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Melanoma: HELP
Articles by Richard D. Carvajal
Based on 70 articles published since 2009
(Why 70 articles?)

Between 2009 and 2019, R. Carvajal wrote the following 70 articles about Melanoma.
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Editorial Another option in our KIT of effective therapies for advanced melanoma. 2013

Carvajal, Richard D. ·Memorial Sloan-Kettering Cancer Center, New York, NY. ·J Clin Oncol · Pubmed #23940226.

ABSTRACT: -- No abstract --

2 Review Mucosal Melanoma: New Insights and Therapeutic Options for a Unique and Aggressive Disease. 2017

Lerner, Benjamin A / Stewart, Latoya A / Horowitz, David P / Carvajal, Richard D. · ·Oncology (Williston Park) · Pubmed #29179253.

ABSTRACT: Mucosal melanoma is a rare disease that is distinct from melanomas arising at other sites in the body. While melanocytes are most abundant in the skin, they can be found in smaller numbers in the mucous membranes, as well as in the eye. There are epidemiologic, genetic, and other physiologic differences between melanomas arising from melanocytes at these various sites, and these differences have important implications for both disease prognosis and treatment. Here, we review the features of mucosal melanoma that distinguish it from melanomas arising at other sites, and we highlight recent biological discoveries and emerging treatment options for this aggressive disease.

3 Review Oncolytic immunotherapy: unlocking the potential of viruses to help target cancer. 2017

Hamid, Omid / Hoffner, Brianna / Gasal, Eduard / Hong, Jenny / Carvajal, Richard D. ·The Angeles Clinic and Research Institute, 11818 Wilshire Blvd #200, Los Angeles, CA, 90025, USA. ohamid@theangelesclinic.org. · University of Colorado Hospital, Aurora, CO, USA. · Amgen Inc., Thousand Oaks, CA, USA. · Cedars-Sinai Medical Center, Los Angeles, CA, USA. · Columbia University Medical Center, New York, NY, USA. ·Cancer Immunol Immunother · Pubmed #28712033.

ABSTRACT: Oncolytic immunotherapy is a research area of cancer immunotherapy investigating the use of modified viruses to target cancer cells. A variety of different viral backbones (e.g., adenovirus, reovirus) with a diverse range of genetic modifications are currently being investigated for the treatment of a variety of cancers. The oncolytic virus that has advanced the furthest in clinical development is talimogene laherparepvec, a recombinant HSV-1 virus expressing granulocyte-macrophage colony-stimulating factor (GM-CSF). In a phase 3 study in patients with unresectable metastatic melanoma, intralesional talimogene laherparepvec treatment resulted in a higher durable response rate compared with subcutaneous GM-CSF treatment (16.3 versus 2.1%; P < 0.001). Notably, responses were observed at uninjected lesions including visceral lesions, indicating a systemic antitumor response had occurred. Studies evaluating combination treatments involving oncolytic viruses and immunologic agents are ongoing. This review focuses on the mechanisms of action for oncolytic viruses and highlights select agents and combinations currently in development.

4 Review Advances in the Treatment of Advanced Extracutaneous Melanomas and Nonmelanoma Skin Cancers. 2017

Komatsubara, Kimberly M / Jeter, Joanne / Carvajal, Richard D / Margolin, Kim / Schadendorf, Dirk / Hauschild, Axel. ·From the Columbia University Medical Center, New York, NY; Ohio State University Medical Center, Columbus, OH; City of Hope, Duarte, CA; Department of Dermatology, University Hospital Essen, Essen, Germany; Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany. ·Am Soc Clin Oncol Educ Book · Pubmed #28561682.

ABSTRACT: Cutaneous malignancies make up the greatest proportion of all human cancers and include melanomas as well as nonmelanoma skin cancers (NMSCs) such as basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), as well as less common Merkel cell carcinoma (MCC), cutaneous lymphomas, cutaneous adnexal tumors, Kaposi sarcomas, and other sarcomas. Each of these NMSCs differ significantly in biology, clinical behavior, and optimal treatment recommendations from each other and from cutaneous melanoma. Similarly, less common extracutaneous melanomas, such as mucosal (MMs) and uveal (UMs), are unique biologic and clinical entities that require distinct diagnostic and management considerations. In this review, we summarize recent advances in biology and treatment of extracutaneous melanomas and NMSCs, including MMs, UMs, cSCC, BCC, and MCC.

5 Review Immunotherapy for the Treatment of Uveal Melanoma: Current Status and Emerging Therapies. 2017

Komatsubara, Kimberly M / Carvajal, Richard D. ·Division of Hematology/Oncology, Columbia University Medical Center, 177 Fort Washington Avenue, MHB 6GN-435, New York, NY, 10032, USA. · Division of Hematology/Oncology, Columbia University Medical Center, 177 Fort Washington Avenue, MHB 6GN-435, New York, NY, 10032, USA. carvajalr@columbia.edu. ·Curr Oncol Rep · Pubmed #28508938.

ABSTRACT: PURPOSE OF REVIEW: Uveal melanoma is a distinct subset of melanoma with a biology and treatment approach that is unique from that of cutaneous melanoma. Here we will review the current data evaluating immunotherapies in both the adjuvant and metastatic settings in uveal melanoma. RECENT FINDINGS: In the adjuvant setting, interferon demonstrated no survival benefit in uveal melanoma, and studies evaluating immune-based strategies such as vaccine therapy are ongoing. Anti-CTLA-4 and anti-PD-1/ PD-L1 blockade in uveal melanoma have been evaluated in several small prospective and/or retrospective studies with rare responses and no overall survival benefit demonstrated. Ongoing studies evaluating combination checkpoint inhibition and other antibody-based therapies are ongoing. Although immunotherapy with anti-CTLA-4 and anti-PD-1 agents has dramatically changed the treatment approach to cutaneous melanoma, its success in uveal melanoma has been much more limited. Clinical trial participation should be prioritized in patients with uveal melanoma.

