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Melanoma: HELP
Articles by April K. S. Salama
Based on 42 articles published since 2010
(Why 42 articles?)
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Between 2010 and 2020, April Salama wrote the following 42 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline New NCCN Guidelines for Uveal Melanoma and Treatment of Recurrent or Progressive Distant Metastatic Melanoma. 2018

Barker, Christopher A / Salama, April K. ·Presented by Christopher A. Barker, MD, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, and April K. Salama, MD, Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina. ·J Natl Compr Canc Netw · Pubmed #29784747.

ABSTRACT: The NCCN Guidelines Panel for Melanoma debuted new guidelines for uveal melanoma at the NCCN 23rd Annual Conference. Although uveal melanoma and cutaneous melanoma share the same name, they do have different characteristics and treatments. The NCCN Guidelines describe how tumor size guides therapeutic options, which for most tumors is radiotherapy. Predictors of melanoma-related mortality include advanced age, larger tumor size, and histopathologic and molecular features. The NCCN Guidelines for Cutaneous Melanoma have not changed notably, but adjuvant therapy with immunotherapies is now recommended. The best second-line treatment in the metastatic setting remains unclear.

2 Guideline NCCN Guidelines Insights: Melanoma, Version 3.2016. 2016

Coit, Daniel G / Thompson, John A / Algazi, Alain / Andtbacka, Robert / Bichakjian, Christopher K / Carson, William E / Daniels, Gregory A / DiMaio, Dominick / Fields, Ryan C / Fleming, Martin D / Gastman, Brian / Gonzalez, Rene / Guild, Valerie / Johnson, Douglas / Joseph, Richard W / Lange, Julie R / Martini, Mary C / Materin, Miguel A / Olszanski, Anthony J / Ott, Patrick / Gupta, Aparna Priyanath / Ross, Merrick I / Salama, April K / Skitzki, Joseph / Swetter, Susan M / Tanabe, Kenneth K / Torres-Roca, Javier F / Trisal, Vijay / Urist, Marshall M / McMillian, Nicole / Engh, Anita. ·From Memorial Sloan Kettering Cancer Center; Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance; UCSF Helen Diller Family Comprehensive Cancer Center; Huntsman Cancer Institute at the University of Utah; University of Michigan Comprehensive Cancer Center; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; UC San Diego Moores Cancer Center; Fred & Pamela Buffett Cancer Center; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; The University of Tennessee Health Science Center; Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute; University of Colorado Cancer Center; Aim at Melanoma; Vanderbilt-Ingram Cancer Center; Mayo Clinic Cancer Center; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Robert H. Lurie Comprehensive Cancer Center of Northwestern University; Yale Cancer Center/Smilow Cancer Hospital; Fox Chase Cancer Center; Dana-Farber/Brigham and Women's Cancer Center; The University of Texas MD Anderson Cancer Center; Duke Cancer Institute; Roswell Park Cancer Institute; Stanford Cancer Institute; Massachusetts General Hospital Cancer Center; Moffitt Cancer Center; City of Hope Comprehensive Cancer Center; University of Alabama at Birmingham Comprehensive Cancer Center; and National Comprehensive Cancer Network. ·J Natl Compr Canc Netw · Pubmed #27496110.

ABSTRACT: The NCCN Guidelines for Melanoma have been significantly revised over the past few years in response to emerging data on a number of novel agents and treatment regimens. These NCCN Guidelines Insights summarize the data and rationale supporting extensive changes to the recommendations for systemic therapy in patients with metastatic or unresectable melanoma.

3 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.

4 Guideline Melanoma, version 4.2014. 2014

Coit, Daniel G / Thompson, John A / Andtbacka, Robert / Anker, Christopher J / Bichakjian, Christopher K / Carson, William E / Daniels, Gregory A / Daud, Adil / Dimaio, Dominick / Fleming, Martin D / Gonzalez, Rene / Guild, Valerie / Halpern, Allan C / Hodi, F Stephen / Kelley, Mark C / Khushalani, Nikhil I / Kudchadkar, Ragini R / Lange, Julie R / Martini, Mary C / Olszanski, Anthony J / Ross, Merrick I / Salama, April / Swetter, Susan M / Tanabe, Kenneth K / Trisal, Vijay / Urist, Marshall M / McMillian, Nicole R / Ho, Maria / Anonymous5190793. ·From 1Memorial Sloan-Kettering Cancer Center; 2Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance; 3Huntsman Cancer Institute at the University of Utah; 4University of Michigan Comprehensive Cancer Center; 5The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; 6UC San Diego Moores Cancer Center; 7UCSF Helen Diller Family Comprehensive Cancer Center; 8Fred & Pamela Buffett Cancer Center at The Nebraska Medical Center; 9St. Jude Children's Research Hospital/The University of Tennessee Health Science Center; 10University of Colorado Cancer Center; 11Aim at Melanoma; 12Dana-Farber/Brigham and Women's Cancer Center; 13Vanderbilt-Ingram Cancer Center; 14Roswell Park Cancer Institute; 15Moffitt Cancer Center; 16The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; 17Robert H. Lurie Comprehensive Cancer Center of Northwestern University; 18Fox Chase Cancer Center; 19The University of Texas MD Anderson Cancer Center; 20Duke Cancer Institute; 21Stanford Cancer Institute; 22Massachusetts General Hospital Cancer Center; 23City of Hope Comprehensive Cancer Center; 24University of Alabama at Birmingham Comprehensive Cancer Center; and 25National Comprehensive Cancer Network. ·J Natl Compr Canc Netw · Pubmed #24812131.

ABSTRACT: The NCCN Guidelines for Melanoma provide multidisciplinary recommendations for the management of patients with melanoma. These NCCN Guidelines Insights highlight notable recent updates. Dabrafenib and trametinib, either as monotherapy (category 1) or combination therapy, have been added as systemic options for patients with unresectable metastatic melanoma harboring BRAF V600 mutations. Controversy continues regarding the value of adjuvant radiation for patients at high risk of nodal relapse. This is reflected in the category 2B designation to consider adjuvant radiation following lymphadenectomy for stage III melanoma with clinically positive nodes or recurrent disease.

