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Melanoma: HELP
Articles by Marc S. Ernstoff
Based on 36 articles published since 2010
(Why 36 articles?)
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Between 2010 and 2020, M. Ernstoff wrote the following 36 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline An update on the Society for Immunotherapy of Cancer consensus statement on tumor immunotherapy for the treatment of cutaneous melanoma: version 2.0. 2018

Sullivan, Ryan J / Atkins, Michael B / Kirkwood, John M / Agarwala, Sanjiv S / Clark, Joseph I / Ernstoff, Marc S / Fecher, Leslie / Gajewski, Thomas F / Gastman, Brian / Lawson, David H / Lutzky, Jose / McDermott, David F / Margolin, Kim A / Mehnert, Janice M / Pavlick, Anna C / Richards, Jon M / Rubin, Krista M / Sharfman, William / Silverstein, Steven / Slingluff, Craig L / Sondak, Vernon K / Tarhini, Ahmad A / Thompson, John A / Urba, Walter J / White, Richard L / Whitman, Eric D / Hodi, F Stephen / Kaufman, Howard L. ·Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. · Georgetown University, Washington, DC, 20057, USA. · University of Pittsburgh, Pittsburgh, PA, 15213, USA. · St. Luke's Cancer Center and Temple University, Center Valley, PA, 18034, USA. · Loyola University Medical Center, Maywood, IL, 60153, USA. · Roswell Park Cancer Institute, Buffalo, NY, 14263, USA. · University of Michigan, Ann Arbor, MI, 48109, USA. · University of Chicago Medical Center, Chicago, IL, 60637, USA. · Cleveland Clinic, Cleveland, OH, 44195, USA. · Emory Winship Cancer Institute, Atlanta, GA, 30322, USA. · Mt. Sinai Medical Center, Miami Beach, FL, 33140, USA. · Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. · City of Hope, Duarte, CA, 91010, USA. · Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA. · New York University Cancer Institute, New York, NY, 10016, USA. · Lutheran General Hospital, Park Ridge, IL, 60068, USA. · The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 21231, USA. · Melanoma Research Foundation, Woodcliff Lake, NJ, 07077, USA. · University of Virginia, Charlottesville, VA, 22908, USA. · H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA. · Cleveland Clinic Taussig Cancer Center, Cleveland, OH, 44195, USA. · Seattle Cancer Care Alliance, Seattle, WA, 98109, USA. · Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, 97213, USA. · Carolinas Medical Center, Charlotte, NC, 28204, USA. · Carol G. Simon Cancer Center, Morristown, NJ, 07046, USA. · Dana-Farber Cancer Institute, Boston, MA, 02215, USA. · Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. howardkaufman6@gmail.com. ·J Immunother Cancer · Pubmed #29848375.

ABSTRACT: BACKGROUND: Cancer immunotherapy has been firmly established as a standard of care for patients with advanced and metastatic melanoma. Therapeutic outcomes in clinical trials have resulted in the approval of 11 new drugs and/or combination regimens for patients with melanoma. However, prospective data to support evidence-based clinical decisions with respect to the optimal schedule and sequencing of immunotherapy and targeted agents, how best to manage emerging toxicities and when to stop treatment are not yet available. METHODS: To address this knowledge gap, the Society for Immunotherapy of Cancer (SITC) Melanoma Task Force developed a process for consensus recommendations for physicians treating patients with melanoma integrating evidence-based data, where available, with best expert consensus opinion. The initial consensus statement was published in 2013, and version 2.0 of this report is an update based on a recent meeting of the Task Force and extensive subsequent discussions on new agents, contemporary peer-reviewed literature and emerging clinical data. The Academy of Medicine (formerly Institute of Medicine) clinical practice guidelines were used as a basis for consensus development with an updated literature search for important studies published between 1992 and 2017 and supplemented, as appropriate, by recommendations from Task Force participants. RESULTS: The Task Force considered patients with stage II-IV melanoma and here provide consensus recommendations for how they would incorporate the many immunotherapy options into clinical pathways for patients with cutaneous melanoma. CONCLUSION: These clinical guidleines provide physicians and healthcare providers with consensus recommendations for managing melanoma patients electing treatment with tumor immunotherapy.

2 Guideline Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. 2016

Coit, Daniel G / Thompson, John A / Algazi, Alain / Andtbacka, Robert / Bichakjian, Christopher K / Carson, William E / Daniels, Gregory A / DiMaio, Dominick / Ernstoff, Marc / Fields, Ryan C / Fleming, Martin D / Gonzalez, Rene / Guild, Valerie / Halpern, Allan C / Hodi, F Stephen / Joseph, Richard W / Lange, Julie R / Martini, Mary C / Materin, Miguel A / Olszanski, Anthony J / Ross, Merrick I / Salama, April K / Skitzki, Joseph / Sosman, Jeff / Swetter, Susan M / Tanabe, Kenneth K / Torres-Roca, Javier F / Trisal, Vijay / Urist, Marshall M / McMillian, Nicole / Engh, Anita. · ·J Natl Compr Canc Netw · Pubmed #27059193.

ABSTRACT: This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma focuses on adjuvant therapy and treatment of in-transit disease, because substantial changes were made to the recommendations for the 2016 update. Depending on the stage of the disease, options for adjuvant therapy now include biochemotherapy and high-dose ipilimumab. Treatment options for in-transit disease now include intralesional injection with talimogene laherparepvec (T-VEC), a new immunotherapy. These additions prompted re-assessment of the data supporting older recommended treatment options for adjuvant therapy and in-transit disease, resulting in extensive revisions to the supporting discussion sections.

3 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.

4 Editorial Is pediatric melanoma always malignant? 2013

Coit, Daniel G / Ernstoff, Marc S / Busam, Klaus J. ·Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York. ·Cancer · Pubmed #24022827.

ABSTRACT: -- No abstract --

5 Editorial Been there, not done that--melanoma in the age of molecular therapy. 2011

Ernstoff, Marc S. · ·N Engl J Med · Pubmed #21639809.

