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Melanoma: HELP
Articles by William H. Sharfman
Based on 16 articles published since 2008
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Between 2008 and 2019, William Sharfman wrote the following 16 articles about Melanoma.
 
+ Citations + Abstracts
1 Guideline The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. 2013

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

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

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

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

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

3 Clinical Trial Safety and immunologic correlates of Melanoma GVAX, a GM-CSF secreting allogeneic melanoma cell vaccine administered in the adjuvant setting. 2015

Lipson, Evan J / Sharfman, William H / Chen, Shuming / McMiller, Tracee L / Pritchard, Theresa S / Salas, January T / Sartorius-Mergenthaler, Susan / Freed, Irwin / Ravi, Sowmya / Wang, Hao / Luber, Brandon / Sproul, Janice Davis / Taube, Janis M / Pardoll, Drew M / Topalian, Suzanne L. ·Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, 1550 Orleans Street, Room 507, Baltimore, MD, 21287, USA. evanlipson@jhmi.edu. · Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21287, USA. sharfwi@jhmi.edu. · Department of Surgery, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. shuming1@jhu.edu. · Department of Surgery, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. tmcmill3@jhmi.edu. · Department of Surgery, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. tsalay1@jhmi.edu. · Department of Surgery, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. jansalas@gmail.com. · Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21287, USA. sartosu@jhmi.edu. · Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21287, USA. ifreed@jhmi.edu. · Department of Dermatology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. sravi2@jhmi.edu. · Division of Biostatistics and Bioinformatics, Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. hwang76@jhmi.edu. · Division of Biostatistics and Bioinformatics, Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. bluber1@jhmi.edu. · Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21287, USA. davisja@jhmi.edu. · Department of Dermatology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. jtaube1@jhmi.edu. · Department of Pathology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. jtaube1@jhmi.edu. · Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21287, USA. dpardol1@jhmi.edu. · Department of Surgery, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. stopali1@jhmi.edu. ·J Transl Med · Pubmed #26143264.

ABSTRACT: BACKGROUND: Limited adjuvant treatment options exist for patients with high-risk surgically resected melanoma. This first-in-human study investigated the safety, tolerability and immunologic correlates of Melanoma GVAX, a lethally irradiated granulocyte-macrophage colony stimulating factor (GM-CSF)-secreting allogeneic whole-cell melanoma vaccine, administered in the adjuvant setting. METHODS: Patients with stage IIB-IV melanoma were enrolled following complete surgical resection. Melanoma GVAX was administered intradermally once every 28 days for four cycles, at 5E7 cells/cycle (n = 3), 2E8 cells/cycle (n = 9), or 2E8 cells/cycle preceded by cyclophosphamide 200 mg/m(2) to deplete T regulatory cells (Tregs; n = 8). Blood was collected before each vaccination and at 4 and 6 months after treatment initiation for immunologic studies. Vaccine injection site biopsies and additional blood samples were obtained 2 days after the 1st and 4th vaccines. RESULTS: Among 20 treated patients, 18 completed 4 vaccinations. Minimal treatment-related toxicity was observed. One patient developed vitiligo and patches of white hair during the treatment and follow-up period. Vaccine site biopsies demonstrated complex inflammatory infiltrates, including significant increases in eosinophils and PD-1+ lymphocytes from cycle 1 to cycle 4 (P < 0.05). Serum GM-CSF concentrations increased significantly in a dose-dependent manner 48 h after vaccination (P = 0.0086), accompanied by increased numbers of activated circulating monocytes (P < 0.0001) and decreased percentages of myeloid-derived suppressor cells among monocytes (CD14+ , CD11b+ , HLA-DR low or negative; P = 0.002). Cyclophosphamide did not affect numbers of circulating Tregs. No significant changes in anti-melanoma immunity were observed in peripheral T cells by interferon-gamma ELIPSOT, or immunoglobulins by serum Western blotting. CONCLUSION: Melanoma GVAX was safe and tolerable in the adjuvant setting. Pharmacodynamic testing revealed complex vaccine site immune infiltrates and an immune-reactive profile in circulating monocytic cell subsets. These findings support the optimization of Melanoma GVAX with additional monocyte and dendritic cell activators, and the potential development of combinatorial treatment regimens with synergistic agents. TRIAL REGISTRATION: NCT01435499.