5 Review Updates in adjuvant systemic therapy for melanoma. 2019

Kwak, Minyoung / Farrow, Norma E / Salama, April K S / Mosca, Paul J / Hanks, Brent A / Slingluff, Craig L / Beasley, Georgia M. ·Department of Surgery, University of Virginia, Charlottesville, Virginia. · Department of Surgery, Duke University, Durham, North Carolina. · Department of Medicine, Duke University, Durham, North Carolina. · Department of Pharmacology and Cancer Biology. ·J Surg Oncol · Pubmed #30481375.

ABSTRACT: There has been a rapid increase in adjuvant therapies approved for treatment following surgical resection of stages III/IV melanoma. We review current indications for adjuvant therapy, which currently includes a heterogenous group of stages III and IV patients with melanoma. We describe several pivotal clinical trials of systemic immune therapies, targeted immune therapies, and adjuvant vaccine strategies. Finally, we discuss the evidence for selecting the most appropriate treatment regimen(s) for the individual patient.

6 Review Can binimetinib, encorafenib and masitinib be more efficacious than currently available mutation-based targeted therapies for melanoma treatment? 2017

Turner, Megan C / Rossfeld, Kara / Salama, April K S / Tyler, Douglas / Beasley, Georgia. ·a Department of Surgery , Duke University , Durham , NC , USA. · b Department of Surgery , Ohio State University , Columbus , OH , USA. · c Department of Medicine , Duke University , Durham , NC , USA. · d Department of Surgery , University of Texas Medical Branch at Galveston , Galveston , TX , USA. ·Expert Opin Pharmacother · Pubmed #28277830.

ABSTRACT: INTRODUCTION: Historically, there were few effective and durable treatments for metastatic melanoma. Recently, mutation based targeted therapies have revolutionized treatment and outcomes for patients with metastatic melanoma. Specifically, inhibitors aimed at BRAF, NRAS, and C-KIT mutations are now commonly used in treatment for patients harboring the specific mutations. Areas covered: A brief review of current BRAF, NRAS, and C-KIT inhibitors provides background for a thorough review of newly developed agents namely binimetinib, a MEK inhibitor, encorafenib a BRAF inhibitor, and masitinib which inhibits C-KIT. Expert opinion: While the 3 novel agents reviewed here have potential for use in melanoma, optimal utilization will occur once a more personalized approach incorporating genomic, proteomic, and immunologic data guides therapeutic decisions.

7 Review Copper suppression as cancer therapy: the rationale for copper chelating agents in 2016

Sammons, Sarah / Brady, Donita / Vahdat, Linda / Salama, April Ks. ·Hematology/Oncology, Department of Internal Medicine, Duke University Medical Center, 203 Research Drive, MSRB1, Room 397, Box 2639, Durham, NC 27710, USA. · Department of Cancer Biology & Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, 421 Curie Boulevard, 612 BRBII/III, Philadelphia, PA 19104, USA. · Division of Hematology & Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA. · Melanoma Program, Division of Medical Oncology, Department of Internal Medicine, Duke University Medical Center, 25176 Morris Bldg, DUMC 3198, Durham, NC 27710, USA. ·Melanoma Manag · Pubmed #30190890.

ABSTRACT: The successful targeting of oncogenic

8 Review Updates in Therapy for Advanced Melanoma. 2016

Singh, Bhavana P / Salama, April K S. ·Department of Internal Medicine, Duke University Medical Center, Durham, NC 27710, USA. bhavana.pendurthi@dm.duke.edu. · Division of Medical Oncology, Department of Internal Medicine, Duke University Medical Center, Durham, NC 27710, USA. april.salama@dm.duke.edu. ·Cancers (Basel) · Pubmed #26784231.

ABSTRACT: Cutaneous melanoma is one of the most aggressive forms of skin cancer, and is correlated with a large proportion of skin cancer-related deaths. Therapy for cutaneous melanoma has advanced greatly through careful identification of therapeutic targets and the development of novel immunotherapeutic approaches. The identification of BRAF as well as other driver mutations, have allowed for a specialized approach to treatment. In addition, immune checkpoint inhibition has dramatically changed the treatment landscape over the past 5-10 years. The successful targeting of CTLA-4, as well as PD-1/PD-L1, has been translated into meaningful clinical benefit for patients, with multiple other potential agents in development. Systemic therapy for cutaneous melanoma is becoming more nuanced and often takes a multifaceted strategy. This review aims to discuss the benefits and limitations of current therapies in systemic melanoma treatment as well as areas of future development.

9 Review MEK inhibition in the treatment of advanced melanoma. 2013

Salama, April K S / Kim, Kevin B. ·Division of Medical Oncology, Duke University Medical Center, DUMC 3476, Durham, NC, 27710, USA, april.salama@duke.edu. ·Curr Oncol Rep · Pubmed #23975010.

ABSTRACT: The RAS-RAF-MEK-ERK pathway is considered to be the most important signal transduction pathway in melanoma, and alterations in this pathway via various genetic mutations, such as BRAF and NRAS mutations, are known to be important drivers of melanomagenesis. As MEK is an essential intermediary kinase protein within this pathway, inhibition of MEK has been of a great interest as a molecular target therapy in melanoma. In fact, trametinib, a selective MEK inhibitor, has been shown to have a survival benefit over cytotoxic chemotherapy in patients with V600 BRAF-mutant metastatic melanoma, leading to the FDA approval for this patient population. MEK inhibitors may also be useful in treatment of advanced melanoma harboring other genetic mutations, such as NRAS and GNAQ/GNA11 mutations. Here, we review and discuss the preclinical and clinical data regarding MEK inhibitors and their role in the treatment of advanced melanoma.