ABSTRACT: -- No abstract --

6 Review Primary melanoma of the spinal cord: a case report, molecular footprint, and review of the literature. 2011

Fuld, Alexander D / Speck, Maren E / Harris, Brent T / Simmons, Nathan E / Corless, Christopher L / Tsongalis, Gregory J / Pastel, David A / Hartford, Alan C / Ernstoff, Marc S. ·Dartmouth Hitchcock Medical Center and Dartmouth Medical School, Lebanon, NH, USA. ·J Clin Oncol · Pubmed #21444862.

ABSTRACT: -- No abstract --

7 Clinical Trial Sequencing Ipilimumab Immunotherapy Before or After Chemotherapy (Nab-Paclitaxel and Bevacizumab) for the Treatment of BRAFwt (BRAF Wild-Type) Metastatic Malignant Melanoma: Results of a Study of Academic and Community Cancer Research United (ACCRU) RU261206I. 2020

Markovic, Svetomir N / Suman, Vera J / Javed, Asad / Reid, Joel M / Wall, Darci J / Erickson, Lori A / Ernstoff, Marc / Anderson, Daniel M. ·Department of Medicine, Division of Medical Oncology. · Department of Health Sciences Research, Division of Biomedical Statistics and Bioinformatics. · Department of Medicine, Division of Radiology. · Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic Rochester, Rochester. · Roswell Park Cancer Institute, Buffalo NY. · Metro Minnesota Community Oncology Research Consortium, St Louis Park, MN. ·Am J Clin Oncol · Pubmed #31809326.

ABSTRACT: OBJECTIVES: With the introduction of novel immune therapeutics for the treatment of disseminated malignancies, we sought to evaluate whether deliberate sequencing of immunotherapy before/after conventional cytotoxic chemotherapy would have an impact on clinical outcomes in patients with previously treated metastatic melanoma. We sought to evaluate whether or not ipilimumab immunotherapy administered before or after cytotoxic chemotherapy (nab-paclitaxel+bevacizumab, AB) would impact clinical outcomes. METHODS: We conducted a randomized phase 2 clinical trial of patients with BRAF wild-type metastatic melanoma (up to 2 prior therapies) who received either: (A) AB followed by ipilimumab therapy at progression; or (B) ipilimumab followed by AB treatment at progression. The primary goal of the study was a comparison of AB versus ipilimumab progression-free survival, with secondary clinical and laboratory endpoints. RESULTS: This study did not reach full accrual due to concurrent Food and Drug Administration approval of anti-programmed cell death 1 agents. Nevertheless, the available data suggests a cumulative therapeutic advantage to the sequential use of ipilimumab followed by AB. Correlative laboratory data revealed a favorable effect on systemic immune homeostasis in patients receiving AB therapy, of potential interest in further investigations, especially in the context of chemotherapy/immunotherapy combinations. CONCLUSION: Albeit limited in scope, our data suggest that cytotoxic therapy with nab-paclitaxel and bevacizumab appear to favorably alter systemic parameters of immune function of potential benefit in combination T-cell directed immune checkpoint inhibitor therapy.

8 Clinical Trial NCI 8628: A randomized phase 2 study of ziv-aflibercept and high-dose interleukin 2 or high-dose interleukin 2 alone for inoperable stage III or IV melanoma. 2018

Tarhini, Ahmad A / Frankel, Paul / Ruel, Christopher / Ernstoff, Marc S / Kuzel, Timothy M / Logan, Theodore F / Khushalani, Nikhil I / Tawbi, Hussein A / Margolin, Kim A / Awasthi, Sanjay / Butterfield, Lisa H / McDermott, David / Chen, Alice / Lara, Primo N / Kirkwood, John M. ·University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania. · Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center, Cleveland, Ohio. · City of Hope National Medical Center, Duarte, California. · Roswell Park Comprehensive Cancer Center, Buffalo, New York. · Rush University Medical Center, Chicago, Illinois. · Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana. · Moffitt Cancer Center, Tampa, Florida. · The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. · Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. · Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. · Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland. · University of California at Davis Comprehensive Cancer Center, Sacramento, California. ·Cancer · Pubmed #30303516.

ABSTRACT: BACKGROUND: Interleukin 2 (IL-2) is a growth factor for T and natural killer cells, promotes proinflammatory cytokines, and can lead to durable responses in patients with melanoma. Vascular endothelial growth factor (VEGF) promotes angiogenesis and modulates host innate and adaptive immunity. High VEGF levels were found to be associated with nonresponse to IL-2. Ziv-aflibercept may deplete VEGF and thereby enhance antitumor T-cell responses, thus supporting a combination immunotherapeutic strategy with IL-2. METHODS: NCI 8628 was a phase 2 trial of ziv-aflibercept and IL-2 (arm A) versus IL-2 alone (arm B) randomized at 2:1, respectively. Eligible patients had inoperable American Joint Committee on Cancer stage III or stage IV melanoma. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 89 patients were enrolled and 84 patients were treated. The median follow-up was 41.4 months. Among treated patients (55 patients in arm A and 29 patients in arm B), PFS was significantly improved in favor of arm A, with a median of 6.9 months (95% confidence interval [95% CI], 4.1-8.7 months) versus 2.3 months (95% CI, 1.6-3.5 months) (P<.001). No significant difference was noted with regard to overall survival, with a median of 26.9 months (95% CI, 14.4-63.6 months) for arm A and 24.2 months (95% CI, 11.3-36.4 months) for arm B. The response rate (according to Response Evaluation Criteria In Solid Tumors [RECIST]) was 22% in arm A (4 complete responses [CRs] and 8 partial responses [PRs]) and 17% in arm B (1 CR and 4 PRs). Stable disease or PR or CR was noted in 65% of patients in arm A and 48% of patients in arm B. The combination was found to be superior to monotherapy in patients with high and low levels of serum VEGF and VEGF receptor 2. Adverse events were consistent with the expected profiles of monotherapy with IL-2 and ziv-aflibercept. CONCLUSIONS: Ziv-aflibercept and IL-2 were found to significantly improve PFS compared with IL-2 alone, thereby meeting the primary endpoint of the current study. These findings support further study of immunotherapeutic combination strategies involving VEGF inhibitors.