6 Review Metastatic disease from uveal melanoma: treatment options and future prospects. 2017

Carvajal, Richard D / Schwartz, Gary K / Tezel, Tongalp / Marr, Brian / Francis, Jasmine H / Nathan, Paul D. ·Division of Hematology/Oncology, Columbia University Medical Center, New York, USA. · Department of Ophthalmology, Columbia University Medical Center, New York, USA. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA. · Division of Cancer Services, Mt Vernon Cancer Centre, Northwood, UK. ·Br J Ophthalmol · Pubmed #27574175.

ABSTRACT: Uveal melanoma represents ∼85% of all ocular melanomas and up to 50% of patients develop metastatic disease. Metastases are most frequently localised to the liver and, as few patients are candidates for potentially curative surgery, this is associated with a poor prognosis. There is currently little published evidence for the optimal management and treatment of metastatic uveal melanoma and the lack of effective therapies in this setting has led to the widespread use of systemic treatments for patients with cutaneous melanoma. Uveal and cutaneous melanomas are intrinsically different diseases and so dedicated management strategies and therapies for uveal melanoma are much needed. This review explores the biology of uveal melanoma and how this relates to ongoing trials of targeted therapies in the metastatic disease setting. In addition, we consider the options to optimise patient management and care.

7 Review Selumetinib for the treatment of metastatic uveal melanoma: past and future perspectives. 2016

Komatsubara, Kimberly M / Manson, Daniel K / Carvajal, Richard D. ·Division of Hematology/Oncology, Columbia University Medical Center, New York, NY, USA. ·Future Oncol · Pubmed #27044592.

ABSTRACT: Uveal melanoma is a rare but aggressive subtype of melanoma. Nearly 50% of patients will develop metastatic disease despite primary enucleation or radiation therapy. There is currently no standard of care therapy for metastatic uveal melanoma, and no therapy that has been shown to prolong overall survival. Uveal melanoma is characterized by activation of signaling pathways including the MAPK pathway and the PI3K/AKT pathway, among others, via mutations in the G-α-proteins GNAQ and GNA11. MEK inhibition with selumetinib has been evaluated as a therapeutic strategy in metastatic uveal melanoma. This review will discuss preclinical and clinical studies evaluating selumetinib in metastatic uveal melanoma, as well as potential future perspectives on MEK inhibition in the management of metastatic uveal melanoma.

8 Review Clinical Management of Uveal and Conjunctival Melanoma. 2016

Blum, Elyse S / Yang, Jessica / Komatsubara, Kimberly M / Carvajal, Richard D. · ·Oncology (Williston Park) · Pubmed #26791842.

ABSTRACT: Ocular melanoma is a rare but potentially devastating malignancy arising from the melanocytes of the uveal tract, conjunctiva, or orbit; it represents less than 5% of all melanoma cases in the United States. The management of ocular melanoma varies depending on its anatomic origin, since uveal and conjunctival melanoma have distinct biologies and thus different treatment strategies. Uveal melanoma is the most common type of ocular melanoma and is characterized by activation of the mitogen-activated protein kinase (MAPK) pathway (among other signaling pathways) via mutations in GNAQ or GNA11. Despite primary radiation or surgical therapy, up to 50% of patients will eventually develop metastatic disease, for which there is no standard therapy and no treatment that has been shown to improve overall survival. The biology of conjunctival melanoma is less well characterized but has been associated with BRAF and NRAS mutations, and results in metastatic disease in 20% to 30% of cases. Clinical trials are currently ongoing to further evaluate and optimize the role of targeted therapies, as well as immunotherapies, as both adjuvant and metastatic treatment in uveal and conjunctival melanoma.

9 Review Treatment of Uveal Melanoma. 2016

Shoushtari, Alexander N / Carvajal, Richard D. ·Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY, 10065, USA. shoushta@mskcc.org. · Melanoma and Experimental Therapeutics Services, Columbia University Medical Center, 161 Fort Washington Avenue, New York, NY, 10032, USA. rdc2150@cumc.columbia.edu. ·Cancer Treat Res · Pubmed #26601868.

ABSTRACT: Uveal melanoma (UM) comprises approximately 5 % of all melanoma diagnoses in the USA each year. Approximately half of patients with UM eventually develop metastases, most commonly involving the liver. Historically, prognosis for these patients has been poor, with death occurring 6-12 months from the time of metastases. Multiple trials of cytotoxic treatments largely extrapolated from cutaneous melanoma have been ineffective in metastatic UM. Trials of regional hepatic-directed therapy have led to high response rates, but these have yet to be translated into a survival benefit. Recently, it was discovered that the majority of UMs harbor activating mutations in genes encoding one of two G-alpha protein subunits, GNAQ and GNA11. This knowledge has led to the rational development of clinical trials specifically for UM utilizing targeted inhibitors of the activated signaling pathways such as mitogen-activated protein kinase, Akt, and protein kinase C. A recent trial of the oral MEK inhibitor selumetinib was the first to show clinical benefit for any systemic therapy in a randomized fashion. This increasing understanding of the biology of UM offers hope that novel treatments will continue to benefit patients with metastatic disease.