10 Review BRAF in melanoma: current strategies and future directions. 2013

Salama, April K S / Flaherty, Keith T. ·Division of Medical Oncology, Duke University Medical Center, Durham North Carolina, USA. ·Clin Cancer Res · Pubmed #23770823.

ABSTRACT: Selective BRAF inhibitors have now been established as a standard of care option for patients diagnosed with metastatic melanoma whose tumors carry a BRAF mutation. Their successful development represents a milestone in the treatment of this disease, and has the potential to impact therapy for other malignancies as well. The use of these agents, however, has introduced a number of critical questions about the optimal use and selection of patients for BRAF inhibitor therapy. This review discusses the current status of BRAF inhibitor clinical development, the clinicopathologic features of BRAF-mutated melanoma, as well as strategies for overcoming resistance.

11 Review Trametinib (GSK1120212) in the treatment of melanoma. 2013

Salama, April K S / Kim, Kevin B. ·Duke University Medical Center, Division of Medical Oncology, Durham, NC, USA. ·Expert Opin Pharmacother · Pubmed #23432625.

ABSTRACT: INTRODUCTION: The discovery of somatic mutations in melanoma has advanced our knowledge of the biology of the disease. The mutations, such as those in NRAS, BRAF, GNAQ and GNA11, promote the growth of melanoma cells in most part through the mitogen-activated protein kinase (MAPK) pathway. Understanding the molecular pathways of some of these mutations has resulted in the successful development of selective BRAF inhibitors. Yet, a cure for advanced melanoma is far from reality. Targeting MAPK/ERK kinase (MEK), an essential intermediary kinase protein within the MAPK pathway, may be a promising way to treat patients with BRAF or other genomic mutation. AREAS COVERED: The authors discuss the MAPK pathway in melanoma and review the preclinical and clinical studies of the MEK inhibitor, trametinib , in melanoma. They also discuss the potential of using trametinib in the targeted therapy of advanced melanoma. EXPERT OPINION: Studies have demonstrated the activity of trametinib in BRAF-mutant melanoma, suggesting that it could be a very reasonable alternative to BRAF inhibitors for these patients. Current clinical investigations have shown great promise with the combination of trametinib and dabrafenib in patients with BRAF-mutant melanoma; a number of clinical trials of trametinib in combination with other targeted drugs are underway.

12 Clinical Trial A phase 2 study of glembatumumab vedotin, an antibody-drug conjugate targeting glycoprotein NMB, in patients with advanced melanoma. 2019

Ott, Patrick A / Pavlick, Anna C / Johnson, Douglas B / Hart, Lowell L / Infante, Jeffrey R / Luke, Jason J / Lutzky, Jose / Rothschild, Neal E / Spitler, Lynn E / Cowey, C Lance / Alizadeh, Aaron R / Salama, April K / He, Yi / Hawthorne, Thomas R / Bagley, Rebecca G / Zhang, Joshua / Turner, Christopher D / Hamid, Omid. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Medical Oncology, New York University School of Medicine, New York, New York. · Department of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. · Florida Cancer Specialists and Research Institute, Fort Myers, Florida. · Tennessee Oncology, PLLC, Nashville, Tennessee. · Department of Hematology/Oncology, University of Chicago Medical Center, Chicago, Illinois. · Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida. · Florida Cancer Specialists, West Palm Beach, Florida. · St. Mary's Medical Center, San Francisco, California. · Northern California Melanoma Center, Baylor University Medical Center, Dallas, Texas. · Northside Hospital Cancer Institute, Decatur, Georgia. · Department of Medical Oncology, Duke University, Durham, North Carolina. · Celldex Therapeutics, Inc, Hampton, New Jersey. · The Angeles Clinic and Research Institute, Los Angeles, California. ·Cancer · Pubmed #30690710.

ABSTRACT: BACKGROUND: Glembatumumab vedotin is an antibody-drug conjugate that produced preliminary clinical activity against advanced melanoma in a phase 1 dose-escalation trial. The objective of the current study was to investigate further the antitumor activity of glembatumumab vedotin at the recommended phase 2 dose in heavily pretreated patients with melanoma. METHODS: This single-arm, phase 2 study enrolled patients with stage IV melanoma who were refractory to checkpoint inhibition and to B-raf proto-oncogene, serine/threonine kinase (BRAF)/mitogen-activated protein kinase kinase (MEK) inhibition (in the presence of a BRAF valine mutation at codon 600). Patients received 1.9 mg/kg glembatumumab vedotin intravenously every 3 weeks until they developed disease progression or intolerance. The primary endpoint was objective response rate (ORR), which was determined according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included progression-free survival (PFS), duration of response, overall survival (OS), safety, and clinical efficacy versus tumor glycoprotein NMB (gpNMB) expression. Tumor expression of gpNMB was assessed using immunohistochemistry. RESULTS: In total, 62 patients received treatment. The ORR was 11% and the median response duration was 6.0 months (95% confidence interval [CI], 4.1 months to not reached). The median PFS was 4.4 months (95% CI, 2.6-5.5 months), and the median OS was 9.0 months (95% CI, 6.1-11.7 months). For patients who developed rash during the first cycle versus those who did not, the ORR was 21% versus 7%, respectively, and there was an overall improvement in PFS (hazard ratio, 0.43; P = .013) and OS (hazard ratio, 0.43; P = .017). The most frequent adverse events were alopecia, neuropathy, rash, fatigue, and neutropenia. With one exception, all evaluable tumors were positive for gpNMB, and 46 of 59 tumors (76%) had 100% gpNMB-positive epithelial cells. CONCLUSIONS: Glembatumumab vedotin had modest activity and an acceptable safety profile in patients with advanced melanoma who were refractory to checkpoint inhibitors and MEK/BRAF inhibition. Treatment-related rash may be associated with response.