4 Clinical Trial Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. 2014

Johnson, Douglas B / Flaherty, Keith T / Weber, Jeffrey S / Infante, Jeffrey R / Kim, Kevin B / Kefford, Richard F / Hamid, Omid / Schuchter, Lynn / Cebon, Jonathan / Sharfman, William H / McWilliams, Robert R / Sznol, Mario / Lawrence, Donald P / Gibney, Geoffrey T / Burris, Howard A / Falchook, Gerald S / Algazi, Alain / Lewis, Karl / Long, Georgina V / Patel, Kiran / Ibrahim, Nageatte / Sun, Peng / Little, Shonda / Cunningham, Elizabeth / Sosman, Jeffrey A / Daud, Adil / Gonzalez, Rene. ·Douglas B. Johnson and Jeffrey A. Sosman, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center · Jeffrey R. Infante and Howard A. Burris III, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN · Keith T. Flaherty and Donald P. Lawrence, Massachusetts General Hospital Cancer Center, Boston MA · Jeffrey S. Weber and Geoffrey T. Gibney, Moffitt Cancer Center, Tampa, FL · Kevin B. Kim and Gerald S. Falchook, University of Texas MD Anderson Cancer Center, Houston, TX · Richard F. Kefford and Georgina V. Long, Melanoma Institute Australia, University of Sydney and Westmead Hospital, Sydney, New South Wales · Jonathan Cebon, Joint Ludwig-Austin Oncology Unit, Austin Health, Melbourne, Victoria, Australia · Omid Hamid, Angeles Clinic and Research Institute, Los Angeles · Alain Algazi and Adil Daud, University of California, San Francisco, San Francisco, CA · Lynn Schuchter, University of Pennsylvania Abramson Cancer Center · Nageatte Ibrahim, Peng Sun, Shonda Little, and Elizabeth Cunningham, GlaxoSmithKline, Philadelphia, PA · William H. Sharfman, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD · Robert R. McWilliams, Mayo Clinic, Rochester, MN · Mario Sznol, Yale University School of Medicine and Smilow Cancer Center, Yale-New Haven Hospital, New Haven, CT · Karl Lewis and Rene Gonzalez, University of Colorado, Denver, CO · and Kiran Patel, Incyte, Wilmington, DE. ·J Clin Oncol · Pubmed #25287827.

ABSTRACT: PURPOSE: Preclinical and early clinical studies have demonstrated that initial therapy with combined BRAF and MEK inhibition is more effective in BRAF(V600)-mutant melanoma than single-agent BRAF inhibitors. This study assessed the safety and efficacy of dabrafenib and trametinib in patients who had received prior BRAF inhibitor treatment. PATIENTS AND METHODS: In this open-label phase I/II study, we evaluated the pharmacology, safety, and efficacy of dabrafenib and trametinib. Here, we report patients treated with combination therapy after disease progression with BRAF inhibitor treatment administered before study enrollment (part B; n = 26) or after cross-over at progression with dabrafenib monotherapy (part C; n = 45). RESULTS: In parts B and C, confirmed objective response rates (ORR) were 15% (95% CI, 4% to 35%) and 13% (95% CI, 5% to 27%), respectively; an additional 50% and 44% experienced stable disease ≥ 8 weeks, respectively. In part C, median progression-free survival (PFS) was 3.6 months (95% CI, 2 to 4), and median overall survival was 11.8 months (95% CI, 8 to 25) from cross-over. Patients who previously received dabrafenib ≥ 6 months had superior outcomes with the combination compared with those treated < 6 months; median PFS was 3.9 (95% CI, 3 to 7) versus 1.8 months (95% CI, 2 to 4; hazard ratio, 0.49; P = .02), and ORR was 26% (95% CI, 10% to 48%) versus 0% (95% CI, 0% to 15%). CONCLUSION: Dabrafenib plus trametinib has modest clinical efficacy in patients with BRAF inhibitor-resistant melanoma. This regimen may be a therapeutic strategy for patients who previously benefited from BRAF inhibitor monotherapy ≥ 6 months but demonstrates minimal efficacy after rapid progression with BRAF inhibitor therapy.