9 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 .).

10 Clinical Trial A multi-center phase II study of high dose interleukin-2 sequenced with vemurafenib in patients with BRAF-V600 mutation positive metastatic melanoma. 2018

Clark, Joseph I / Singh, Jatinder / Ernstoff, Marc S / Lao, Christopher D / Flaherty, Lawrence E / Logan, Theodore F / Curti, Brendan / Agarwala, Sanjiv S / Taback, Bret / Cranmer, Lee / Lutzky, Jose / Luna, Theresa L / Aung, Sandra / Lawson, David H. ·Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL, 60153, USA. jclark@lumc.edu. · Primary Biostatistical Solutions, Victoria, BC, Canada. · Roswell Park Cancer Institute, Buffalo, NY, USA. · University of Michigan, Ann Arbor, MI, USA. · The Karmanos Cancer Institute, Detroit, MI, USA. · Indiana University, Indianapolis, IN, USA. · Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, USA. · St. Luke's Hospital and Health Network, Bethlehem, PA, USA. · Columbia University/Herbert Irving Comprehensive Cancer Center, New York, NY, USA. · Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA. · Mt. Sinai Comprehensive Cancer Center, Miami Beach, FL, USA. · Prometheus Laboratories Inc, San Diego, CA, USA. · Nektar Inc, San Diego, CA, USA. · Emory Winship Cancer Institute at Emory University, Atlanta, GA, USA. ·J Immunother Cancer · Pubmed #30053905.

ABSTRACT: BACKGROUND: Preclinical studies suggest that BRAF inhibitors enhance anti-tumor immunity and antigen presentation. Combination BRAF inhibition with immunotherapy is an appealing therapeutic approach. We sequenced vemurafenib with HD IL-2 in patients with BRAF-mutated metastatic melanoma to improve long term outcomes. METHODS: Eligible patients were HD IL-2 eligible with metastatic BRAF V600 mutated melanoma. Cohort 1 was treatment naïve and received vemurafenib 960 mg BID for 6 weeks before HD IL-2. Cohort 2 received vemurafenib for 7-18 weeks before enrollment. Both cohorts received HD IL-2 at 600,000 IU/kg every 8 h days 1-5 and days 15-19. The primary objective was to assess complete responses (CR) at 10 weeks ±3 (assessment 1) and 26 weeks ±3 (assessment 2) from the start of HD IL-2. RESULTS: Fifty-three patients were enrolled, (cohort 1, n = 38; cohort 2, n = 15). Of these, 39 underwent assessment 1 and 15 assessment 2. The CR rate at assessment 1 was 10% (95% CI 3-24) for both cohorts combined, and 27% (95% CI 8-55) at assessment 2. Three-year survival was 30 and 27% for cohort 1 and cohort 2, respectively. No unexpected toxicities occurred. A shift in the melanoma treatment landscape during this trial adversely affected accrual, leading to early trial closure. CONCLUSIONS: Vemurafenib in sequence with HD IL-2 did not change the known toxicity profile for either agent. Lower than expected response rates to vemurafenib were observed. Overall response rates and durability of responses appear similar to that observed with HD IL-2 alone. TRIAL REGISTRATION: NCTN, NCT01683188. Registered 11 September 2012, http://www.clinicaltrials.gov/NCT01683188.

11 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.

12 Clinical Trial Randomized, Placebo-Controlled, Phase III Trial of Yeast-Derived Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Versus Peptide Vaccination Versus GM-CSF Plus Peptide Vaccination Versus Placebo in Patients With No Evidence of Disease After Complete Surgical Resection of Locally Advanced and/or Stage IV Melanoma: A Trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E4697). 2015

Lawson, David H / Lee, Sandra / Zhao, Fengmin / Tarhini, Ahmad A / Margolin, Kim A / Ernstoff, Marc S / Atkins, Michael B / Cohen, Gary I / Whiteside, Theresa L / Butterfield, Lisa H / Kirkwood, John M. ·David H. Lawson, Winship Cancer Institute of Emory University, Atlanta, GA · Sandra Lee and Fengmin Zhao, Dana-Farber Cancer Institute · Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA · Ahmad A. Tarhini, Theresa L. Whiteside, Lisa H. Butterfield, and John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, PA · Kim A. Margolin, Seattle Cancer Care Alliance, Seattle, WA · Marc S. Ernstoff, Dartmouth-Hitchcock Medical Center, Lebanon, NH · and Gary I. Cohen, Greater Baltimore Medical Center, Baltimore, MD. ·J Clin Oncol · Pubmed #26351350.