13 Clinical Trial Efficacy and Safety of Pembrolizumab in Patients Enrolled in KEYNOTE-030 in the United States: An Expanded Access Program. 2017

Gangadhar, Tara C / Hwu, Wen-Jen / Postow, Michael A / Hamid, Omid / Daud, Adil / Dronca, Roxana / Joseph, Richard / O'Day, Steven J / Hodi, F S / Pavlick, Anna C / Kluger, Harriet / Oxborough, Romina P / Yang, Aiming / Gazdoiu, Mihaela / Kush, Debra A / Ebbinghaus, Scot / Salama, April K S. ·*Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA †The University of Texas MD Anderson Cancer Center, Houston, TX ‡Memorial Sloan Kettering Cancer Center §Weill Cornell Medical College §§NYU Clinical Cancer Center, New York, NY ∥The Angeles Clinic and Research Institute, Los Angeles ¶Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco ††The John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA #Mayo Clinic, Rochester, MN **Mayo Clinic, Jacksonville, FL ‡‡Dana-Farber Cancer Institute, Boston, MA ∥∥Yale Cancer Center, New Haven, CT ¶¶Clinigen, Weybridge, UK ##Merck & Co. Inc., Kenilworth, NJ ***Duke Cancer Institute, Durham, NC. ·J Immunother · Pubmed #29028788.

ABSTRACT: KEYNOTE-030 (ClinicalTrials.gov ID, NCT02083484) was a global expanded access program that allowed access to pembrolizumab, an antiprogrammed death 1 antibody, for patients with advanced melanoma before its regulatory approval. Patients with unresectable stage III/IV melanoma that progressed after standard-of-care therapy, including ipilimumab and, if BRAF mutant, a BRAF inhibitor, were eligible to receive pembrolizumab 2 mg/kg every 3 weeks. Response was assessed by immune-related response criteria by investigator review. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. In the United States, 979 patients enrolled between April and September 2014. Of the 947 evaluable patients, 621 (65.6%) remained on treatment and transitioned to receive commercial pembrolizumab following approval by the Food and Drug Administration, whereas 326 (34.4%) discontinued, most commonly for disease progression (39.6%) or death (26.4%). Objective response rate was 14.5% (95% confidence interval, 12.2%-16.8%) in the treated population (n=947) and 22.1% (95% confidence interval, 18.8%-25.5%) in patients who had ≥1 response assessment reported (n=619). Twelve patients achieved complete response. One hundred eighty-one (19.1%) patients experienced ≥1 treatment-related AE, most commonly general disorders (8.0%), skin/subcutaneous tissue disorders (7.3%), and gastrointestinal disorders (6.4%); 29 (3.1%) patients experienced ≥1 grade 3/4 treatment-related AE. Immune-mediated AEs were also reported. There were no treatment-related deaths. The safety and efficacy observed in this expanded access program were consistent with those previously reported for similar populations and support the use of pembrolizumab for patients with advanced melanoma.

14 Clinical Trial Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. 2017

Hamid, Omid / Puzanov, Igor / Dummer, Reinhard / Schachter, Jacob / Daud, Adil / Schadendorf, Dirk / Blank, Christian / Cranmer, Lee D / Robert, Caroline / Pavlick, Anna C / Gonzalez, Rene / Hodi, F Stephen / Ascierto, Paolo A / Salama, April K S / Margolin, Kim A / Gangadhar, Tara C / Wei, Ziwen / Ebbinghaus, Scot / Ibrahim, Nageatte / Ribas, Antoni. ·The Angeles Clinic and Research Institute, Los Angeles, CA, USA. Electronic address: ohamid@theangelesclinic.org. · Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. · University of Zürich, Zürich, Switzerland. · Ella Lemelbaum Institute of Melanoma, Sheba Medical Center, Tel Hashomer, Israel. · University of California, San Francisco, San Francisco, CA, USA. · University Hospital Essen, Essen, Germany. · Netherlands Cancer Institute, Amsterdam, The Netherlands. · University of Arizona Cancer Center, Tucson, AZ, USA. · Gustave Roussy and Paris-Sud University, Villejuif, France. · New York University Cancer Institute, New York, NY, USA. · University of Colorado Denver, Aurora, CO, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, Italy. · Duke Cancer Institute, Durham, NC, USA. · City of Hope, Duarte, CA, USA. · Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA. · Merck & Co., Inc., Kenilworth, NJ, USA. · University of California Los Angeles, Los Angeles, CA, USA. ·Eur J Cancer · Pubmed #28961465.

ABSTRACT: AIM: To evaluate the protocol-specified final analysis of overall survival (OS) in the KEYNOTE-002 study (NCT01704287) of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory, advanced melanoma. METHODS: In this randomised, phase II study, eligible patients had advanced melanoma with documented progression after two or more ipilimumab doses, previous BRAF or MEK inhibitor or both, if BRAF RESULTS: A total of 180 patients were randomised to pembrolizumab 2 mg/kg, 181 to pembrolizumab 10 mg/kg and 179 to chemotherapy. At a median follow-up of 28 months (range 24.1-35.5), 368 patients died and 98 (55%) crossed over to pembrolizumab. Pembrolizumab 2 mg/kg (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.67-1.10, p = 0.117) and 10 mg/kg (0.74, 0.57-0.96, p = 0.011) resulted in a non-statistically significant improvement in OS versus chemotherapy; median OS was 13.4 (95% CI 11.0-16.4) and 14.7 (95% CI 11.3-19.5), respectively, versus 11.0 months (95% CI 8.9-13.8), with limited improvement after censoring for crossover. Two-year survival rates were 36% and 38%, versus 30%. Progression-free survival, objective response rate and duration of response improved with pembrolizumab versus chemotherapy, regardless of dose. Grade III-V treatment-related adverse events occurred in 24 (13.5%), 30 (16.8%) and 45 (26.3%) patients, respectively. CONCLUSION: Improvement in OS with pembrolizumab was not statistically significant at either dose versus chemotherapy.

15 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.