10 Review Biology of advanced uveal melanoma and next steps for clinical therapeutics. 2015

Luke, Jason J / Triozzi, Pierre L / McKenna, Kyle C / Van Meir, Erwin G / Gershenwald, Jeffrey E / Bastian, Boris C / Gutkind, J Silvio / Bowcock, Anne M / Streicher, Howard Z / Patel, Poulam M / Sato, Takami / Sossman, Jeffery A / Sznol, Mario / Welch, Jack / Thurin, Magdalena / Selig, Sara / Flaherty, Keith T / Carvajal, Richard D. ·Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. ·Pigment Cell Melanoma Res · Pubmed #25113308.

ABSTRACT: Uveal melanoma is the most common intraocular malignancy although it is a rare subset of all melanomas. Uveal melanoma has distinct biology relative to cutaneous melanoma, with widely divergent patient outcomes. Patients diagnosed with a primary uveal melanoma can be stratified for risk of metastasis by cytogenetics or gene expression profiling, with approximately half of patients developing metastatic disease, predominately hepatic in location, over a 15-yr period. Historically, no systemic therapy has been associated with a clear clinical benefit for patients with advanced disease, and median survival remains poor. Here, as a joint effort between the Melanoma Research Foundation's ocular melanoma initiative, CURE OM and the National Cancer Institute, the current understanding of the molecular and immunobiology of uveal melanoma is reviewed, and on-going laboratory research into the disease is highlighted. Finally, recent investigations relevant to clinical management via targeted and immunotherapies are reviewed, and next steps in the development of clinical therapeutics are discussed.

11 Review GNAQ and GNA11 mutations in uveal melanoma. 2014

Shoushtari, Alexander N / Carvajal, Richard D. ·aMelanoma and Immunotherapeutics Service bDepartment of Developmental Therapeutics, Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. ·Melanoma Res · Pubmed #25304237.

ABSTRACT: G-protein-coupled receptors signal through heterotrimeric G proteins, Gα and G-βγ, to manage numerous aspects of physiologic homeostasis. Many neoplastic processes harbor alterations in G-protein-coupled receptors and/or G-α proteins, best exemplified by recurrent activating mutations in GNAQ or GNA11 in uveal melanomas. This review will discuss the multiple activated signaling targets downstream of mutant GNAQ and GNA11 in uveal melanoma, including MEK, PI3-kinase/Akt, protein kinase C, and YAP. This knowledge has led to the rapid expansion of clinical trials that are specific to patients with uveal melanoma and promises future breakthroughs in therapies.

12 Review Treatments for noncutaneous melanoma. 2014

Khalil, Danny N / Carvajal, Richard D. ·Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. · Developmental Therapeutics, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 300 East 66th Street, No. 1071, New York, NY 10065, USA. Electronic address: carvajar@mskcc.org. ·Hematol Oncol Clin North Am · Pubmed #24880944.

ABSTRACT: Historically the approach to treating noncutaneous melanoma was largely guided by the experience with cutaneous melanoma, particularly in the metastatic setting. However, as genetic tools have allowed clinicians to better characterize these malignancies, their unique biology has become apparent. The ability to accurately distinguish the subtypes of melanoma and the genetic alterations that drive them is beginning to yield the tools that are shifting this disease from one that has proved to be intractable in the advanced setting to one that can be effectively treated.

13 Review Melanoma mutagenesis and aberrant cell signaling. 2013

Bello, Danielle M / Ariyan, Charlotte E / Carvajal, Richard D. ·Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. carvajar@mskcc.org. ·Cancer Control · Pubmed #24077403.

ABSTRACT: BACKGROUND: Malignant melanoma is the most fatal type of skin cancer. Traditional melanoma classification has been based on histological subtype or anatomical location. However, recent evidence suggests that melanoma comprises a group of diseases characterized by distinct molecular mutations. These mutations affect disease behavior but provide unique opportunities for targeted therapy. METHODS: In this review, several signaling pathways in melanoma are described as well as how mutations of BRAF, NRAS, KIT, GNAQ, and GNA11 genes cause aberrant signaling and malignant transformation. RESULTS: Multiple genes affecting both the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathway are mutated in melanoma. Melanomas harboring the BRAF V600E mutation have demonstrated sensitivity to both RAF and MAPK/extracellular signal regulated kinase (ERK) inhibitors in vitro and in vivo. In addition, KIT-mutant melanomas, often arising from mucosal, acral, and chronically sun-damaged skin surfaces, have shown clinical response to several inhibitors of the type III transmembrane receptor tyrosine kinase KIT. Uveal melanoma, which often harbors GNAQ or GNA11 mutations, may also be sensitive to MAPK/ERK or protein kinase C/PI3K pathway inhibition. CONCLUSIONS: Emerging knowledge of these molecular alterations has led to clinical advances in patients with melanoma. The study of known mutations and identification of new potential targets must continue in an effort to develop more effective therapies for this disease.

14 Review Surveillance options for patients with uveal melanoma following definitive management. 2013

Francis, Jasmine H / Patel, Sapna P / Gombos, Dan S / Carvajal, Richard D. ·From the Ophthalmic Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY; Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX; Section of Ophthalmology, University of Texas MD Anderson Cancer Center, Houston, TX; Melanoma and Sarcoma Service, Memorial Sloan-Kettering Cancer Center, New York, NY. ·Am Soc Clin Oncol Educ Book · Pubmed #23714555.