ABSTRACT: PURPOSE: We conducted a double-blind, placebo-controlled trial to evaluate the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) and peptide vaccination (PV) on relapse-free survival (RFS) and overall survival (OS) in patients with resected high-risk melanoma. PATIENTS AND METHODS: Patients with completely resected stage IV or high-risk stage III melanoma were grouped by human leukocyte antigen (HLA) -A2 status. HLA-A2-positive patients were randomly assigned to receive GM-CSF, PV, both, or placebo; HLA-A2-negative patients, GM-CSF or placebo. Treatment lasted for 1 year or until recurrence. Efficacy analyses were conducted in the intent-to-treat population. RESULTS: A total of 815 patients were enrolled. There were no significant improvements in OS (stratified log-rank P = .528; hazard ratio, 0.94; 95% repeated CI, 0.77 to 1.15) or RFS (P = .131; hazard ratio, 0.88; 95% CI, 0.74 to 1.04) in the patients assigned to GM-CSF (n = 408) versus those assigned to placebo (n = 407). The median OS times with GM-CSF versus placebo treatments were 69.6 months (95% CI, 53.4 to 83.5 months) versus 59.3 months (95% CI, 44.4 to 77.3 months); the 5-year OS probability rates were 52.3% (95% CI, 47.3% to 57.1%) versus 49.4% (95% CI, 44.3% to 54.3%), respectively. The median RFS times with GM-CSF versus placebo were 11.4 months (95% CI, 9.4 to 14.8 months) versus 8.8 months (95% CI, 7.5 to 11.2 months); the 5-year RFS probability rates were 31.2% (95% CI, 26.7% to 35.9%) versus 27.0% (95% CI, 22.7% to 31.5%), respectively. Exploratory analyses showed a trend toward improved OS in GM-CSF-treated patients with resected visceral metastases. When survival in HLA-A2-positive patients who received PV versus placebo was compared, RFS and OS were not significantly different. Treatment-related grade 3 or greater adverse events were similar between GM-CSF and placebo groups. CONCLUSION: Neither adjuvant GM-CSF nor PV significantly improved RFS or OS in patients with high-risk resected melanoma. Exploratory analyses suggest that GM-CSF may be beneficial in patients with resected visceral metastases; this observation requires prospective validation.

13 Clinical Trial Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. 2013

Hodi, F Stephen / Corless, Christopher L / Giobbie-Hurder, Anita / Fletcher, Jonathan A / Zhu, Meijun / Marino-Enriquez, Adrian / Friedlander, Philip / Gonzalez, Rene / Weber, Jeffrey S / Gajewski, Thomas F / O'Day, Steven J / Kim, Kevin B / Lawrence, Donald / Flaherty, Keith T / Luke, Jason J / Collichio, Frances A / Ernstoff, Marc S / Heinrich, Michael C / Beadling, Carol / Zukotynski, Katherine A / Yap, Jeffrey T / Van den Abbeele, Annick D / Demetri, George D / Fisher, David E. ·F. Stephen Hodi, Anita Giobbie-Hurder, Philip Friedlander, Jason J. Luke, Katherine A. Zukotynski, Jeffrey T. Yap, Annick D. Van den Abbeele, and George D. Demetri, Dana-Farber Cancer Institute · Jonathan A. Fletcher, Meijun Zhu, and Adrian Marino-Enriquez, Brigham and Women's Hospital · Donald Lawrence, Keith T. Flaherty, and David E. Fisher, Massachusetts General Hospital, Boston, MA · Christopher L. Corless, Michael C. Heinrich, and Carol Beadling, Portland Veterans Administration Medical Center and Oregon Health & Science University, Portland, OR · Philip Friedlander, Mount Sinai Medical Center, New York, NY · Rene Gonzalez, University of Colorado Cancer Center, Aurora, CO · Jeffrey S. Weber, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL · Thomas F. Gajewski, University of Chicago, Chicago, IL · Steven J. O'Day, Beverly Hills Cancer Center, Beverly Hills, CA · Kevin B. Kim, The University of Texas MD Anderson Cancer Center, Houston, TX · Frances A. Collichio, The University of North Carolina at Chapel Hill, Chapel Hill, NC · and Marc S. Ernstoff, Geisel School of Medicine and Norris Cotton Cancer Center, Hanover, NH. ·J Clin Oncol · Pubmed #23775962.

ABSTRACT: PURPOSE: Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities. PATIENTS AND METHODS: We conducted a multicenter phase II trial of imatinib in metastatic mucosal, acral, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations. Patients received imatinib 400 mg once per day or 400 mg twice per day if there was no initial response. Dose reductions were permitted for treatment-related toxicities. Additional oncogene mutation screening was performed by mass spectroscopy. RESULTS: Twenty-five patients were enrolled (24 evaluable). Eight patients (33%) had tumors with KIT mutations, 11 (46%) with KIT amplifications, and five (21%) with both. Median follow-up was 10.6 months (range, 3.7 to 27.1 months). Best overall response rate (BORR) was 29% (21% excluding nonconfirmed responses) with a two-stage 95% CI of 13% to 51%. BORR was significantly greater than the hypothesized null of 5% and statistically significantly different by mutation status (7 of 13 or 54% KIT mutated v 0% KIT amplified only). There were no statistical differences in rates of progression or survival by mutation status or by melanoma site. The overall disease control rate was 50% but varied significantly by KIT mutation status (77% mutated v 18% amplified). Four patients harbored pretreatment NRAS mutations, and one patient acquired increased KIT amplification after treatment. CONCLUSION: Melanomas that arise on mucosal, acral, or CSD skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.

14 Clinical Trial Phase I trial of bortezomib and dacarbazine in melanoma and soft tissue sarcoma. 2013

Poklepovic, Andrew / Youssefian, Leena E / Winning, Mary / Birdsell, Christine A / Crosby, Nancy A / Ramakrishnan, Viswanathan / Ernstoff, Marc S / Roberts, John D. ·Massey Cancer Center and the Division of Hematology, Oncology & Palliative Care, Virginia Commonwealth University, Richmond, VA 23298-0037, USA. ·Invest New Drugs · Pubmed #23315028.

ABSTRACT: PURPOSE: Preclinical studies in human melanoma cell lines and murine xenograft tumor models suggest that the proteasome inhibitor bortezomib enhances the activity of the cytotoxic agent dacarbazine. We performed a phase I trial of bortezomib and dacarbazine in melanoma, soft tissue sarcoma, and amine precursor uptake and decarboxylation tumors. The primary objective was to identify recommended phase II doses for the combination. EXPERIMENTAL DESIGN: Bortezomib and dacarbazine were both administered intravenously once weekly. All patients received prophylactic antiemetics. Dose escalation proceeded using a standard 3 + 3 design. Response was assessed according to NCI RECIST v1.0. RESULTS: Twenty eight patients were enrolled to six dose levels. Bortezomib 1.6 mg/m(2) and dacarbazine 580 mg/m(2) are the recommended phase II weekly doses. The combination was generally well tolerated. Among 15 patients with melanoma there was one durable complete response in a patient with an exon-11 cKIT mutation, and one partial response. Among 12 patients with soft tissue sarcoma there was one partial response. CONCLUSIONS: Bortezomib 1.6 mg/m(2) and dacarbazine 580 mg/m(2) administered intravenously once weekly is well tolerated and has at least minimal activity in melanoma and soft tissue sarcoma.