16 Clinical Trial Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. 2016

Schadendorf, Dirk / Dummer, Reinhard / Hauschild, Axel / Robert, Caroline / Hamid, Omid / Daud, Adil / van den Eertwegh, Alfons / Cranmer, Lee / O'Day, Steven / Puzanov, Igor / Schachter, Jacob / Blank, Christian / Salama, April / Loquai, Carmen / Mehnert, Janice M / Hille, Darcy / Ebbinghaus, Scot / Kang, S Peter / Zhou, Wei / Ribas, Antoni. ·University Hospital Essen, Hufelandstrasse 55, D-45147 Essen, Germany. Electronic address: dirk.schadendorf@uk-essen.de. · Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, 8091 Zurich, Switzerland. Electronic address: Reinhard.Dummer@usz.ch. · Department of Dermatology, Venereology, and Allergology, University Hospital Schleswig-Holstein, Kiel Campus, Arnold-Heller Strasse 3, 24105 Kiel, Germany. Electronic address: ahauschild@dermatology.uni-kiel.de. · Gustave Roussy Cancer Campus and Paris-Sud University, 114 Rue Edouard Vaillant, 94800 Villejuif, France. Electronic address: Caroline.Robert@gustaveroussyr.fr. · The Angeles Clinic and Research Institute, 2001 Santa Monica Blvd, Ste 560W, Santa Monica, CA 90404, USA. Electronic address: ohamid@theangelesclinic.org. · University of California, San Francisco School of Medicine, 1600 Divisadero St, NZ Bldg A, San Francisco, CA 94115, USA. Electronic address: Adil.Daud@ucsf.edu. · Department of Medical Oncology, VU University Medical Center Amsterdam, De Boelelaan 1118, 1081 HZ Amsterdam, The Netherlands. Electronic address: vandeneertwegh@VUMC.nl. · Department of Hematology/Oncology, University of Arizona Cancer Center at UMC North, 3838 N. Campbell Ave, Tucson, AZ 85724, USA. Electronic address: lcranmer@uacc.arizona.edu. · The Los Angeles Skin Cancer Institute, The Beverly Hills Cancer Center, 8900 Wilshire Blvd, Beverly Hills, CA 90211, USA. Electronic address: stevenjoday@gmail.com. · Vanderbilt-Ingram Cancer Center, 2220 Pierce Ave, 777 Preston Research Building, Nashville, TN 37232, USA. Electronic address: igor.puzanov@vanderbilt.edu. · Department of Oncology, Ella Institute for Melanoma, Sheba Medical Center, Derech Sheba 2, Tel-Hashomer, Ramat-Gan, Israel. Electronic address: Jacob.Schachter@sheba.health.gov.il. · Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Electronic address: c.blank@nki.nl. · Division of Medical Oncology, Duke Cancer Institute, Duke University Medical Center, Box 3198, 20 Duke Medicine Circle, Durham, NC 27710, USA. Electronic address: april.salama@duke.edu. · Skin Clinic, Universitätsmedizin Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. Electronic address: carmen.loquai@unimedizin-mainz.de. · Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA. Electronic address: mehnerja@cinj.rutgers.edu. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: darcy_hille@merck.com. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: scot_ebbinghaus@merck.com. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: s.peter.kang@merck.com. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: wei.zhou2@merck.com. · Department of Medicine, Division of Hematology-Oncology, Jonsson Comprehensive Cancer Center (JCCC) at the University of California, Los Angeles (UCLA), 10833 Le Conte Ave, Los Angeles, CA 90095, USA. Electronic address: aribas@mednet.ucla.edu. ·Eur J Cancer · Pubmed #27596353.

ABSTRACT: BACKGROUND: In KEYNOTE-002, pembrolizumab significantly prolonged progression-free survival and was associated with a better safety profile compared with chemotherapy in patients with advanced melanoma that progressed after ipilimumab. We present health-related quality of life (HRQoL) outcomes from KEYNOTE-002. METHODS: Patients were randomly assigned 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or investigator-choice chemotherapy. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 instrument. A constrained longitudinal data analysis model was implemented to assess between-arm differences in HRQoL scores. The study is registered with ClinicalTrials.gov, number NCT01704287. RESULTS: Of the 540 patients enrolled, 520 were included in the HRQoL analysis. Baseline global health status (GHS) was similar across treatment arms. Compliance rates at week 12 were 76.6% (n = 108), 82.3% (n = 121), and 86.4% (n = 133) for the control, pembrolizumab 2 mg/kg Q3W, and pembrolizumab 10 mg/kg Q3W arms, respectively. From baseline to week 12, GHS/HRQoL scores were maintained to a higher degree in the pembrolizumab arms compared with the chemotherapy arm (decrease of -2.6 for each pembrolizumab arm versus -9.1 for chemotherapy; P = 0.01 for each pembrolizumab arm versus chemotherapy). Fewer patients treated with pembrolizumab experienced deterioration in GHS at week 12 (31.8% for pembrolizumab 2 mg/kg, 26.6% for 10 mg/kg, and 38.3% for chemotherapy), with similar trends observed for the individual functioning and symptoms scales. CONCLUSIONS: HRQoL was better maintained with pembrolizumab than with chemotherapy in KEYNOTE-002, supporting the use of pembrolizumab in patients with ipilimumab-refractory melanoma.

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

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

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

18 Clinical Trial Immunotherapy following regional chemotherapy treatment of advanced extremity melanoma. 2014

Jiang, Betty S / Beasley, Georgia M / Speicher, Paul J / Mosca, Paul J / Morse, Michael A / Hanks, Brent / Salama, April / Tyler, Douglas S. ·Department of Surgery, Duke University Medical Center, Durham, NC, USA. ·Ann Surg Oncol · Pubmed #24700302.