ABSTRACT: Even though less than 1% of uveal melanoma patients are found to have radiographic or clinical evidence of distant disease at the time of treatment for their intraocular disease, they carry a lifetime risk of disease recurrence, with approximately 50% of patients ultimately developing fatal metastases. Despite this significant risk, there is no consensus within the ophthalmologic or oncologic community regarding the role of surveillance for detection of metastatic disease in these patients. The lack of consensus is due to the notable absence of clear data regarding the best radiologic or serum surveillance modalities, the optimal frequency of testing, or the ideal length of follow-up. Given the ability to assess prognosis by cytogenetics, gene expression profiling, or other methods, questions remain about whether surveillance strategies should be tailored by level of risk. Importantly, no survival benefit from the early detection of asymptomatic disease in uveal melanoma has been documented, resulting in controversy over the value of routine surveillance and advocacy from some clinicians to forego surveillance altogether. However, there are several factors supporting surveillance: the patient's enhanced emotional well-being, the potential to identify oligometastatic disease amenable to surgery or other local therapies, decreased morbidity/complications from advanced disease, and identification of patients eligible for clinical trials that assess novel therapies for advanced uveal melanoma. The selection of surveillance modality used varies according to local expertise and resources and may include serum markers (liver function tests and others) and/or imaging (chest x-ray, abdominal ultrasound, computed tomography, positron emission tomography, and magnetic resonance imaging).

15 Review Mucosal melanoma: pathogenesis, clinical behavior, and management. 2012

Postow, Michael A / Hamid, Omid / Carvajal, Richard D. ·Department of Medicine, Weill-Cornell Medical College, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. postowm@mskcc.org ·Curr Oncol Rep · Pubmed #22661391.

ABSTRACT: Mucosal melanoma represents a rare subtype of melanoma with distinct biological, clinical, and management considerations. Knowledge regarding optimal treatment strategies for mucosal melanoma is limited and based primarily upon small case series and single-institution, retrospective analyses. Surgery remains the standard of care for loco-regional management, but the common presence of multifocal disease and the high rate of distant recurrence should be considered before pursuing aggressive surgical interventions associated with inherent significant morbidity. The role of sentinel lymph node biopsy and lymph node dissection remains unclear. Radiotherapy has not been shown to improve overall survival but may reduce the rate of local recurrence. Significant advances in the treatment of metastatic disease have been made with novel immunotherapeutic agents, the discovery of KIT and BRAF mutations and the development of targeted agents that inhibit these oncogenic pathways.

16 Review Therapeutic implications of KIT in melanoma. 2012

Postow, Michael A / Carvajal, Richard D. ·Memorial Sloan-Kettering Cancer Center, Melanoma-Sarcoma Division, New York, NY 10065, USA. ·Cancer J · Pubmed #22453014.

ABSTRACT: Melanoma is a heterogeneous disease representing distinct biologic and genetic subsets. Activating mutations in KIT have been discovered in a significant proportion of melanomas arising from acral, mucosal, and chronically sun-damaged sites and represent an important melanoma genetic subset. Initially, KIT was believed to function as a tumor suppressor, but additional research suggests that, in certain contexts, KIT functions as an oncogene. Therapeutic strategies targeting KIT with imatinib demonstrated remarkable efficacy in patients with gastrointestinal stromal tumors, but initial trials in melanoma were unsuccessful. Nevertheless, case reports continued to surface that demonstrated the remarkable efficacy of imatinib for patients with specific KIT genetic aberrations. Recently, trials of imatinib have selected patients with KIT genetic aberrations and have shown promising results. Current efforts are investigating additional agents that target KIT and testing KIT inhibitors in combination with other agents to improve the outcome for patients with this genetic subset of melanoma.

17 Review Mucosal melanoma: a clinically and biologically unique disease entity. 2012

Carvajal, Richard D / Spencer, Sharon A / Lydiatt, William. ·Department of Medicine, Melanoma/Sarcoma Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. carvajar@mskcc.org ·J Natl Compr Canc Netw · Pubmed #22393195.

ABSTRACT: Mucosal melanoma (MM) is an aggressive and clinically complex malignancy made more challenging by its relative rarity. Because of the rarity of MM as a whole, and because of the unique biology and clinical challenges of MM arising from each anatomic location, understanding of this disease and its optimal management remains limited. The impact of various treatment strategies on disease control and survival has been difficult to assess because of the small size of most reported series of MM arising from any one particular site, the retrospective nature of most series, and the lack of a uniform comprehensive staging system for this disease. This article summarizes the clinical, pathologic, and molecular features, and the diagnostic and therapeutic considerations for the management of MM, underscoring the similarities and differences from cutaneous melanoma. Furthermore, the distinct clinical features and management implications unique to melanoma arising from the mucosal surfaces of the head and neck, the anorectal region, and the female genital tract are highlighted.

18 Review Treatment implications of the emerging molecular classification system for melanoma. 2011

Romano, Emanuela / Schwartz, Gary K / Chapman, Paul B / Wolchock, Jedd D / Carvajal, Richard D. ·Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. ·Lancet Oncol · Pubmed #21349766.

ABSTRACT: Melanoma is an aggressive disease with few standard treatment options. The conventional classification system for this disease is based on histological growth patterns, with division into four subtypes: superficial spreading, lentigo maligna, nodular, and acral lentiginous. Major limitations of this classification system are absence of prognostic importance and little correlation with treatment outcomes. Recent preclinical and clinical findings support the notion that melanoma is not one malignant disorder but rather a family of distinct molecular diseases. Incorporation of genetic signatures into the conventional histopathological classification of melanoma has great implications for development of new and effective treatments. Genes of the mitogen-associated protein kinase (MAPK) pathway harbour alterations sometimes identified in people with melanoma. The mutation Val600Glu in the BRAF oncogene (designated BRAF(V600E)) has been associated with sensitivity in vitro and in vivo to agents that inhibit BRAF(V600E) or MEK (a kinase in the MAPK pathway). Melanomas arising from mucosal, acral, chronically sun-damaged surfaces sometimes have oncogenic mutations in KIT, against which several inhibitors have shown clinical efficacy. Some uveal melanomas have activating mutations in GNAQ and GNA11, rendering them potentially susceptible to MEK inhibition. These findings suggest that prospective genotyping of patients with melanoma should be used increasingly as we work to develop new and effective treatments for this disease.

