunotherapy for brain metastases is unknown. We retrospectively identified patients with melanoma brain metastases treated with SRT between 2007 and 2015. Patients who did not have at least 3 months of follow-up with imaging after SRT were excluded from the analysis. Outcomes were compared between patients who were treated with or without immunotherapy. A total of 58 patients were included; of these, 29 were treated with SRT and immunotherapy. MAPK inhibitors (BRAF, MEK inhibitors) were used more often in the immunotherapy group (nine vs. two patients). There was a higher incidence of intracranial complications in patients treated with immunotherapy and SRT. Eight patients had radiation necrosis; all occurred in patients who were treated with immunotherapy. Nine patients had hemorrhage, of which seven occurred in patients who were treated with immunotherapy (P=0.08). However, patients treated with immunotherapy and SRT had a significant overall survival advantage compared with SRT without immunotherapy (15 vs. 6 months, P=0.0013). Patients treated with SRT and immunotherapy have a higher incidence/risk of intracranial complications, but a longer overall survival.

23 Article Use of Susceptibility-Weighted Imaging (SWI) in the Detection of Brain Hemorrhagic Metastases from Breast Cancer and Melanoma. 2016

Franceschi, Ana Marija / Moschos, Stergios J / Anders, Carey K / Glaubiger, Samuel / Collichio, Frances A / Lee, Carrie B / Castillo, Mauricio / Lee, Yueh Z. ·From the *Department of Radiology, New York University Medical Center, New York, NY; and †Division of Hematology and Oncology, Department of Medicine, UNC at Chapel Hill, Chapel Hill, NC; ‡Neuroradiology Section, Department of Radiology, The University of North Carolina School of Medicine, Chapel Hill, NC. ·J Comput Assist Tomogr · Pubmed #27636126.

ABSTRACT: PURPOSE: Susceptibility-weighted imaging (SWI) has significantly increased our sensitivity in detecting hemorrhagic brain lesions. We sought to explore the prevalence of intratumoral hemorrhage as detected by SWI in brain metastases from melanoma and breast cancer. METHODS: Lesions with a size of 0.1 cm were categorized as micrometastases, whereas larger lesions were categorized as macrometastases. Susceptibility-weighted imaging findings on locations corresponding to enhancing lesions were categorized as either positive or negative based on presence/absence of signal dropout. The percentage of SWI positivity was then estimated as a function of lesion size. Two-tailed Fisher exact test was performed to examine differences in the contingency tables. RESULTS: Magnetic resonance imaging studies from 73 patients with 1173 brain metastases, which enhanced on postcontrast T1-weighted imaging (T1WI) were selected for analysis. Of these lesions, 952 had SWI data available, and 342 of 952 were micrometastases. Only 10 of the 342 micrometastases and 410 (67.2%) of the 610 macrometastases were SWI positive (P < 0.0001). When examined by tumor type, 76.9% (melanoma) versus 55.6% (breast cancer) were SWI positive (P < 0.0001), regardless of tumor size. All melanoma lesions (8/8) and only 1 of 15 breast cancer lesions larger than 1.5 cm were SWI positive. CONCLUSION: With the use of combined SWI and contrast-enhanced high-resolution T1 imaging, we found that presence of intratumoral brain hemorrhage is uncommon in micrometastases but common in metastases greater than 0.1 cm from breast cancer or melanoma. Large metastases commonly harbored hemorrhage, and this occurred more frequently in patients with melanoma than with breast cancer.