ABSTRACT: PURPOSE: Following regional chemotherapy (RC) for melanoma, approximately 75 % of patients will progress. The role of immunotherapy after RC has not been well established. METHODS: A prospective, single-institution database of 243 patients with in-transit melanoma (1995-2013) was queried for patients who had progression of disease after RC with melphalan and subsequently received systemic immunotherapy. Fifteen patients received IL-2 only, 12 received ipilimumab only, and 6 received IL-2 followed by ipilimumab. Fisher's exact test was used to determine if there was a difference in number of complete responders after immunotherapy. RESULTS: With IL-2 alone, all patients progressed. After ipilimumab alone, three patients had a complete response and nine had progressive disease. Six additional patients received IL-2 first then ipilimumab. All six progressed on IL-2 but three went on to have a complete response to ipilimumab while three progressed. The use of ipilimumab at any time in patients who progressed after RC was associated with higher rate of complete response compared to use of IL-2 alone (33 vs. 0 %; p = 0.021). CONCLUSIONS: Patients with progression after regional therapy for melanoma may benefit from immunologic therapy. In this group of patients, immune checkpoint blockade with ipilimumab has a higher complete response rate than T cell stimulation with IL-2, with no complete responders in the IL-2 only group. Furthermore, the complete response rate for ipilimumab in our cohort is higher than reported response rates in the literature for ipilimumab alone, suggesting that the effects of immunotherapy may be bolstered by previous regional treatment.

19 Clinical Trial Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104). 2012

Gajewski, Thomas F / Salama, April K S / Niedzwiecki, Donna / Johnson, Jeffrey / Linette, Gerald / Bucher, Cynthia / Blaskovich, Michelle A / Sebti, Said M / Haluska, Frank / Anonymous3900744. ·The University of Chicago, Section of Hematology/Oncology, 5841 S, Maryland Ave, MC2115, Chicago, IL 60637, USA. tgajewsk@medicine.bsd.uchicago.edu ·J Transl Med · Pubmed #23228035.

ABSTRACT: BACKGROUND: Multiple farnesylated proteins are involved in signal transduction in cancer. Farnesyltransferase inhibitors (FTIs) have been developed as a strategy to inhibit the function of these proteins. As FTIs inhibit proliferation of melanoma cell lines, we undertook a study to assess the impact of a FTI in advanced melanoma. As farnesylated proteins are also important for T cell activation, measurement of effects on T cell function was also pursued. METHODS: A 3-stage trial design was developed with a maximum of 40 patients and early stopping if there were no responders in the first 14, or fewer than 2 responders in the first 28 patients. Eligibility included performance status of 0-1, no prior chemotherapy, at most 1 prior immunotherapy, no brain metastases, and presence of at least 2 cutaneous lesions amenable to biopsy. R115777 was administered twice per day for 21 days of a 28-day cycle. Patients were evaluated every 2 cycles by RECIST. Blood and tumor were analyzed pre-treatment and during week 7. RESULTS: Fourteen patients were enrolled. Two patients had grade 3 toxicities, which included myelosuppression, nausea/vomiting, elevated BUN, and anorexia. There were no clinical responses. All patients analyzed showed potent inhibition of FT activity (85-98%) in tumor tissue; inhibition of phosphorylated ERK and Akt was also observed. T cells showed evidence of FT inhibition and diminished IFN-γ production. CONCLUSIONS: Despite potent target inhibition, R115777 showed no evidence of clinical activity in this cohort of melanoma patients. Inhibition of T cell function by FTIs has potential clinical implications. Clinicaltrials.gov number NCT00060125.

20 Article Retrospective analysis of safety and efficacy of anti-PD-1 therapy and radiation therapy in advanced melanoma: A bi-institutional study. 2019

Mowery, Yvonne M / Patel, Kirtesh / Chowdhary, Mudit / Rushing, Christel N / Roy Choudhury, Kingshuk / Lowe, Jared R / Olson, Adam C / Wisdom, Amy J / Salama, Joseph K / Hanks, Brent A / Khan, Mohammad K / Salama, April K S. ·Department of Radiation Oncology, Duke University Medical Center, Durham, United States. Electronic address: yvonne.mowery@duke.edu. · Department of Radiation Oncology, Emory University School of Medicine, Atlanta, United States. Electronic address: kirtesh.patel@yale.edu. · Department of Radiation Oncology, Emory University School of Medicine, Atlanta, United States. Electronic address: Mudit_Chowdhary@rush.edu. · Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, United States. Electronic address: christel.rushing@duke.edu. · Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, United States; Department of Radiology, Duke University Medical Center, Durham, United States. Electronic address: kingshuk.roy.choudhury@duke.edu. · Department of Medicine, Duke University Medical Center, Durham, United States. Electronic address: jared.lowe@duke.edu. · Department of Radiation Oncology, Duke University Medical Center, Durham, United States. Electronic address: olsonac2@upmc.edu. · Duke University School of Medicine, Durham, United States. Electronic address: amy.wisdom@duke.edu. · Department of Radiation Oncology, Duke University Medical Center, Durham, United States. Electronic address: joseph.salama@duke.edu. · Department of Medicine, Duke University Medical Center, Durham, United States. Electronic address: brent.hanks@duke.edu. · Department of Radiation Oncology, Emory University School of Medicine, Atlanta, United States. Electronic address: m.k.khan@emory.edu. · Department of Medicine, Duke University Medical Center, Durham, United States. Electronic address: april.salama@duke.edu. ·Radiother Oncol · Pubmed #31252292.

ABSTRACT: BACKGROUND AND PURPOSE: Antibodies against programmed cell death protein 1 (PD-1) are standard treatments for advanced melanoma. Palliative radiation therapy (RT) is commonly administered for this disease. Safety and optimal timing for this combination for melanoma has not been established. MATERIALS AND METHODS: In this retrospective cohort study, records for melanoma patients who received anti-PD-1 therapy at Duke University or Emory University (1/1/2013-12/30/2015) were reviewed. Patients were categorized by receipt of RT and RT timing relative to anti-PD-1. RESULTS: 151 patients received anti-PD-1 therapy. Median follow-up was 12.9 months. Patients receiving RT (n = 85) had worse baseline prognostic factors than patients without RT (n = 66). One-year overall survival (OS) was lower for RT patients than patients without RT (66%, 95% CI: 55-77% vs 83%, 95% CI: 73-92%). One-year OS was 61% for patients receiving RT before anti-PD-1 (95% CI: 46-76%), 78% for RT during anti-PD-1 (95% CI: 60-95%), and 58% for RT after anti-PD-1 (95% CI: 26-89%). On Cox regression, OS for patients without RT did not differ significantly from patients receiving RT during anti-PD-1 (HR 1.07, 95% CI: 0.41-2.84) or RT before anti-PD-1 (HR 0.56, 95% CI: 0.21-1.45). RT and anti-PD-1 therapy administered within 6 weeks of each other was well tolerated. CONCLUSION: RT can be safely administered with anti-PD-1 therapy. Despite worse baseline prognostic characteristics for patients receiving RT, OS was similar for patients receiving concurrent RT with anti-PD-1 therapy compared to patients receiving anti-PD-1 therapy alone.

