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Melanoma: HELP
Articles by Ryan J. Sullivan
Based on 78 articles published since 2009
(Why 78 articles?)
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Between 2009 and 2019, R. Sullivan wrote the following 78 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Review Mechanisms of Resistance to Immune Checkpoint Blockade. 2019

Liu, David / Jenkins, Russell W / Sullivan, Ryan J. ·Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Yawkey 7E, Boston, MA, 02114, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. · Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Yawkey 7E, Boston, MA, 02114, USA. RSULLIVAN7@mgh.harvard.edu. ·Am J Clin Dermatol · Pubmed #30259383.

ABSTRACT: The recent development of effective immune checkpoint inhibition (ICI), first demonstrated in melanoma, has revolutionized cancer treatment. Monoclonal antibodies blocking the immune checkpoints cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 receptor (PD-1) have shown substantial clinical benefit in a subset of patients across tumor types and in both the metastatic and adjuvant settings. In this article, we review the interaction between the immune system and solid tumors, and describe modes of immune response failure and the physiologic role of immune checkpoints. We also review the known mechanisms of immune checkpoint inhibitors, focusing on US FDA-approved agents targeting CTLA-4 and PD-1. Within this framework, we classify hypothesized tumor intrinsic and extrinsic predictive markers for response and resistance to ICI, and map them to their putative underlying biological mechanism. Finally, we outline future directions in ICI, including the development of new therapeutic targets, rational combination therapies, integrated predictive models for individual patients to optimize therapy, and expansion into different disease types.

2 Review Immune checkpoint inhibitors in challenging populations. 2017

Johnson, Douglas B / Sullivan, Ryan J / Menzies, Alexander M. ·Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. · Department of Medicine, Melanoma Institute Australia, University of Sydney Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia. ·Cancer · Pubmed #28241095.

ABSTRACT: Immune checkpoint inhibitors, including those targeting the programmed cell death 1/programmed cell death ligand 1 and cytotoxic T lymphocyte antigen 4 pathways, are revolutionizing cancer therapeutics. Both activity and toxicities largely stem from unleashing tumor- or host-specific cytotoxic T cells. Many patients seen in routine clinical practice have not qualified for or have been seriously underrepresented in immune checkpoint inhibitor clinical trials. Thus, a major gap in knowledge regarding the safety and efficacy of these agents persists in many populations, even after regulatory approval. To address this challenge, this review aggregates and synthesizes the available preclinical and clinical data surrounding immune checkpoint inhibitor therapy in challenging clinical populations to assist both academic and community oncologists in treatment decision making. Specifically, this review focuses on the safety and activity of immune checkpoint inhibitors in patients with autoimmune disorders, organ transplant patients, patients with chronic viral infections, patients with ongoing immunosuppressant use, patients with organ dysfunction, pregnant patients, patients with brain metastases, patients at extremes of age, and patients with an impaired functional status. Cancer 2017;123:1904-1911. © 2017 American Cancer Society.

3 Review New Translational Research in the Medical Management of Orbital Melanoma. 2016

Dagi Glass, Lora / Sullivan, Ryan / Freitag, Suzanne K. ·a Ophthalmic Plastic Surgery Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School , Boston , Massachusetts , USA and. · b Massachusetts General Hospital Cancer Center, Harvard Medical School , Boston , Massachusetts , USA. ·Semin Ophthalmol · Pubmed #26959130.

ABSTRACT: New translational research has paved the way for more optimistic management of melanoma. Medications targeting oncogenic signaling cascades and immune regulatory molecules have significantly improved overall survival for patients with metastatic melanoma. While isolated, operable orbital melanoma may still benefit from surgery, there potentially is an opportunity to provide patients with neoadjuvant systemic therapy with sustainable long-term effects. Additionally, patients with non-resectable orbital melanoma can benefit from systemic treatment.

4 Review The role of mitogen-activated protein targeting in melanoma beyond BRAFV600. 2016

Sullivan, Ryan J. ·Center for Melanoma, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA. ·Curr Opin Oncol · Pubmed #26844986.