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

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

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

6 Clinical Trial Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. 2013

Lipson, Evan J / Sharfman, William H / Drake, Charles G / Wollner, Ira / Taube, Janis M / Anders, Robert A / Xu, Haiying / Yao, Sheng / Pons, Alice / Chen, Lieping / Pardoll, Drew M / Brahmer, Julie R / Topalian, Suzanne L. ·Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA. evanlipson@jhmi.edu ·Clin Cancer Res · Pubmed #23169436.

ABSTRACT: PURPOSE: Results from the first-in-human phase I trial of the anti-programmed death-1 (PD-1) antibody BMS-936558 in patients with treatment-refractory solid tumors, including safety, tolerability, pharmacodynamics, and immunologic correlates, have been previously reported. Here, we provide long-term follow-up on three patients from that trial who sustained objective tumor regressions off therapy, and test the hypothesis that reinduction therapy for late tumor recurrence can be effective. EXPERIMENTAL DESIGN: Three patients with colorectal cancer, renal cell cancer, and melanoma achieved objective responses on an intermittent dosing regimen of BMS-936558. Following cessation of therapy, patients were followed for more than 3 years. A patient with melanoma who experienced a prolonged partial regression followed by tumor recurrence received reinduction therapy. RESULTS: A patient with colorectal cancer experienced a complete response, which is ongoing after 3 years. A patient with renal cell cancer experienced a partial response lasting 3 years off therapy, which converted to a complete response, which is ongoing at 12 months. A patient with melanoma achieved a partial response that was stable for 16 months off therapy; recurrent disease was successfully treated with reinduction anti-PD-1 therapy. CONCLUSION: These data represent the most prolonged observation to date of patients with solid tumors responding to anti-PD-1 immunotherapy and the first report of successful reinduction therapy following delayed tumor progression. They underscore the potential for immune checkpoint blockade with anti-PD-1 to reset the equilibrium between tumor and the host immune system.

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

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

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

8 Clinical Trial Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. 2010

Brahmer, Julie R / Drake, Charles G / Wollner, Ira / Powderly, John D / Picus, Joel / Sharfman, William H / Stankevich, Elizabeth / Pons, Alice / Salay, Theresa M / McMiller, Tracee L / Gilson, Marta M / Wang, Changyu / Selby, Mark / Taube, Janis M / Anders, Robert / Chen, Lieping / Korman, Alan J / Pardoll, Drew M / Lowy, Israel / Topalian, Suzanne L. ·Johns Hopkins University School of Medicine, and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. ·J Clin Oncol · Pubmed #20516446.