21 Article The Emerging Role of Surgery for Patients With Advanced Melanoma Treated With Immunotherapy. 2019

Puza, Charles J / Bressler, Elizabeth Schell / Terando, Alicia M / Howard, John Harrison / Brown, Michael C / Hanks, Brent / Salama, April K S / Beasley, Georgia M. ·Department of Surgery, Duke University, Durham, North Carolina. Electronic address: Charles.puza@duke.edu. · Department of Pathology and Department of Dermatology, Duke University, Durham, North Carolina. · Division of Surgical Oncology, Ohio State University, Columbus, Ohio. · Department of Surgery, Duke University, Durham, North Carolina. · Division of Medical Oncology, Duke University, Durham, North Carolina. ·J Surg Res · Pubmed #30694757.

ABSTRACT: BACKGROUND: The emergence of immune checkpoint inhibitors (ICIs) has improved survival for patients with metastatic melanoma. The types of disease-response patterns to ICI therapy can be more complex relative to traditional chemotherapy and include mixed responses, pseudoprogression, and oligoprogression. The potential benefit of surgery after incomplete response to ICI therapy has not been explored. The purpose of this study was to explore outcomes of surgery after ICI therapy in patients with metastatic melanoma. METHODS: A retrospective study was conducted at two centers and included patients with melanoma who underwent surgery after treatment with monotherapy or combination therapy with anti-programmed cell death protein (PD) 1 and/or anti-cytotoxic T-lymphocyte associated protein (CTLA)-4 checkpoint blockade. RESULTS: Of 25 patients, nine received anti-CTLA-4 therapy, eight received anti-PD-1 therapy, and eight received both anti-CTLA-4 and anti-PD-1 therapies before surgery. Five patients were treated in the adjuvant setting and developed new lesions, whereas 20 patients were treated for metastatic disease and underwent surgery for persistent disease on imaging after ICI therapy. Twenty-five patients underwent 30 operations without complications. Twenty-seven of 30 masses were confirmed to be melanoma on pathology, one was a desmoid tumor and two were necrosis. At a median follow-up of 14.2 months, 2 patients died, 8 were alive with a known disease, and 15 continued to have no further evidence of disease. CONCLUSIONS: Surgery was well tolerated in this cohort of patients receiving ICI therapy for melanoma. Surgery may benefit select patients with an oligoprogressive disease after ICI therapy. After a mixed response, surgery remains the only definitive method to render some patients free of disease.

22 Article Delayed onset of neurosarcoidosis after concurrent ipilimumab/nivolumab therapy. 2018

Tan, Irena / Malinzak, Michael / Salama, April K S. ·Department of Internal Medicine, Duke University Medical Center, 2301 Erwin Rd, Durham, NC, 27701, USA. irena.tan@duke.edu. · Department of Neuroradiology, Duke University Medical Center, 2301 Erwin Rd, Durham, NC, 27701, USA. · Division of Medical Oncology, Duke University Medical Center, 2301 Erwin Rd, Durham, NC, 27701, USA. ·J Immunother Cancer · Pubmed #30064495.

ABSTRACT: BACKGROUND: Immune checkpoint inhibitors have transformed the treatment landscape for many cancers, including metastatic melanoma, but have also opened the door for a diverse variety of immune-related adverse effects. CASE PRESENTATION: We describe the first reported case of presumed neurosarcoidosis as an immune-related adverse effect that developed nearly a year after discontinuation of treatment with combination ipilimumab and nivolumab for recurrent metastatic melanoma. The patient was noted to develop clinical signs consistent with systemic sarcoidosis shortly after the initiation of treatment and underwent a biopsy of hilar lymphadenopathy that confirmed sarcoidosis and after which immunotherapy was discontinued. His melanoma remained stable on surveillance imaging for the next year after which time he developed neurological symptoms and was found to have MRI brain abnormalities without evidence of intracranial metastatic disease, consistent with probable neurosarcoidosis given biopsy-proven systemic sarcoidosis and lack of evidence of CNS infection or malignancy. He underwent treatment with high dose steroids, followed by infliximab, and then methotrexate with both clinical and radiographic improvement within 4 months of starting treatment. CONCLUSIONS: Immune-related adverse effects often occur within 3-6 months of receiving immune checkpoint inhibitor therapy, with some reports of late toxicity. This report highlights a case of probable neurosarcoidosis nearly a year after discontinuation of immune checkpoint therapy. The potential for durable responses after discontinuation of therapy also likely underscores a potential for late toxicity. In patients presenting with new or unexplained symptoms after checkpoint inhibitor therapy, the index of suspicion for an immune-related adverse effect should remain high, irrespective of timing.

23 Article Metastatic melanoma patients' sensitivity to ipilimumab cannot be predicted by tumor characteristics. 2017

Rossfeld, Kara / Hade, Erinn M / Gangi, Alexandra / Perez, Matthew / Kinsey, Emily N / Grabska, Joanna / Ederle, Ashley / Zager, Jonathan / Salama, April K / Olencki, Thomas E / Beasley, Georgia M. ·Division of Surgical Oncology. · Department of Internal Medicine, Division of Medical Oncology, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH. · H. Lee Moffitt Cancer Center, Tampa, FL. · Division of Medical Oncology, Duke University, Durham, NC. · Division of Advanced Oncologic and Gastrointestinal Surgery, Duke University, Durham, NC. ·Int J Surg Oncol (N Y) · Pubmed #29177235.