19 Clinical Trial Selumetinib in Combination With Dacarbazine in Patients With Metastatic Uveal Melanoma: A Phase III, Multicenter, Randomized Trial (SUMIT). 2018

Carvajal, Richard D / Piperno-Neumann, Sophie / Kapiteijn, Ellen / Chapman, Paul B / Frank, Stephen / Joshua, Anthony M / Piulats, Josep M / Wolter, Pascal / Cocquyt, Veronique / Chmielowski, Bartosz / Evans, T R Jeffry / Gastaud, Lauris / Linette, Gerald / Berking, Carola / Schachter, Jacob / Rodrigues, Manuel J / Shoushtari, Alexander N / Clemett, Delyth / Ghiorghiu, Dana / Mariani, Gabriella / Spratt, Shirley / Lovick, Susan / Barker, Peter / Kilgour, Elaine / Lai, Zhongwu / Schwartz, Gary K / Nathan, Paul. ·Richard D. Carvajal and Gary K. Schwartz, Columbia University Medical Center · Paul B. Chapman and Alexander N. Shoushtari, Memorial Sloan Kettering Cancer Center, New York, NY · Sophie Piperno-Neumann and Manuel J. Rodrigues, Institut Curie, Paris · Lauris Gastaud, Centre Antoine-Lacassagne, Nice, France · Ellen Kapiteijn, Leiden University Medical Center, Leiden, the Netherlands · Stephen Frank, Hebrew University Hadassah Medical School - The Sharett Institute of Oncology, Jerusalem · Jacob Schachter, Sheba Medical Center at Tel Hashomer, and Tel-Aviv University Medical School, Tel Aviv, Israel · Anthony M. Joshua, Princess Margaret Cancer Centre, Toronto, ON, Canada · Josep M. Piulats, Institut Catala d'Oncologia L'Hospitalet, L'Hospitalet de Llobregat, Barcelona, Spain · Pascal Wolter, University Hospitals Leuven, Leuven, Belgium · Veronique Cocquyt, Ghent University Hospital, Ghent, Belgium · Bartosz Chmielowski, University of California, Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, CA · T.R. Jeffry Evans, University of Glasgow, Glasgow · Delyth Clemett, Shirley Spratt, Susan Lovick, and Elaine Kilgour, AstraZeneca, Macclesfield · Dana Ghiorghiu and Gabriella Mariani, AstraZeneca, Cambridge · Paul Nathan, Mt Vernon Cancer Centre, Northwood, United Kingdom · Gerald Linette, Washington University School of Medicine, St Louis, MO · Carola Berking, University Hospital of Munich, Munich, Germany · Peter Barker, AstraZeneca, Gaithersburg, MD · and Zhongwu Lai, AstraZeneca, Waltham, MA. ·J Clin Oncol · Pubmed #29528792.

ABSTRACT: Purpose Uveal melanoma is the most common primary intraocular malignancy in adults with no effective systemic treatment option in the metastatic setting. Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective MEK1/2 inhibitor with a short half-life, which demonstrated single-agent activity in patients with metastatic uveal melanoma in a randomized phase II trial. Methods The Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) in Metastatic Uveal Melanoma (SUMIT) study was a phase III, double-blind trial ( ClinicalTrial.gov identifier: NCT01974752) in which patients with metastatic uveal melanoma and no prior systemic therapy were randomly assigned (3:1) to selumetinib (75 mg twice daily) plus dacarbazine (1,000 mg/m

20 Clinical Trial A phase 2 study of ontuxizumab, a monoclonal antibody targeting endosialin, in metastatic melanoma. 2018

D'Angelo, Sandra P / Hamid, Omid A / Tarhini, Ahmad / Schadendorf, Dirk / Chmielowski, Bartosz / Collichio, Frances A / Pavlick, Anna C / Lewis, Karl D / Weil, Susan C / Heyburn, John / Schweizer, Charles / O'Shannessy, Daniel J / Carvajal, Richard D. ·Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Weill Cornell Medical College, New York, NY, USA. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · University of Pittsburgh, Pittsburgh, PA, USA. · Universitätsklinikum Essen, Essen, Germany. · University of California, Los Angeles, CA, USA. · University of North Carolina, Chapel Hill, NC, USA. · New York University, Lake Success, NY, USA. · University of Colorado Cancer Center, Aurora, CO, USA. · Morphotek, Inc., Exton, PA, USA. · Columbia University Medical Center, 177 Ft Washington Avenue, New York, NY, 10032, USA. rdc2150@cumc.columbia.edu. ·Invest New Drugs · Pubmed #29127533.