ABSTRACT: PURPOSE: Programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, may suppress antitumor immunity. This phase I study sought to determine the safety and tolerability of anti-PD-1 blockade in patients with treatment-refractory solid tumors and to preliminarily assess antitumor activity, pharmacodynamics, and immunologic correlates. PATIENTS AND METHODS: Thirty-nine patients with advanced metastatic melanoma, colorectal cancer (CRC), castrate-resistant prostate cancer, non-small-cell lung cancer (NSCLC), or renal cell carcinoma (RCC) received a single intravenous infusion of anti-PD-1 (MDX-1106) in dose-escalating six-patient cohorts at 0.3, 1, 3, or 10 mg/kg, followed by a 15-patient expansion cohort at 10 mg/kg. Patients with evidence of clinical benefit at 3 months were eligible for repeated therapy. RESULTS: Anti-PD-1 was well tolerated: one serious adverse event, inflammatory colitis, was observed in a patient with melanoma who received five doses at 1 mg/kg. One durable complete response (CRC) and two partial responses (PRs; melanoma, RCC) were seen. Two additional patients (melanoma, NSCLC) had significant lesional tumor regressions not meeting PR criteria. The serum half-life of anti-PD-1 was 12 to 20 days. However, pharmacodynamics indicated a sustained mean occupancy of > 70% of PD-1 molecules on circulating T cells > or = 2 months following infusion, regardless of dose. In nine patients examined, tumor cell surface B7-H1 expression appeared to correlate with the likelihood of response to treatment. CONCLUSION: Blocking the PD-1 immune checkpoint with intermittent antibody dosing is well tolerated and associated with evidence of antitumor activity. Exploration of alternative dosing regimens and combinatorial therapies with vaccines, targeted therapies, and/or other checkpoint inhibitors is warranted.

9 Clinical Trial A randomized phase 2 study of etaracizumab, a monoclonal antibody against integrin alpha(v)beta(3), + or - dacarbazine in patients with stage IV metastatic melanoma. 2010

Hersey, Peter / Sosman, Jeffrey / O'Day, Steven / Richards, Jon / Bedikian, Agop / Gonzalez, Rene / Sharfman, William / Weber, Robert / Logan, Theodore / Buzoianu, Manuela / Hammershaimb, Luz / Kirkwood, John M / Anonymous2640649. ·Newcastle Melanoma Unit, Newcastle, Australia. ·Cancer · Pubmed #20108344.

ABSTRACT: BACKGROUND: The alpha (v) beta (3) (alpha(v)beta(3)) integrin is involved in intracellular signaling regulating cell proliferation, migration, and differentiation and is important for tumor-induced angiogenesis. METHODS: This phase 2, randomized, open-label, 2-arm study was designed to capture safety data and evaluate the antitumor efficacy of etaracizumab (Abegrin), an IgG1 humanized monoclonal antibody against the alpha(v)beta(3) integrin, in patients with previously untreated metastatic melanoma. The objective was to evaluate whether etaracizumab + or - dacarbazine had sufficient clinical activity to warrant further study in a phase 3 clinical trial. RESULTS: One hundred twelve patients were randomized to receive etaracizumab alone (N = 57) or etaracizumab + dacarbazine (N = 55). Safety of etaracizumab + or - dacarbazine was acceptable with infusion-related, gastrointestinal, and metabolic reactions being the most common adverse events (AEs). The majority of AEs were grade 1 or 2 in severity in both study arms; most events were not considered serious, except for cardiovascular (myocardial infarction, atrial fibrillation) and thromboembolic events, which occurred in 3 and 5 patients, respectively. None of the patients in the etaracizumab-alone study arm and 12.7% of patients in the etaracizumab + dacarbazine study arm achieved an objective response. The median duration of objective response in the etaracizumab + dacarbazine study arm was 4.2 months. Stable disease rate, time to progression (TTP), and progression-free survival (PFS) appeared to be similar between the 2 treatment arms. Stable disease occurred in 45.6% of patients in the etaracizumab-alone study arm and 40.0% of patients in the etaracizumab + dacarbazine study arm. Median TTP and median PFS were both 1.8 months in the etaracizumab-alone study arm and 2.5 and 2.6 months in the etaracizumab + dacarbazine study arm, respectively. Median overall survival was 12.6 months in the etaracizumab-alone study arm and 9.4 months in the etaracizumab + dacarbazine study arm. CONCLUSIONS: The survival results in both treatment arms of this study were considered unlikely to result in clinically meaningful improvement over dacarbazine alone.