ABSTRACT: Immune checkpoint inhibitors have dramatically changed the prognosis for patients with metastatic melanoma. However, not all patients respond to therapy and toxicities can be severe leaving need for reliable clinical predictive markers. Methods: We examined primary tumor characteristics including ulceration, BRAF mutation status, and Breslow depth in patients who subsequently developed stage IV disease and were treated with ipilimumab at 3 institutions. Patients in this study were not treated on clinical trials. To investigate the relationship between patient characteristics at the time of diagnosis and survival following melanoma diagnosis we utilized Cox proportional hazards models, accounting for delayed entry into the study cohort. Cox models estimate the age and institution adjusted hazard ratios for risk of death. Results: Of patients (n=385) treated with ipilimumab for stage IV melanoma, 302 met inclusion criteria. The complete response to ipilimumab was 5%, partial response was 13%, 18% had stable disease, 62% had progressive disease, and 5 unknown. The median overall survival rate was 2.03 years [95% confidence interval (CI): 0.13, 3.05]. Primary tumor Breslow depth, lymphovascular invasion, BRAF status, and ulceration did not predict sensitivity to ipilimumab. In this study patient cohort, BRAF mutation (adjusted hazard ratio: 1.43, 95% CI: 0.98, 2.07) and presence of ulceration (adjusted hazard ratio: 1.47, 95% CI: 0.95, 2.26) contributed to an increased risk of death. Conclusions: The presence of ulceration did not correlate with sensitivity to ipilimumab. Ulceration of the primary tumor and a BRAF mutation were moderately associated with worse survival in patients with metastatic melanoma treated with ipilimumab.

24 Article Sentinel Lymph Node Biopsy for Recurrent Melanoma: A Multicenter Study. 2017

Beasley, Georgia M / Hu, Yinin / Youngwirth, Linda / Scheri, Randall P / Salama, April K / Rossfeld, Kara / Gardezi, Syed / Agnese, Doreen M / Howard, J Harrison / Tyler, Douglas S / Slingluff, Craig L / Terando, Alicia M. ·Division of Surgical Oncology, Ohio State University Wexner Medical Center, Columbus, OH, USA. Georgia.beasley@osumc.edu. · Division of Surgical Oncology, University of Virginia, Charlottesville, VA, USA. · Department of Surgery, Duke University, Durham, NC, USA. · Division of Medical Oncology, Duke University, Durham, NC, USA. · Division of Surgical Oncology, Ohio State University Wexner Medical Center, Columbus, OH, USA. · Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA. ·Ann Surg Oncol · Pubmed #28508145.

ABSTRACT: BACKGROUND: Sentinel lymph node biopsy (SLNB) is routinely performed for primary cutaneous melanomas; however, limited data exist for SLNB after locally recurrent (LR) or in-transit (IT) melanoma. METHODS: Data from three centers performing SLNB for LR/IT melanoma (1997 to the present) were reviewed, with the aim of assessing (1) success rate; (2) SLNB positivity; and (3) prognostic value of SLNB in this population. RESULTS: The study cohort included 107 patients. Management of the primary melanoma included prior SLNB for 56 patients (52%), of whom 10 (18%) were positive and 12 had complete lymph node dissections (CLNDs). In the present study, SLNB was performed for IT disease (48/107, 45%) or LR melanoma (59/107, 55%). A sentinel lymph node (SLN) was removed in 96% (103/107) of cases. Nodes were not removed for four patients due to lymphoscintigraphy failures (2) or nodes not found during surgery (2). SLNB was positive in 41 patients (40%, 95% confidence interval (CI) 31.5-50.5), of whom 35 (88%) had CLND, with 13 (37%) having positive nonsentinel nodes. Median time to disease progression after LR/IT metastasis was 1.4 years (95% CI 0.75-2.0) for patients with a positive SLNB, and 5.9 years (95% CI 1.7-10.2) in SLNB-negative patients (p = 0.18). There was a trend towards improved overall survival for patients with a negative SLNB (p = 0.06). CONCLUSION: SLNB can be successful in patients with LR/IT melanoma, even if prior SLNB was performed. In this population, the rates of SLNB positivity and nonsentinel node metastases were 40% and 37%, respectively. SLNB may guide management and prognosis after LR/IT disease.

25 Article Outcomes and toxicity of stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab. 2016

Olson, Adam C / Thomas, Samantha / Qin, Rosie / Singh, Bhavana / Salama, Joseph K / Kirkpatrick, John / Salama, April Ks. ·Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA. · Department of Biostatistics, Duke Cancer Institute, Durham, NC, USA. · Duke University School of Medicine, Durham, NC, USA. · Department of Medicine, Duke University Medical Center, Durham, NC, USA. · Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC, USA. ·Melanoma Manag · Pubmed #30190887.

ABSTRACT: Purpose: Patients with melanoma treated with ipilimumab and radiosurgery (stereotactic radiosurgery [SRS]) were reviewed for efficacy/safety. Methods: Patients who received ipilimumab and SRS for brain metastases were analyzed for control of SRS-treated metastasis and overall survival. Results: We identified 27 patients, 26 were assessable for outcomes. Median time-to-treated metastasis progression was 6.3 months (95% CI: 3.1-12.2). Overall survival was 23.4 months (95% CI: 5.7-not estimable) for SRS prior to/during ipilimumab (n = 14), and 10.4 months (95% CI: 1.9-not estimable) for SRS after ipilimumab (n = 12). Overall, no unexpected toxicities were seen: 11% of patients experienced grade 3 CNS toxicity and 7% developed radionecrosis. Conclusion: SRS for melanoma brain metastases with ipilimumab was well-tolerated. There may be improved survival for patients receiving SRS prior to/during ipilimumab.

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