ABSTRACT: PURPOSE OF REVIEW: Targeted therapy in melanoma is well established for patients with tumors harboring BRAF mutations, but less so for other molecularly defined subsets. In this review, emerging preclinical, genomic, and early clinical data are discussed regarding the use of mitogen-activated protein (MAPK) pathway inhibitors in other molecular subsets of melanoma. RECENT FINDINGS: There are now four well defined subsets of melanoma based on The Cancer Genome Atlas: BRAF driven, NRAS driven, NF1 mutant, and 'triple wild type'. The former three subtypes predict signaling through the MAPK pathway and sensitivity to inhibitors of this pathway's mediators. With ongoing translation of preclinical findings into clinical trials, there is great hope that these strategies will improve the care of patients who fall into these other molecular subsets. SUMMARY: A more comprehensive understanding of genetically defined subtypes of melanoma is emerging. Efforts in the clinic are already underway, but additional, well designed trials of MAPK-targeted therapy planned and needed.

5 Review The Future of Molecular Analysis in Melanoma: Diagnostics to Direct Molecularly Targeted Therapy. 2016

Akabane, Hugo / Sullivan, Ryan J. ·Department of Medicine, Metrowest Medical Center, Framingham, MA, USA. · Center for Melanoma, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA, 02114, USA. rsullivan7@mgh.harvard.edu. ·Am J Clin Dermatol · Pubmed #26518880.

ABSTRACT: Melanoma is a malignancy of pigment-producing cells that is driven by a variety of genetic mutations and aberrations. In most cases, this leads to upregulation of the mitogen-activated protein kinase (MAPK) pathway through activating mutations of upstream mediators of the pathway including BRAF and NRAS. With the advent of effective MAPK pathway inhibitors, including the US FDA-approved BRAF inhibitors vemurafenib and dabrafenib and MEK inhibitor trametinib, molecular analysis has become an integral part of the care of patients with metastatic melanoma. In this article, the key molecular targets and strategies to inhibit these targets therapeutically are presented, and the techniques of identifying these targets, in both tissue and blood, are discussed.

6 Review Achievements and challenges of molecular targeted therapy in melanoma. 2015

Sullivan, Ryan / LoRusso, Patricia / Boerner, Scott / Dummer, Reinhard. ·From the Massachusetts General Hospital Cancer Center, Boston, MA; Yale Cancer Center, New Haven, CT; Yale University, New Haven, CT; University Hospital of Zurich, Zurich, Switzerland. ·Am Soc Clin Oncol Educ Book · Pubmed #25993155.

ABSTRACT: The treatment of melanoma has been revolutionized over the past decade with the development of effective molecular and immune targeted therapies. The great majority of patients with melanoma have mutations in oncogenes that predominantly drive signaling through the mitogen activated protein kinase (MAPK) pathway. Analytic tools have been developed that can effectively stratify patients into molecular subsets based on the identification of mutations in oncogenes and/or tumor suppressor genes that drive the MAPK pathway. At the same time, potent and selective inhibitors of mediators of the MAPK pathway such as RAF, MEK, and ERK have become available. The most dramatic example is the development of single-agent inhibitors of BRAF (vemurafenib, dabrafenib, encorafenib) and MEK (trametinib, cobimetinib, binimetinib) for patients with metastatic BRAFV600-mutant melanoma, a subset that represents 40% to 50% of patients with metastatic melanoma. More recently, the elucidation of mechanisms underlying resistance to single-agent BRAF inhibitor therapy led to a second generation of trials that demonstrated the superiority of BRAF inhibitor/MEK inhibitor combinations (dabrafenib/trametinib; vemurafenib/cobimetinib) compared to single-agent BRAF inhibitors. Moving beyond BRAFV600 targeting, a number of other molecular subsets--such as mutations in MEK, NRAS, and non-V600 BRAF and loss of function of the tumor suppressor neurofibromatosis 1 (NF1)--are predicted to respond to MAPK pathway targeting by single-agent pan-RAF, MEK, or ERK inhibitors. As these strategies are being tested in clinical trials, preclinical and early clinical trial data are now emerging about which combinatorial approaches might be best for these patients.

7 Review Dabrafenib in combination with trametinib for the treatment of metastatic melanoma. 2015

Awad, Mark M / Sullivan, Ryan J. ·Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA. ·Expert Rev Clin Pharmacol · Pubmed #25473943.