ABSTRACT: Objectives Ontuxizumab (MORAB-004) is a first-in-class monoclonal antibody that interferes with endosialin function, which is important in tumor stromal cell function, angiogenesis, and tumor growth. This Phase 2 study evaluated the 24-week progression-free survival (PFS) value, pharmacokinetics, and tolerability of 2 doses of ontuxizumab in patients with metastatic melanoma. Patients and methods Patients with metastatic melanoma and disease progression after receiving at least 1 prior systemic treatment were randomized to receive ontuxizumab (2 or 4 mg/kg) weekly, without dose change, until disease progression. Results Seventy-six patients received at least 1 dose of ontuxizumab (40 received 2 mg/kg, 36 received 4 mg/kg). The primary endpoint, 24-week PFS value, was 11.4% (95% Confidence Interval [CI]: 5.3%-19.9%) for all patients (13.5% for 2 mg/kg and 8.9% for 4 mg/kg). The median PFS for all patients was 8.3 weeks (95% CI: 8.1-12.3 weeks). One patient receiving 4 mg/kg had a partial response, as measured by Response Evaluation Criteria in Solid Tumors v1.1. Twenty-seven of 66 response evaluable patients (40.9%) had stable disease. The median overall survival was 31.0 weeks (95% CI: 28.3-44.0 weeks). The most common adverse events overall were headache (55.3%), fatigue (48.7%), chills (42.1%), and nausea (36.8%), mostly grade 1 or 2. Conclusions Ontuxizumab at both doses was well tolerated. The 24-week PFS value was 11.4% among all ontuxizumab-treated patients. The overall response rate was 3.1% at the 4 mg/kg dose, with clinical benefit achieved in 42.4% of response evaluable patients. Efficacy of single-agent ontuxizumab at these doses in melanoma was low.

21 Clinical Trial Relationship between physician-adjudicated adverse events and patient-reported health-related quality of life in a phase II clinical trial (NCT01143402) of patients with metastatic uveal melanoma. 2017

Atkinson, Thomas M / Hay, Jennifer L / Shoushtari, Alexander / Li, Yuelin / Paucar, Daniel J / Smith, Sloane C / Kudchadkar, Ragini R / Doyle, Austin / Sosman, Jeffrey A / Quevedo, Jorge Fernando / Milhem, Mohammed M / Joshua, Anthony M / Linette, Gerald P / Gajewski, Thomas F / Lutzky, Jose / Lawson, David H / Lao, Christopher D / Flynn, Patrick J / Albertini, Mark R / Sato, Takami / Lewis, Karl / Marr, Brian / Abramson, David H / Dickson, Mark Andrew / Schwartz, Gary K / Carvajal, Richard D. ·Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, 641 Lexington Ave., 7th Floor, New York, NY, 10022, USA. atkinsot@mskcc.org. · Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, 641 Lexington Ave., 7th Floor, New York, NY, 10022, USA. · Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY, USA. · Winship Cancer Institute of Emory University, Atlanta, GA, USA. · Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA. · Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA. · Mayo Clinic, Rochester, MN, USA. · University of Iowa Carver College of Medicine, Iowa City, IA, USA. · Princess Margaret Hospital University Health Network, Toronto, ON, Canada. · Penn Medicine, Philadelphia, PA, USA. · University of Chicago, Chicago, IL, USA. · Mount Sinai Medical Center, Miami Beach, FL, USA. · University of Michigan, Ann Arbor, MI, USA. · Minnesota Oncology, Woodbury, MN, USA. · Univeristy of Wisconsin School of Medicine and Public Health, Madison, WI, USA. · Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA. · University of Colorado - Denver, Denver, CO, USA. · Columbia University Medical Center, New York, NY, USA. ·J Cancer Res Clin Oncol · Pubmed #27921276.

ABSTRACT: PURPOSE: Clinical trials commonly use physician-adjudicated adverse event (AE) assessment via the common terminology criteria for adverse events (CTCAE) for decision-making. Patient-reported health-related quality of life (HRQoL) data are becoming more frequent in oncology; however, the relationship between physician-adjudicated AE assessment and HRQoL is understudied. METHODS: Data from a phase II trial (clinicaltrials.gov identifier: NCT01143402) where patients with metastatic uveal melanoma were randomized to receive selumetinib, an oral MEK inhibitor, or chemotherapy were analyzed. Patients reported HRQoL at baseline, after 1 month, and end of treatment (n = 118), whereas physicians adjudicated AEs via CTCAE. Mean HRQoL scores were compared between patient randomization arms, as well as between those patients who did/did not receive dose modifications. RESULTS: Ninety-four percent had a CTCAE grade ≥1 for at least one treatment-associated AE, with 18% undergoing dose modification due to toxicity. Mean HRQoL scores did not significantly differ at each of the three time points. Patient and physician-adjudicated reports of nausea were significantly correlated at the start (r = 0.31, p < 0.01) and end of treatment (r = 0.42, p < 0.05). There were no significant correlations between need for dose modification and HRQoL scores. CONCLUSIONS: Despite the high rate of physician-adjudicated AEs and need for dose modifications with selumetinib, patient-reported HRQoL was not impacted by treatment. Since HRQoL did not differ in the subgroup of patients who received dosage reductions due to AEs, patients may be willing to tolerate select AEs without dose modification (if medically appropriate). More research is needed to determine how to best integrate HRQoL data into clinical trial conduct.

22 Clinical Trial A phase 2 trial of everolimus and pasireotide long-acting release in patients with metastatic uveal melanoma. 2016

Shoushtari, Alexander N / Ong, Leonard T / Schoder, Heiko / Singh-Kandah, Shahnaz / Abbate, Kelly T / Postow, Michael A / Callahan, Margaret K / Wolchok, Jedd / Chapman, Paul B / Panageas, Katherine S / Schwartz, Gary K / Carvajal, Richard D. ·aMelanoma and Immunotherapeutics Service bMolecular Imaging and Therapy Service cDepartment of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center dWeill Cornell Medical College eDivision of Hematology/Oncology, Columbia University Medical Center, New York, New York, USA. ·Melanoma Res · Pubmed #26795274.