10 Article Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma. 2018

Chen, Linda / Douglass, Jacqueline / Kleinberg, Lawrence / Ye, Xiaobu / Marciscano, Ariel E / Forde, Patrick M / Brahmer, Julie / Lipson, Evan / Sharfman, William / Hammers, Hans / Naidoo, Jarushka / Bettegowda, Chetan / Lim, Michael / Redmond, Kristin J. ·Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Hospital, Baltimore, Maryland. · Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Hospital, Baltimore, Maryland; Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, Maryland; Department of Oncology Biostatistics and Bioinformatics, Johns Hopkins School of Medicine, Baltimore, Maryland. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, Maryland. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, Maryland; Department of Medical and Surgical Oncology, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern, Dallas, Texas. · Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, Maryland. · Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, Maryland. Electronic address: mlim3@jhmi.edu. · Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Hospital, Baltimore, Maryland. Electronic address: kjanson3@jhmi.edu. ·Int J Radiat Oncol Biol Phys · Pubmed #29485071.

ABSTRACT: PURPOSE: To characterize the effect of concurrent stereotactic radiosurgery-stereotactic radiation therapy (SRS-SRT) and immune checkpoint inhibitors on patient outcomes and safety in patients with brain metastases (BMs). METHODS AND MATERIALS: We retrospectively identified metastatic non-small cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We included SRS-SRT patients who were treated with anti-cytotoxic T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death protein 1 receptor (nivolumab, pembrolizumab). Patients who were given immune checkpoint inhibitors on active or unreported clinical trials were excluded, and concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2 weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent ICI, or SRS-SRT with concurrent ICI. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier survival curves, and Cox proportional hazards models were used for multivariate analysis. Logistic regression was used to identify predictors of acute neurologic toxicity, immune-related adverse events, and new BMs. RESULTS: A total of 260 patients were treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of ≥3 new BMs after SRS-SRT (P=.045; odds ratio, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5 months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated with improved OS compared with SRS-SRT alone (P=.002; hazard ratio [HR], 2.69) and compared with nonconcurrent SRS-SRT and ICI (P=.006; HR, 2.40) on multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was significant in comparison with patients treated with SRS-SRT before ICI (P=.002; HR, 3.82) or after ICI (P=.021; HR, 2.64). CONCLUSIONS: Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events.

11 Article Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab. 2017

Riaz, Nadeem / Havel, Jonathan J / Makarov, Vladimir / Desrichard, Alexis / Urba, Walter J / Sims, Jennifer S / Hodi, F Stephen / Martín-Algarra, Salvador / Mandal, Rajarsi / Sharfman, William H / Bhatia, Shailender / Hwu, Wen-Jen / Gajewski, Thomas F / Slingluff, Craig L / Chowell, Diego / Kendall, Sviatoslav M / Chang, Han / Shah, Rachna / Kuo, Fengshen / Morris, Luc G T / Sidhom, John-William / Schneck, Jonathan P / Horak, Christine E / Weinhold, Nils / Chan, Timothy A. ·Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR 97213, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. · Medical Oncology, Clínica Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. · Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98105, USA. · Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA. · Department of Surgery and University of Virginia Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. · Bristol-Myers Squibb, Princeton, NJ 08648, USA. · Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: weinholn@mskcc.org. · Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: chant@mskcc.org. ·Cell · Pubmed #29033130.

ABSTRACT: The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific transcriptional networks, and upregulation of immune checkpoint genes that were more pronounced in patients with response. Temporal changes in intratumoral TCR repertoire revealed expansion of T cell clones in the setting of neoantigen loss. Comprehensive genomic profiling data in this study provide insight into nivolumab's mechanism of action.

12 Article Two Cases of Sinusitis Induced by Immune Checkpoint Inhibition. 2017

Dein, Eric / Sharfman, William / Kim, Jean / Gellad, Fouad / Shah, Ami A / Bingham, Clifton O / Cappelli, Laura C. ·Departments of *Medicine, Division of Rheumatology †Oncology ‡Otolaryngology §Radiology, Johns Hopkins School of Medicine, Baltimore, MD. ·J Immunother · Pubmed #28614096.