ABSTRACT: Oncogenic BRAF mutations are present in approximately 40-50% of patients with metastatic melanoma. Targeting BRAF mutations with either small molecule inhibitors of BRAF or one of the downstream mediators of oncogenic BRAF - MEK - is associated with improved outcomes compared with chemotherapy and has led to the US FDA approval of two BRAF inhibitors - vemurafenib and dabrafenib - and the MEK inhibitor trametinib. Further, the combination of dabrafenib and trametinib is well tolerated and associated with higher responses and improved survival compared with single-agent BRAF inhibitors.

8 Review Understanding the biology of melanoma and therapeutic implications. 2014

Sullivan, Ryan J / Fisher, David E. ·Center for Melanoma, Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA. · Department of Dermatology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Bartlett 6, 55 Fruit Street, Boston, MA 02114, USA. Electronic address: dfisher3@partners.org. ·Hematol Oncol Clin North Am · Pubmed #24880940.

ABSTRACT: From 1976 to 2010, only 2 medications were approved for treating metastatic melanoma. Between 2011 and 2013, 4 agents were approved and other therapies have shown great promise in clinical trials. Fundamental discoveries, such as the identification of oncogenic mutations in most melanomas, the elucidation of the molecular signaling resulting from these mutations, and the revelation that several cell surface molecules serve as regulators of immune activation, have been instrumental in this progress. This article summarizes the molecular pathogenesis of melanoma, describes the current efforts to target oncogene-driven signaling, and presents the rationale for combining immune and molecular targeting.

9 Review Major therapeutic developments and current challenges in advanced melanoma. 2014

Sullivan, R J / Flaherty, K T. ·Massachusetts General Hospital Cancer Center, 55 Fruit Street, Yawkey 9E, Boston, MA, 02114, U.S.A. ·Br J Dermatol · Pubmed #24443912.

ABSTRACT: Malignant melanoma is rising in incidence. The treatment options have been very limited but advances in molecular biology and immunology have led to a greater understanding of the pathogenesis of the disease. Four drugs have been approved for the treatment of advanced melanoma in the past 2 years and two new classes of agents have recently been shown to lead to durable responses in a substantial minority of patients. The identification of biomarkers has helped clinicians and researchers segregate patients into molecular subgroups, which facilitates the selection of therapy. Preliminary work has begun on determining the ideal sequences of the various therapies. Investigations have been carried out on why these treatments work and what the mechanisms of resistance are to these therapies. It is hoped that combinations of therapies will emerge that lead to a high percentage of durable responses.

10 Review Emerging clinical issues in melanoma in the molecularly targeted era. 2014

Sullivan, Ryan J / Atkins, Michael B. ·Center for Melanoma, Massachusetts General Hospital Cancer Center, Boston, MA, USA. ·Methods Mol Biol · Pubmed #24258971.

ABSTRACT: The standard of care of patients with malignant melanoma is dramatically changing, hallmarked by the approval of three new agents for the treatment of malignant melanoma in 2011. In this changing therapeutic landscape, several clinical issues are emerging which will best be addressed through the application of advances in molecular analytics, diagnostics, and therapeutics. It is expected that dedicated and coordinated efforts in basic, translational, and clinical will be responsible for the next major breakthroughs in the care of patients with this dreaded disease. In this chapter, five critical, emerging clinical issues are presented with descriptions of approaches that might be expected to help solve these challenges to optimal patient care.

11 Review The intersection of immune-directed and molecularly targeted therapy in advanced melanoma: where we have been, are, and will be. 2013

Sullivan, Ryan J / Lorusso, Patricia M / Flaherty, Keith T. ·Authors' Affiliations: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; and Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. ·Clin Cancer Res · Pubmed #24089441.