15 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.

16 Clinical Trial Phase 3 study of docosahexaenoic acid-paclitaxel versus dacarbazine in patients with metastatic malignant melanoma. 2011

Bedikian, A Y / DeConti, R C / Conry, R / Agarwala, S / Papadopoulos, N / Kim, K B / Ernstoff, M. ·Department of Melanoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. abedikia@mdanderson.org ·Ann Oncol · Pubmed #20855467.

ABSTRACT: BACKGROUND: Docosahexaenoic acid-paclitaxel (DHA-paclitaxel, Taxoprexin(®)) is made by covalently conjugating the essential fatty acid DHA to the paclitaxel molecule. Preclinical studies of DHA-paclitaxel have demonstrated increased activity relative to paclitaxel and the potential for an improved therapeutic ratio. In the present study, the efficacy and toxicity profiles of DHA-paclitaxel were compared with those of dacarbazine. METHODS: In this study, 393 chemonaive patients with metastatic melanoma were randomly assigned to receive either DHA-paclitaxel at a starting dose of 900 mg/m(2) IV on day 1 every 3 weeks or dacarbazine at a starting dose of 1000 mg/m(2) IV on day 1 every 3 weeks. The primary end point of the study was the comparison of overall survival (OS). RESULTS: No significant difference in OS was noted between patients in the DHA-paclitaxel and dacarbazine arms. Similarly, there were no significant differences in response rate, duration of response, time to progression, and time to treatment failure between the two drugs. Safety results of the two drugs were as predicted from prior studies. Myelosuppression was more common with DHA-paclitaxel. CONCLUSIONS: DHA-paclitaxel was not superior to dacarbazine. We conclude that further studies with the drug on an every 3-week schedule in melanoma are not warranted.

17 Clinical Trial Cytokine working group study of lymphodepleting chemotherapy, interleukin-2, and granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma: clinical outcomes and peripheral-blood cell recovery. 2010

Gunturu, Krishna S / Meehan, Kenneth R / Mackenzie, Todd A / Crocenzi, Todd S / McDermott, David / Usherwood, Edward J / Margolin, Kim A / Crosby, Nancy A / Atkins, Michael B / Turk, Mary Jo / Ahonen, Cory / Fuse, Shinichiro / Clark, Joseph I / Fisher, Jan L / Noelle, Randolph J / Ernstoff, Marc S. ·Section of Hematology/Oncology, Dartmouth-Hitchcock Medical Center, 1 Medical Center Dr, Lebanon, NH 03756, USA. ·J Clin Oncol · Pubmed #20124177.

ABSTRACT: PURPOSE: Recovery of lymphocyte populations after lymphocyte depletion is implicated in therapeutic immune pathways in animal models and in patients with cancer. We sought to evaluate the effects of chemotherapy-induced lymphodepletion followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) and high-dose interleukin-2 (IL-2) therapy on clinical response and the recovery of lymphocyte subcompartments in patients with metastatic melanoma. PATIENTS AND METHODS: This was a two-stage phase II trial design. Patients with measurable metastatic melanoma were treated with intravenous cyclophosphamide (60 mg/kg, days 1 and 2) and fludarabine (25 mg/m(2), day 3 through 7) followed by two 5-day courses of intravenous high-dose bolus IL-2 (600,000 U/kg; days 8 through 12 and 21 through 25). GM-CSF (250 microg/m(2)/d beginning day 8) was given until granulocyte recovery. Lymphocyte recovery profiles were determined by flow cytometric phenotyping at regular intervals, and clinical outcome was assessed by Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: The trial was stopped at the end of stage 1 with four of 18 objective responses noted. Twelve patients had detailed lymphocyte subcompartments evaluated. After lymphodepletion, we observed an induction of regulatory cells (CD4+ T regulatory cells; CD8+ T suppressor cells) and of T memory cells (CD8+ T central memory cells; T effector memory RA+ cells). Expansion of circulating melanoma-specific CD8(+) cells was observed in one of four HLA-A2-positive patients. CONCLUSION: Chemotherapy-induced lymphodepletion modulates the homeostatic repopulation of the lymphocyte compartment and influences recovering lymphocyte subpopulations. Clinical activity seems similar to standard high-dose aldesleukin alone.

18 Article Combination of pembrolizumab and imatinib in a patient with double KIT mutant melanoma: A case report. 2019

Abdou, Yara / Kapoor, Ankita / Hamad, Lamya / Ernstoff, Marc S. ·Roswell Park Comprehensive Cancer Center, Buffalo. · Rochester General Hospital, Rochester, NY. ·Medicine (Baltimore) · Pubmed #31689840.

ABSTRACT: RATIONALE: The treatment of metastatic melanoma has been revolutionized in the past decade because of the development of immunotherapies and targeted therapies. Despite these developments, there is still an unmet clinical need for more advanced combination therapies for the subset of patients who remain resistant to immunotherapy or targeted therapy alone. To our knowledge, no reports have been published on combinations of PD-1 blockades and c-KIT inhibitors in melanoma patients. Furthermore, data are limited regarding the safety and efficacy of this combination in patients harboring KIT mutations. PATIENT CONCERNS AND DIAGNOSIS: We report a case of an 82-year-old female with metastatic melanoma who was found to have double KIT mutations at V559 and N822I. INTERVENTIONS: She was treated with a combination of c-KIT inhibitor and PD-1 blockade after being resistant to anti-PD-1 monotherapy. OUTCOMES: Patient developed two episodes of grade 2 liver toxicity requiring treatment breaks followed by a dose reduction. Her transaminitis eventually resolved and patient remained on combination treatment for almost two years with good control of her disease prior to progression. LESSONS: Treatment options for patients who progress after PD-1 inhibitors are very limited; therefore, there is a high unmet clinical need for this patient population. Combining Imatinib with checkpoint inhibitors may be efficacious in patients with metastatic melanoma and KIT mutations. This novel combination can cause additional toxicities which seem to be overall manageable.