ABSTRACT: We report the acute onset of aseptic sinusitis in 2 patients receiving the immune checkpoint inhibitors, ipilimumab and nivolumab, for treatment of metastatic melanoma. Ipilimumab, a monoclonal antibody targeting cytotoxic T-lymphocyte antigen-4, and nivolumab, targeting programmed cell death-1, have been associated with numerous immune-related adverse events. To the authors' knowledge, this is the first report of aseptic sinusitis as a consequence of immune checkpoint inhibition therapy.

13 Article Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis. 2017

Larkin, James / Chmielowski, Bartosz / Lao, Christopher D / Hodi, F Stephen / Sharfman, William / Weber, Jeffrey / Suijkerbuijk, Karijn P M / Azevedo, Sergio / Li, Hewei / Reshef, Daniel / Avila, Alexandre / Reardon, David A. ·The Royal Marsden, London, United Kingdom James.larkin@rmh.nhs.uk. · University of California Los Angeles Medical Center, Santa Monica, California, USA. · University of Michigan, Ann Arbor, Michigan, USA. · Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, Maryland, USA. · New York University Langone Medical Center, New York, New York, USA. · University Medical Center Utrecht Cancer Center, Utrecht, Netherlands. · Hospital Mae de Deus, Porto Alegre, Brazil. · Bristol-Myers Squibb, Princeton, New Jersey, USA. ·Oncologist · Pubmed #28495807.

ABSTRACT: BACKGROUND: Despite unprecedented efficacy across multiple tumor types, immune checkpoint inhibitor therapy is associated with a unique and wide spectrum of immune-related adverse events (irAEs), including neurologic events ranging from mild headache to potentially life-threatening encephalitis. Here, we summarize neurologic irAEs associated with nivolumab and ipilimumab melanoma treatment, present cases of treatment-related encephalitis, and provide practical guidance on diagnosis and management. METHODS: We searched a Global Pharmacovigilance and Epidemiology database for neurologic irAEs reported over an 8-year period in patients with advanced melanoma receiving nivolumab with or without ipilimumab from 12 studies sponsored by Bristol-Myers Squibb. Serious neurologic irAEs were reviewed, and relationship to nivolumab or ipilimumab was assigned. RESULTS: In our search of 3,763 patients, 35 patients (0.93%) presented with 43 serious neurologic irAEs, including neuropathy ( CONCLUSION: Both oncologists and neurologists need to be aware of signs and symptoms of serious but uncommon neurologic irAEs associated with checkpoint inhibitors. Prompt diagnosis and management using an established algorithm are critical to minimize serious complications from these neurologic irAEs. IMPLICATIONS FOR PRACTICE: With increasing use of checkpoint inhibitors in cancer, practicing oncologists need to be aware of the potential risk of neurologic immune-related adverse events and be able to provide prompt treatment of this uncommon, but potentially serious, class of adverse events. We summarize neurologic adverse events related to nivolumab alone or in combination with ipilimumab in patients with advanced melanoma from 12 studies and examine in depth 6 cases of encephalitis. We also provide input and guidance on the existing neurologic adverse events management algorithm for nivolumab and ipilimumab.

14 Article Colonic ulcerations may predict steroid-refractory course in patients with ipilimumab-mediated enterocolitis. 2017

Jain, Animesh / Lipson, Evan J / Sharfman, William H / Brant, Steven R / Lazarev, Mark G. ·Animesh Jain, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of North Carolina Chapel Hill, Chapel Hill, NC 27599-7080, United States. ·World J Gastroenterol · Pubmed #28373768.