ABSTRACT: The aim of this study was to test the hypothesis that inhibiting mammalian target of rapamycin and insulin-like growth factor-1 receptor would be efficacious in metastatic uveal melanoma. This was a phase 2 trial of everolimus 10 mg daily plus pasireotide long-acting release 60 mg every 28 days enrolling patients with progressive, metastatic uveal melanoma to treatment until progression by Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1) or unacceptable toxicity. The primary endpoint was clinical benefit rate, defined as any objective response or RECIST 1.1 stable disease at 16 weeks. A subset of patients underwent baseline indium-111-octreotide scans. A total of 14 patients were enrolled, of which 13 were evaluable for the primary endpoint, before the study was terminated due to poor accrual. Three of 13 (26%) patients obtained clinical benefit. Seven of 13 (54%) had stable disease lasting for a median of 8 weeks (range: 8-16 weeks). Grade 3 adverse events deemed at least possibly related to study drugs were hyperglycemia (n=7), oral mucositis (n=2), diarrhea (n=1), hypophosphatemia (n=1), and anemia (n=1). Seven of 14 (50%) patients required at least one dose reduction due to toxicity. Seven of eight (88%) patients with baseline indium-111-octreotide scans had at least one avid lesion, with significant intrapatient heterogeneity. There was a trend toward an association between octreotide avidity and cytostatic response to therapy (P=0.078). The combination of everolimus and pasireotide has limited clinical benefit in this small metastatic uveal melanoma cohort. Dose reductions for side effects were common. Further investigation into the relationship between somatostatin receptor expression and cytostatic activity of somatostatin analogues is warranted.

23 Clinical Trial Study design and rationale for a randomised, placebo-controlled, double-blind study to assess the efficacy of selumetinib (AZD6244; ARRY-142886) in combination with dacarbazine in patients with metastatic uveal melanoma (SUMIT). 2015

Carvajal, Richard D / Schwartz, Gary K / Mann, Helen / Smith, Ian / Nathan, Paul D. ·Division of Hematology/Oncology, Columbia University Medical Center, New York, NY, 10032, USA. rdc2150@cumc.columbia.edu. · Division of Hematology/Oncology, Columbia University Medical Center, New York, NY, 10032, USA. gks2123@cumc.columbia.edu. · AstraZeneca, Macclesfield, UK. Helen.Mann@astrazeneca.com. · AstraZeneca, Macclesfield, UK. smithic@mac.com. · Mt Vernon Cancer Centre, Northwood, UK. nathan.pd@gmail.com. ·BMC Cancer · Pubmed #26059332.

ABSTRACT: BACKGROUND: Uveal melanoma is characterised by mutations in GNAQ and GNA11, resulting in Ras/Raf/MEK/ERK pathway activation. Treatment with selumetinib (AZD6244, ARRY-142886), a MEK1/2 inhibitor, results in antitumour effects in uveal melanoma pre-clinical models. A randomised phase II trial demonstrated improved progression-free survival (PFS) and response rate (RR) with selumetinib monotherapy versus chemotherapy with temozolomide or dacarbazine in patients with metastatic uveal melanoma. Pre-clinically, selumetinib in combination with alkylating agents enhanced antitumour activity compared with chemotherapy alone. We hypothesise that selumetinib in combination with dacarbazine will result in improved clinical outcomes in patients with metastatic uveal melanoma versus dacarbazine alone. METHODS/DESIGN: SUMIT is a randomised, international, double-blind, placebo-controlled, phase III study assessing the efficacy and safety of selumetinib in combination with dacarbazine in patients with metastatic uveal melanoma who have not received prior systemic therapy. Primary endpoint is PFS. Secondary endpoints include objective RR, duration of response, change in tumour size at Week 6, overall survival, safety and tolerability. Exploratory endpoints include efficacy in tumours with GNAQ or GNA11 mutations. Eligible patients must have: ≥1 lesion that can be accurately measured at baseline, and is suitable for accurate repeated measurements; ECOG performance status 0-1; life expectancy>12 weeks. Mutation status for GNAQ/GNA11 will be assessed retrospectively. An estimated 128 patients from approximately 50 sites globally will be randomised (3:1) to selumetinib 75 mg twice daily or placebo in combination with dacarbazine 1000 mg/m(2) on Day 1 of every 21-day cycle until objective disease progression, intolerable toxicity or occurrence of another discontinuation criterion. Randomisation will be stratified by the presence/absence of liver metastases. Tumours will be evaluated by RECIST v1.1 every 6 weeks. All patients have the option of receiving selumetinib with or without dacarbazine at disease progression. Study enrolment began in April 2014 and is expected to complete in early 2015. DISCUSSION: Treatment of patients with metastatic uveal melanoma represents an area of high unmet medical need. This study evaluating selumetinib in combination with dacarbazine was designed with input from the US FDA, and is the first potential registration trial to be conducted in patients with metastatic uveal melanoma. TRIAL REGISTRATION: Clinicaltrials.gov (Date of registration, October 10, 2013) REGISTRATION NUMBER: NCT01974752 Trial abbreviation: SUMIT.

24 Clinical Trial A Retrospective Evaluation of Vemurafenib as Treatment for BRAF-Mutant Melanoma Brain Metastases. 2015

Harding, James J / Catalanotti, Federica / Munhoz, Rodrigo R / Cheng, Donavan T / Yaqubie, Amin / Kelly, Nicole / McDermott, Gregory C / Kersellius, Romona / Merghoub, Taha / Lacouture, Mario E / Carvajal, Richard D / Panageas, Katherine S / Berger, Michael F / Rosen, Neal / Solit, David B / Chapman, Paul B. ·Departments of Medicine and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Human Oncology and Pathogenesis Program, Memorial Hospital Research Laboratories, New York, New York, USA; Immunology and Molecular and Pharmacology and Chemistry Programs, Sloan Kettering Institute, New York, New York, USA HardinJ1@mskcc.org. · Departments of Medicine and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Human Oncology and Pathogenesis Program, Memorial Hospital Research Laboratories, New York, New York, USA; Immunology and Molecular and Pharmacology and Chemistry Programs, Sloan Kettering Institute, New York, New York, USA. ·Oncologist · Pubmed #25956405.