19 Article Perspectives in melanoma: meeting report from the Melanoma Bridge (November 29th-1 December 1st, 2018, Naples, Italy). 2019

Ascierto, Paolo A / Agarwala, Sanjiv S / Botti, Gerardo / Budillon, Alfredo / Davies, Michael A / Dummer, Reinhard / Ernstoff, Marc / Ferrone, Soldano / Formenti, Silvia / Gajewski, Thomas F / Garbe, Claus / Hamid, Omid / Lo, Roger S / Luke, Jason J / Michielin, Oliver / Palmieri, Giuseppe / Zitvogel, Laurence / Marincola, Francesco M / Masucci, Giuseppe / Caracò, Corrado / Thurin, Magdalena / Puzanov, Igor. ·Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy. paolo.ascierto@gmail.com. · Medical Oncology and Hematology, St. Luke's University Hospital and Temple University, Bethlehem, PA, USA. · Istituto Nazionale Tumori-IRCCS Fondazione "G. Pascale", Naples, Italy. · Experimental Pharmacology Unit, Department of Translational Research, Istituto Nazionale Tumori-IRCCS Fondazione "G. Pascale", Naples, Italy. · Department of Melanoma Medical Oncology, Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Dermatology, University of Zurich Hospital, Zurich, Switzerland. · Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. · Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA. · Department of Pathology and Department of Medicine, Section of Hematology/Oncology, The University of Chicago Medicine, Chicago, IL, USA. · Division of Dermatologic Oncology, Department of Dermatology, Eberhard Karls University, Tuebingen, Germany. · The Angeles Clinic, Experimental Therapeutics Cedars Sinai Foundation, Los Angeles, CA, USA. · Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · University of Chicago Medical Center, Chicago, IL, USA. · Oncology Department, UNIL-CHUV, Lausanne, Switzerland. · Unit of Cancer Genetics, Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy. · Institut de Cancérologie, Gustave Roussy Cancer Campus, Villejuif, Paris, France. · Refuge Biotechnologies, Menlo Park, CA, USA. · Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden. · Division of Surgery of Melanoma and Skin Cancer, Istituto Nazionale Tumori-IRCCS Fondazione "G. Pascale", Naples, Italy. · Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, NCI, 9609 Medical Center Drive, Bethesda, MD, 20892-7420, USA. thurinm@mail.nih.gov. · Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. ·J Transl Med · Pubmed #31331337.

ABSTRACT: Diagnosis of melanocytic lesions, correct prognostication of patients, selection of appropriate adjuvant and systemic therapies, and prediction of response to a given therapy remain very real challenges in melanoma. Recent studies have shown that immune checkpoint blockade that represents a forefront in cancer therapy, provide responses but they are not universal. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers they have yet to be fully characterized and implemented clinically. For example, advancements in sequencing and the understanding of the tumor microenvironment in melanoma have led to the use of genome sequencing and gene expression for development of multi-marker assays that show association with inflammatory state of the tumor and potential to predict response to immunotherapy. As such, melanoma serves as a model system for understanding cancer immunity and patient response to immunotherapy, either alone or in combination with other treatment modalities. Overall, the aim for the translational and clinical studies is to achieve incremental improvements through the development and identification of optimal treatment regimens, which increasingly involve doublet as well as triplet combinations, as well as through development of biomarkers to improve immune response. These and other topics in the management of melanoma were the focus of discussions at the fourth Melanoma Bridge meeting (November 29th-December 1st, 2018, Naples, Italy), which is summarised in this report.

20 Article Small and Isolated Immunohistochemistry-positive Cells in Melanoma Sentinel Lymph Nodes Are Associated With Disease-specific and Recurrence-free Survival Comparable to that of Sentinel Lymph Nodes Negative for Melanoma. 2019

LeBlanc, Robert E / Barton, Dorothea T / Li, Zhongze / Angeles, Christina V / Ernstoff, Marc S / Bagley, Eryn / Wimmer, Daniel / Wong, Sandra L / Barth, Richard J / Shirai, Keisuke / Yan, Shaofeng. ·Departments of Pathology and Laboratory Medicine. · Surgery and Dermatology. · Biostatistics Shared Resource, Norris Cotton Cancer Center. · Departments of Surgery. · Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY. · Medicine, Hematology and Oncology Program, Dartmouth Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH. · Inform Diagnostics, Irving, TX. ·Am J Surg Pathol · Pubmed #31091203.

ABSTRACT: Although immunohistochemistry (IHC) has improved our ability to detect melanoma metastases in sentinel lymph nodes (SLN), the American Joint Committee on Cancer (AJCC) does not provide a lower threshold for determining if a SLN is positive for metastasis. Existing literature suggests that even a small aggregate or an enlarged, abnormal cell detectable by IHC can be associated with an adverse outcome. In our experience, however, some SLNs contain small solitary cells the size of neighboring lymphocytes demonstrable only by IHC. We sought to determine their clinical significance. A total of 821 patients underwent a SLN biopsy at our institution over a 12-year period. In all, 639 (77.8%) were SLN-negative, 125 (15.2%) were SLN-positive, and 57 (6.9%) had rare IHC-positive cells of undetermined clinical significance with no disease progression over a mean 59-month follow-up. Kaplan-Meier method with pair-wise comparisons revealed no significant difference in disease-specific survival and recurrence-free survival between SLN-negative and rare IHC-positive groups. There were significant differences in survival and recurrence between patients in the rare IHC-positive group and those with melanoma metastases, including those with solitary melanoma cells and those with tumor burdens ≤0.2 mm. While the lower diagnostic threshold for metastatic melanoma on IHC-stained sections needs to be studied further, our data suggest that rare IHC-positive cells lacking cytomorphologic features of overt malignancy are equivocal for melanoma and could impart a similar prognosis as patients with no evidence of SLN involvement.