ABSTRACT: AIM: To investigate management of patients who develop ipilimumab-mediated enterocolitis, including association of endoscopic findings with steroid-refractory symptoms and utility of infliximab as second-line therapy. METHODS: We retrospectively reviewed all patients at our center with metastatic melanoma who were treated with ipilimumab between March 2011 and May 2014. All patients received a standard regimen of intravenous ipilimumab 3 mg/kg every 3 wk for four doses or until therapy was stopped due to toxicity or disease progression. Basic demographic and clinical data were collected on all patients. For patients who developed grade 2 or worse diarrhea (increase of 4 bowel movements per day), additional data were collected regarding details of gastrointestinal symptoms, endoscopic findings and treatment course. Descriptive statistics were used. RESULTS: A total of 114 patients were treated with ipilimumab during the study period and all were included. Sixteen patients (14%) developed ≥ grade 2 diarrhea. All patients were treated with high-dose corticosteroids (1-2 mg/kg prednisone daily or equivalent). Nine of 16 patients (56%) had ongoing diarrhea despite high-dose steroids. Steroid-refractory patients received one dose of intravenous infliximab at 5 mg/kg, and all but one had brisk resolution of diarrhea. Fourteen of the patients underwent either colonoscopy or sigmoidoscopy with variable endoscopic findings, ranging from mild erythema to colonic ulcers. Among 8 patients with ulcers demonstrated by sigmoidoscopy or colonoscopy, 7 patients (88%) developed steroid-refractory symptoms requiring infliximab. With a median follow-up of 264 d, no major adverse events associated with prednisone or infliximab were reported. CONCLUSION: In patients with ipilimumab-mediated enterocolitis, the presence of colonic ulcers on endoscopy was associated with a steroid-refractory course.

15 Article BRAF-V600 mutational status affects recurrence patterns of melanoma brain metastasis. 2017

Maxwell, Russell / Garzon-Muvdi, Tomas / Lipson, Evan J / Sharfman, William H / Bettegowda, Chetan / Redmond, Kristin J / Kleinberg, Lawrence R / Ye, Xiaobu / Lim, Michael. ·Department of Neurosurgery, Johns Hopkins Medical Institutes, Baltimore, MD. · Department of Oncology, Johns Hopkins Medical Institutes, Baltimore, MD. · Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Medical Institutes, Baltimore, MD. ·Int J Cancer · Pubmed #27342756.

ABSTRACT: Brain metastasis is common and carries a poor prognosis in melanoma. A single institution, retrospective cohort of 225 melanoma patients was analyzed to determine if BRAF-V600 mutational status was associated with brain metastasis. Eighty-three of the 225 patients (37%) had BRAF-V600 mutations. At initial diagnosis, BRAF-V600 mutations were associated with younger age (p ≤ 0.001), higher proportion of females (p = 0.0037), higher AJCC stage (p = 0.030), regional lymph node involvement (p = 0.047), and family history of cancer (p = 0.044). Compared to BRAF-WT, BRAF-V600 patients had an increased risk of brain metastasis in multivariate analysis (OR = 2.24; 95% CL = 1.10-4.58; p = 0.027). However, BRAF-V600 patients treated with a selective BRAF inhibitor (BRAFi) had a similar risk of brain metastasis compared to BRAF-WT patients (OR = 1.00; 95% CL = 0.37-2.65; p = 0.98). Moreover, treatment with BRAFi significantly prolonged the time from initial diagnosis to brain metastasis diagnosis (HR = 0.30; 95% CL = 0.11-0.79; p = 0.015). Compared to other tissues, the brain was the most frequent site of metastasis in BRAF-V600 patients without BRAFi (42% ± 7%). The frequency of brain metastasis was lower in BRAF-WT and BRAF-V600 patients with BRAFi (25% ± 4% and 25% ± 8%, respectively). The proportion of patients with brain metastasis as the only site was 40%, 60%, and 0% in the BRAF-WT, BRAF-V600 without BRAFi, and BRAF-V600 with BRAFi groups, respectively. This study provides evidence on the clinical importance of BRAF-V600 mutations and BRAF inhibition in the progression to melanoma brain metastasis.

16 Article Successful administration of ipilimumab to two kidney transplantation patients with metastatic melanoma. 2014

Lipson, Evan J / Bodell, Mabel A / Kraus, Edward S / Sharfman, William H. ·Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD evanlipson@jhmi.edu. · Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD. ·J Clin Oncol · Pubmed #24493726.

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