ABSTRACT: In three years, four drugs have gained regulatory approval for the treatment of metastatic and unresectable melanoma, with at least seven other drugs having recently completed, currently in, or soon to be in phase III clinical testing. This amazing achievement has been made following a remarkable increase of knowledge in molecular biology and immunology that led to the identification of high-valued therapeutic targets and the clinical development of agents that effectively engage and inhibit these targets. The discovery of either effective molecularly targeted therapies or immunotherapies would have led to dramatic improvements to the standard-of-care treatment of melanoma. However, through parallel efforts that have showcased the efficacy of small-molecule BRAF and MAP-ERK kinase (MEK) inhibitors, as well as the immune checkpoint inhibitors, namely ipilimumab and the anti-PD1/PDL1 antibodies (lambrolizumab, nivolumab, MPDL3280), an opportunity exists to transform the treatment of melanoma specifically and cancer generally by exploring rational combinations of molecularly targeted therapies, immunotherapies, and molecular targeted therapies with immunotherapies. This overview presents the historical context to this therapeutic revolution, reviews the benefits and limitations of current therapies, and provides a look ahead at where the field is headed.

12 Review Resistance to BRAF-targeted therapy in melanoma. 2013

Sullivan, Ryan J / Flaherty, Keith T. ·Center for Melanoma Massachusetts General Hospital Cancer Center 55 Fruit Street, Boston, MA 02114, USA. ·Eur J Cancer · Pubmed #23290787.

ABSTRACT: BRAF mutations are identified in 40-50% of patients with melanoma. Treatment of these patients with either of two BRAF inhibitors (vemurafenib, dabrafenib) or the MEK inhibitor trametinib is associated with improved clinical benefit (response rate, progression free survival, and overall survival) compared with treatment with chemotherapy in three phase III trials. Unfortunately, most patients, including those who experience initial, profound tumour regression, have evidence of disease progression within 6-8 months after commencing therapy with one of these agents. The mechanisms of resistance are varied and include activation of alternative signalling pathways as well as reactivating the MAP kinase pathway through alternative means. This review describes relevant aspects of MAP kinase pathway signalling, summarises the clinical data with BRAF and MEK inhibitors, presents the known resistance mechanisms to BRAF inhibitor therapy, and provides some strategies for how resistance may be overcome.

13 Review MAP kinase signaling and inhibition in melanoma. 2013

Sullivan, R J / Flaherty, K. ·Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA. ·Oncogene · Pubmed #22945644.

ABSTRACT: The mitogen-activated protein kinase (MAPK) pathway is critical to oncogenic signaling in the majority of patients with malignant melanoma. Driver mutations in both NRAS and BRAF have important implications for prognosis and treatment. The development of inhibitors to mediators of the MAPK pathway, including those to CRAF, BRAF, and MEK, has led to major advances in the treatment of patients with melanoma. In particular, the selective BRAF inhibitor vemurafenib has been shown to improve overall survival in patients with tumors harboring BRAF mutations. However, the duration of benefit is limited in many patients and highlights the need for understanding the limitations of therapy in order to devise more effective strategies. MEK inhibitors have proven to particularly active in BRAF mutant melanomas also. Emerging knowledge about mechanisms of resistance as well as a more complete understanding of the biology of MAPK pathway signaling provides insight into rational combination regimens and sequences of molecularly targeted therapies.

14 Review Molecular targeted therapy for patients with melanoma: the promise of MAPK pathway inhibition and beyond. 2010

Sullivan, Ryan J / Atkins, Michael B. ·Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. matkins@bidmc.harvard.edu ·Expert Opin Investig Drugs · Pubmed #20687784.

ABSTRACT: IMPORTANCE OF THE FIELD: Recent discoveries have expanded the understanding of the molecular signaling events critical to melanomagenesis and led to the development of targeted therapeutic agents that are revolutionizing the treatment of patients with advanced melanoma. AREAS COVERED IN THIS REVIEW: This article reviews current therapy and its limitations, describes the key pathogenic mechanisms in melanoma for which inhibitors have been tested, and summarizes the results of clinical trials involving molecularly targeted agents in this disease. WHAT THE READER WILL GAIN: There has been an explosion of preclinical and clinical research aimed at targeting the key molecular alterations in melanoma for therapeutic benefit. These findings will be presented and placed in the proper clinical context, affording information regarding the current molecular targets in the melanoma and the activity and limitations of therapeutic agents directed against them. TAKE HOME MESSAGE: Greater understanding of the pathogenic mechanisms underlying melanoma development has prompted the development of new therapeutic approaches aimed at counteracting these processes. While progress made over the past few years has generated considerable excitement, the benefits of these new therapies are still limited by incomplete and transient tumor regressions. It is hoped that with further investigation, particularly into mechanisms of treatment de novo and acquired treatment resistance, these limitations can be overcome.