21 Article Ex vivo conditioning with IL-12 protects tumor-infiltrating CD8 2019

Lin, Lin / Rayman, Patricia / Pavicic, Paul G / Tannenbaum, Charles / Hamilton, Thomas / Montero, Alberto / Ko, Jennifer / Gastman, Brian / Finke, James / Ernstoff, Marc / Diaz-Montero, C Marcela. ·Cleveland Clinic, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA. · Department of Inflammation and Immunity, Cleveland Clinic, Lerner Research Institute, 9500 Euclid Avenue NE40, Cleveland, OH, 44195, USA. · Department of Hematology and Medical Oncology, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH, USA. · Department of Pathology, Cleveland Clinic, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland, OH, USA. · Department of Plastic Surgery, Dermatology and Plastic Surgery Institute, Cleveland Clinic, Cleveland, OH, USA. · Department of Inflammation and Immunity, Cleveland Clinic, Lerner Research Institute, 9500 Euclid Avenue NE40, Cleveland, OH, 44195, USA. diazc2@ccf.org. ·Cancer Immunol Immunother · Pubmed #30552459.

ABSTRACT: Optimal ex vivo expansion protocols for adoptive cell therapy (ACT) must yield T cells able to effectively home to tumors and survive the inhospitable conditions of the tumor microenvironment (TME), while simultaneously exerting persistent anti-tumor effector functions. Our previous work has shown that ex vivo activation in the presence of IL-12 can induce optimal expansion of murine CD8

22 Article Metabolic reprogramming of stromal fibroblasts by melanoma exosome microRNA favours a pre-metastatic microenvironment. 2018

Shu, Shin La / Yang, Yunchen / Allen, Cheryl L / Maguire, Orla / Minderman, Hans / Sen, Arindam / Ciesielski, Michael J / Collins, Katherine A / Bush, Peter J / Singh, Prashant / Wang, Xue / Morgan, Martin / Qu, Jun / Bankert, Richard B / Whiteside, Theresa L / Wu, Yun / Ernstoff, Marc S. ·Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. · Department of Biomedical Engineering, Jacobs School of Medicine & Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA. · Flow and Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. · Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. · Department of Neurosurgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. · Immune Analysis Facility, Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. · South Campus Instrumentation Center, University at Buffalo, The State University of New York, Buffalo, NY, USA. · Genomics Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. · New York Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY, USA. · Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. · Department of Microbiology and Immunology, Jacobs School of Medicine & Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA. · Department of Pathology, Immunology and Otolaryngology, University of Pittsburgh School of Medicine and UPMC Hillman Cancer Center, Pittsburgh, PA, USA. · Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. Marc.Ernstoff@RoswellPark.org. ·Sci Rep · Pubmed #30150674.

ABSTRACT: Local acidification of stroma is proposed to favour pre-metastatic niche formation but the mechanism of initiation is unclear. We investigated whether Human Melanoma-derived exosomes (HMEX) could reprogram human adult dermal fibroblasts (HADF) and cause extracellular acidification. HMEX were isolated from supernatants of six melanoma cell lines (3 BRAF V600E mutant cell lines and 3 BRAF wild-type cell lines) using ultracentrifugation or Size Exclusion Chromatography (SEC). Rapid uptake of exosomes by HADF was demonstrated following 18 hours co-incubation. Exposure of HDAF to HMEX leads to an increase in aerobic glycolysis and decrease in oxidative phosphorylation (OXPHOS) in HADF, consequently increasing extracellular acidification. Using a novel immuno-biochip, exosomal miR-155 and miR-210 were detected in HMEX. These miRNAs were present in HMEX from all six melanoma cell lines and were instrumental in promoting glycolysis and inhibiting OXPHOS in tumour cells. Inhibition of miR-155 and miR-210 activity by transfection of miRNA inhibitors into HMEX reversed the exosome-induced metabolic reprogramming of HADF. The data indicate that melanoma-derived exosomes modulate stromal cell metabolism and may contribute to the creation of a pre-metastatic niche that promotes the development of metastasis.

23 Article Identification of gene expression levels in primary melanoma associated with clinically meaningful characteristics. 2018

Gorlov, Ivan / Orlow, Irene / Ringelberg, Carol / Hernando, Eva / Ernstoff, Marc S / Cheng, Chao / Her, Stephanie / Parker, Joel S / Thompson, Cheryl L / Gerstenblith, Meg R / Berwick, Marianne / Amos, Christopher. ·Department of Biomedical Data Science, The Geisel School of Medicine, Dartmouth College, Dartmouth-Hitchcock Medical Center, Lebanon. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center. · Department of Pathology, NYU School of Medicine, New York City. · Roswell Park Cancer Institute, Elm & Carlton, Buffalo, New York. · Department of Computer Science, Dartmouth College, Hanover, New Hampshire. · Department of Genetics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. · School of Medicine, Case Western Reserve University, Cleveland, Ohio. · Department of Internal Medicine and Dermatology, University of New Mexico, Albuquerque, New Mexico. · Department of Medicine, Baylor College of Medicine, Houston, Texas, USA. ·Melanoma Res · Pubmed #29975213.

ABSTRACT: Factors influencing melanoma survival include sex, age, clinical stage, lymph node involvement, as well as Breslow thickness, presence of tumor-infiltrating lymphocytes based on histological analysis of primary melanoma, mitotic rate, and ulceration. Identification of genes whose expression in primary tumors is associated with these key tumor/patient characteristics can shed light on molecular mechanisms of melanoma survival. Here, we show results from a gene expression analysis of formalin-fixed paraffin-embedded primary melanomas with extensive clinical annotation. The Cancer Genome Atlas data on primary melanomas were used for validation of nominally significant associations. We identified five genes that were significantly associated with the presence of tumor-infiltrating lymphocytes in the joint analysis after adjustment for multiple testing: IL1R2, PPL, PLA2G3, RASAL1, and SGK2. We also identified two genes significantly associated with melanoma metastasis to the regional lymph nodes (PIK3CG and IL2RA), and two genes significantly associated with sex (KDM5C and KDM6A). We found that LEF1 was significantly associated with Breslow thickness and CCNA2 and UBE2T with mitosis. RAD50 was the gene most significantly associated with survival, with a higher level of expression associated with worse survival.