ABSTRACT: BACKGROUND: RAF inhibitors are an effective therapy for patients with BRAF-mutant melanoma and brain metastasis. Efficacy data are derived from clinical studies enriched with physiologically fit patients; therefore, it is of interest to assess the real-world experience of vemurafenib in this population. Tumor-specific genetic variants that influence sensitivity to RAF kinase inhibitors also require investigation. METHODS: Records of patients with BRAF-mutant melanoma and brain metastases who were treated with vemurafenib were reviewed. Clinical data were extracted to determine extracranial and intracranial objective response rates, progression-free survival (PFS), overall survival (OS), and safety. A bait-capture, next-generation sequencing assay was used to identify mutations in pretreatment tumors that could explain primary resistance to vemurafenib. RESULTS: Among patients with intracranial disease treated with vemurafenib, 27 were included in survival analyses and 22 patients were assessable for response. The extracranial and intracranial objective response rates were 71% and 50%, respectively. Discordant responses were observed between extracranial and intracranial metastatic sites in 4 of 19 evaluable patients. Median PFS was 4.1 months (95% confidence interval [CI]: 2.6-7.9); median intracranial PFS was 4.6 months (95% CI: 2.7-7.9), median OS was 7.5 months (95% CI: 4.3-not reached), with a 30.4% 1-year OS rate. Outcomes were influenced by performance status. Vemurafenib was tolerable, although radiation-induced dermatitis occurred in some patients who received whole-brain radiotherapy. Adequate samples for next-generation sequencing analysis were available for seven patients. Melanomas categorized as "poorly sensitive" (≥20% tumor growth, new lesions, or ≤50% shrinkage for <4 months) harbored co-occurring mutations in genes predicted to activate the phosphatidylinositol 3-kinase-AKT (PI3K-AKT) pathway. CONCLUSION: Vemurafenib is highly active in BRAF-mutant melanoma brain metastases but has limited activity in patients with poor performance status. The safety and efficacy of concurrent radiotherapy and RAF inhibition requires careful clinical evaluation. Combination strategies blocking the MAPK and PI3K-AKT pathway may be warranted in a subset of patients. IMPLICATIONS FOR PRACTICE: Vemurafenib is active for BRAF-mutant intracranial melanoma metastases in an unselected patient population typical of routine oncologic practice. Patients with poor performance status appear to have poor outcomes despite vemurafenib therapy. Preliminary data indicate that co-occurring or secondary alterations in the phosphatidylinositol 3-kinase-AKT (PI3K-AKT) pathway are involved in resistance to RAF inhibition, thus providing a rationale for dual MAPK and PI3K-AKT pathway inhibition in this patient population.

25 Clinical Trial Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition. 2015

Carvajal, Richard D / Lawrence, Donald P / Weber, Jeffrey S / Gajewski, Thomas F / Gonzalez, Rene / Lutzky, Jose / O'Day, Steven J / Hamid, Omid / Wolchok, Jedd D / Chapman, Paul B / Sullivan, Ryan J / Teitcher, Jerrold B / Ramaiya, Nikhil / Giobbie-Hurder, Anita / Antonescu, Cristina R / Heinrich, Michael C / Bastian, Boris C / Corless, Christopher L / Fletcher, Jonathan A / Hodi, F Stephen. ·Memorial Sloan Kettering Cancer Center, New York, New York. Weill Medical College of Cornell University, New York, New York. · Massachusetts General Hospital, Boston, Massachusetts. · H. Lee Moffitt Cancer Center, Tampa, Florida. · The University of Chicago, Chicago, Illinois. · The University of Colorado Cancer Center, Aurora, Colorado. · Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida. · Beverly Hills Cancer Center, Beverly Hills, California. · Angeles Clinic and Research Institute, Los Angeles, California. · Memorial Sloan Kettering Cancer Center, New York, New York. · Dana Farber Cancer Institute, Boston, Massachusetts. · Oregon Health and Science University, Portland, Oregon. · The University of California San Francisco, San Francisco, California. · Dana Farber Cancer Institute, Boston, Massachusetts. Stephen_hodi@dfci.harvard.edu. ·Clin Cancer Res · Pubmed #25695690.

ABSTRACT: PURPOSE: Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown. EXPERIMENTAL DESIGN: We conducted a phase II study of nilotinib 400 mg twice a day in two cohorts of patients with melanomas harboring KIT mutations or amplification: (A) those refractory or intolerant to a prior KIT inhibitor; and (B) those with brain metastases. The primary endpoint was 4-month disease control rate. Secondary endpoints included response rate, time-to-progression (TTP), and overall survival (OS). A Simon two-stage and a single-stage design was planned to assess for the primary endpoint in cohorts A and B, respectively. RESULTS: Twenty patients were enrolled and 19 treated (11 in cohort A; 8 in cohort B). Three patients on cohort A [27%; 95% confidence interval (CI), 8%-56%] and 1 on cohort B (12.5%; 90% CI, 0.6%-47%) achieved the primary endpoint. Two partial responses were observed in cohort A (18.2%; 90% CI, 3%-47%); none were observed in cohort B. The median TTP and OS was 3.3 (90% CI, 2.1-3.9 months) and 9.1 months (90% CI, 4.3-14.2 months), respectively, in all treated patients. CONCLUSIONS: Nilotinib may achieve disease control in patients with melanoma harboring KIT alterations and whose disease progressed after imatinib therapy. The efficacy of this agent in KIT-altered melanoma with brain metastasis is limited.