24 Article IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma. 2015

Carson, Craig C / Moschos, Stergios J / Edmiston, Sharon N / Darr, David B / Nikolaishvili-Feinberg, Nana / Groben, Pamela A / Zhou, Xin / Kuan, Pei Fen / Pandey, Shaily / Chan, Keefe T / Jordan, Jamie L / Hao, Honglin / Frank, Jill S / Hopkinson, Dennis A / Gibbs, David C / Alldredge, Virginia D / Parrish, Eloise / Hanna, Sara C / Berkowitz, Paula / Rubenstein, David S / Miller, C Ryan / Bear, James E / Ollila, David W / Sharpless, Norman E / Conway, Kathleen / Thomas, Nancy E. ·Department of Dermatology, The University of North Carolina, Chapel Hill, North Carolina. · Department of Medicine, The University of North Carolina, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. · Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. · Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, North Carolina. · Department of Biostatistics, The University of North Carolina, Chapel Hill, North Carolina. · Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Biostatistics, The University of North Carolina, Chapel Hill, North Carolina. · Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina. · Department of Surgery, The University of North Carolina, Chapel Hill, North Carolina. · Department of Dermatology, The University of North Carolina, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. · Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, North Carolina. Department of Neurology, The University of North Carolina, Chapel Hill, North Carolina. Neuroscience Center, The University of North Carolina, Chapel Hill, North Carolina. · Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Surgery, The University of North Carolina, Chapel Hill, North Carolina. · Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Epidemiology, The University of North Carolina, Chapel Hill, North Carolina. · Department of Dermatology, The University of North Carolina, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. nthomas@med.unc.edu. ·Clin Cancer Res · Pubmed #25934889.

ABSTRACT: PURPOSE: IL2 inducible T-cell kinase (ITK) promoter CpG sites are hypomethylated in melanomas compared with nevi. The expression of ITK in melanomas, however, has not been established and requires elucidation. EXPERIMENTAL DESIGN: An ITK-specific monoclonal antibody was used to probe sections from deidentified, formalin-fixed paraffin-embedded tumor blocks or cell line arrays and ITK was visualized by IHC. Levels of ITK protein differed among melanoma cell lines and representative lines were transduced with four different lentiviral constructs that each contained an shRNA designed to knockdown ITK mRNA levels. The effects of the selective ITK inhibitor BI 10N on cell lines and mouse models were also determined. RESULTS: ITK protein expression increased with nevus to metastatic melanoma progression. In melanoma cell lines, genetic or pharmacologic inhibition of ITK decreased proliferation and migration and increased the percentage of cells in the G0-G1 phase. Treatment of melanoma-bearing mice with BI 10N reduced growth of ITK-expressing xenografts or established autochthonous (Tyr-Cre/Pten(null)/Braf(V600E)) melanomas. CONCLUSIONS: We conclude that ITK, formerly considered an immune cell-specific protein, is aberrantly expressed in melanoma and promotes tumor development and progression. Our finding that ITK is aberrantly expressed in most metastatic melanomas suggests that inhibitors of ITK may be efficacious for melanoma treatment. The efficacy of a small-molecule ITK inhibitor in the Tyr-Cre/Pten(null)/Braf(V600E) mouse melanoma model supports this possibility.

25 Article DNA methylation profiles in primary cutaneous melanomas are associated with clinically significant pathologic features. 2014

Thomas, Nancy E / Slater, Nathaniel A / Edmiston, Sharon N / Zhou, Xin / Kuan, Pei-Fen / Groben, Pamela A / Carson, Craig C / Hao, Honglin / Parrish, Eloise / Moschos, Stergios J / Berwick, Marianne / Ollila, David W / Conway, Kathleen. ·Department of Dermatology, University of North Carolina, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. ·Pigment Cell Melanoma Res · Pubmed #24986547.

ABSTRACT: DNA methylation studies have elucidated a methylation signature distinguishing primary melanomas from benign nevi and provided new insights about genes that may be important in melanoma development. However, it is unclear whether methylation differences among primary melanomas are related to tumor pathologic features with known clinical significance. We utilized the Illumina GoldenGate Cancer Panel array to investigate the methylation profiles of 47 primary cutaneous melanomas. Arraywide methylation patterns revealed a positive association of methylation with Breslow thickness and mutated BRAF, a negative association with mitotic rate, and a weak association with ulceration. Hierarchical clustering on CpG sites exhibiting the most variable methylation (n = 235) divided the melanoma samples into three clusters, including a highly methylated cluster that was positively associated with Breslow thickness and an intermediately methylated cluster associated with Breslow thickness and mitotic rate. Our findings provide support for the existence of methylation-defined subsets in melanomas with increased methylation associated with Breslow thickness.

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