24 Article Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden. 2018

Morrison, Carl / Pabla, Sarabjot / Conroy, Jeffrey M / Nesline, Mary K / Glenn, Sean T / Dressman, Devin / Papanicolau-Sengos, Antonios / Burgher, Blake / Andreas, Jonathan / Giamo, Vincent / Qin, Moachun / Wang, Yirong / Lenzo, Felicia L / Omilian, Angela / Bshara, Wiam / Zibelman, Matthew / Ghatalia, Pooja / Dragnev, Konstantin / Shirai, Keisuke / Madden, Katherine G / Tafe, Laura J / Shah, Neel / Kasuganti, Deepa / de la Cruz-Merino, Luis / Araujo, Isabel / Saenger, Yvonne / Bogardus, Margaret / Villalona-Calero, Miguel / Diaz, Zuanel / Day, Roger / Eisenberg, Marcia / Anderson, Steven M / Puzanov, Igor / Galluzzi, Lorenzo / Gardner, Mark / Ernstoff, Marc S. ·Center for Personalized Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA. Carl.Morrison@RoswellPark.org. · Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA. Carl.Morrison@RoswellPark.org. · Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA. Carl.Morrison@RoswellPark.org. · OmniSeq Inc., Buffalo, NY, 14203, USA. Carl.Morrison@RoswellPark.org. · OmniSeq Inc., Buffalo, NY, 14203, USA. · Center for Personalized Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA. · Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA. · Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA. · Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA. · Department of Hematology and Oncology, Dartmouth Hitchcock, Lebanon, NH, 03756, USA. · Department of Pathology, Dartmouth Hitchcock, Lebanon, NH, 03756, USA. · Department of Pathology, Community Hospital, Munster, IN, 46321, USA. · Department of Clinical Oncology Development, Hospital Universitario Virgen Macarena, 41009, Sevilla, Spain. · Department of Medicine, Columbia University, New York, NY, 10032, USA. · Miami Cancer Institute, Baptist Health South Florida, Miami, FL, 33176, USA. · Department of Biomedical Informatics and Biostatistics, University of Pittsburgh, Pittsburgh, PA, 15213, USA. · Laboratory Corporation of America Holdings, Burlington, NC, 27215, USA. · Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA. · Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, 10065, USA. · Sandra and Edward Meyer Cancer Center, New York, NY, 10065, USA. · Université Paris Descartes/Paris V, 75006, Paris, France. ·J Immunother Cancer · Pubmed #29743104.

ABSTRACT: BACKGROUND: Immune checkpoint inhibitors (ICIs) have changed the clinical management of melanoma. However, not all patients respond, and current biomarkers including PD-L1 and mutational burden show incomplete predictive performance. The clinical validity and utility of complex biomarkers have not been studied in melanoma. METHODS: Cutaneous metastatic melanoma patients at eight institutions were evaluated for PD-L1 expression, CD8 RESULTS: PD-L1 positivity ≥1% correlated with response and OS in ICI-treated patients, but demonstrated limited predictive performance. High mutational burden was associated with response in ICI-treated patients, but not with OS. Comprehensive immune profiling using RS demonstrated higher sensitivity (72.2%) compared to PD-L1 IHC (34.25%) and tumor mutational burden (32.5%), but with similar specificity. CONCLUSIONS: In this study, the response score derived from comprehensive immune profiling in a limited melanoma cohort showed improved predictive performance as compared to PD-L1 IHC and tumor mutational burden.

25 Article VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival. 2018

Kuklinski, Lawrence F / Yan, Shaofeng / Li, Zhongze / Fisher, Jan L / Cheng, Chao / Noelle, Randolph J / Angeles, Christina V / Turk, Mary Jo / Ernstoff, Marc S. ·Geisel School of Medicine at Dartmouth, Hanover, NH, USA. · Department of Medicine, Santa Barbara Cottage Hospital, Santa Barbara, CA, USA. · Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. · Biostatistics Shared Resource, Norris Cotton Cancer Center, Dartmouth-Hitchock Medical Center, Lebanon, NH, USA. · Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. · Departments of Biomedical Data Sciences, Molecular and Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, USA. · Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. · Department of Surgery, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA. · Roswell Park Cancer Institute, University of Buffalo, The State University of New York, Elm and Carlton, Buffalo, NY, 14263, USA. marc.ernstoff@roswellpark.org. ·Cancer Immunol Immunother · Pubmed #29737375.

ABSTRACT: Adaptive immune responses contribute to the pathogenesis of melanoma by facilitating immune evasion. V-domain Ig suppressor of T-cell activation (VISTA) is a potent negative regulator of T-cell function and is expressed at high levels on monocytes, granulocytes, and macrophages, and at lower densities on T-cell populations within the tumor microenvironment. In this study, 85 primary melanoma specimens were selected from pathology tissue archives and immunohistochemically stained for CD3, PD-1, PD-L1, and VISTA. Pearson's correlation coefficients identified associations in expression between VISTA and myeloid infiltrate (r = 0.28, p = 0.009) and the density of PD-1+ inflammatory cells (r = 0.31, p = 0.005). The presence of VISTA was associated with a significantly worse disease-specific survival in univariate analysis (hazard ratio = 3.57, p = 0.005) and multivariate analysis (hazard ratio = 3.02, p = 0.02). Our findings show that VISTA expression is an independent negative prognostic factor in primary cutaneous melanoma and suggests its potential as an adjuvant immunotherapeutic intervention in the future.

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