15 Review Cytokine therapy in melanoma. 2010

Sullivan, Ryan J / Atkins, Michael B. ·Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. ·J Cutan Pathol · Pubmed #20482677.

ABSTRACT: -- No abstract --

16 Review Molecular-targeted therapy in malignant melanoma. 2009

Sullivan, Ryan J / Atkins, Michael B. ·Beth Israel Deaconess Medical Center, Harvard Medical School, Division of Hematology/Oncology, Boston, MA, USA. ·Expert Rev Anticancer Ther · Pubmed #19445574.

ABSTRACT: Malignant melanoma is a deadly disease in which standard treatment options have remained remarkably static over the past 30 years. Recent discoveries have expanded the understanding of the molecular processes critical to melanomagenesis. During this same time period, therapeutic agents have been developed that target these processes, leading to an explosion of preclinical research. Several agents that have shown promise in the preclinical setting have now entered clinical trials. To date, the success of these molecularly targeted approaches as single agents has been limited. Although more encouraging results have been seen when these agents have been used in combination with cytotoxic therapy, the specific contribution of the targeted agents to the observed anti-tumor effects remains to be established in randomized controlled Phase III trials. This article presents a review of the limitations of current therapy, a description of key pathogenic mechanisms for which inhibitors exist and a summary of therapeutic trials of molecularly targeted agents in this disease.

17 Clinical Trial Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. 2019

Sullivan, Ryan J / Hamid, Omid / Gonzalez, Rene / Infante, Jeffrey R / Patel, Manish R / Hodi, F Stephen / Lewis, Karl D / Tawbi, Hussein A / Hernandez, Genevive / Wongchenko, Matthew J / Chang, YiMeng / Roberts, Louise / Ballinger, Marcus / Yan, Yibing / Cha, Edward / Hwu, Patrick. ·Massachusetts General Hospital Cancer Center, Boston, MA, USA. rsullivan7@mgh.harvard.edu. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · University of Colorado Cancer Center, Aurora, CO, USA. · Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA. · Sarah Cannon Research Institute/Florida Cancer Specialists & Research Institute, Sarasota, FL, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · MD Anderson Cancer Center, Houston, TX, USA. · Genentech, Inc., South San Francisco, CA, USA. ·Nat Med · Pubmed #31171876.

ABSTRACT: Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAF

18 Clinical Trial Results from phase II trial of HSP90 inhibitor, STA-9090 (ganetespib), in metastatic uveal melanoma. 2018

Shah, Shalin / Luke, Jason J / Jacene, Heather A / Chen, Tianqi / Giobbie-Hurder, Anita / Ibrahim, Nageatte / Buchbinder, Elizabeth L / McDermott, David F / Flaherty, Keith T / Sullivan, Ryan J / Lawrence, Donald P / Ott, Patrick A / Hodi, F Stephen. ·Department of Medicine, Medical University of South Carolina, Charleston, South Carolina. · Department of Medicine, University of Chicago, Chicago, Illinois. · Department of Radiology, Brigham and Women's Hospital. · Department of Biostatics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · Department of Medicine, Dana-Farber Cancer Institute. · Department of Medicine, Beth Israel Deaconess Medical Center. · Department of Medicine, Massachusetts General Hospital Cancer Center. ·Melanoma Res · Pubmed #30211813.

ABSTRACT: Uveal melanoma (UM) is a rare form of melanoma without effective therapy. The biology of UM relies on several heat-shock protein 90 (Hsp90)-dependent molecules such as MET, MEK and AKT, making Hsp90 inhibition a rational approach. Patients with stage IV UM, measurable disease, and no previous chemotherapy were eligible. Patients received either ganetespib 200 mg weekly (cohort A) or 150 mg twice a week (cohort B). Primary endpoint response rate (RR) was assessed by RECIST. A total of 17 patients were accrued for this study, with seven in cohort A and 10 in cohort B. Liver metastases were present in 59%. Response outcomes included one partial response, four stable disease, 11 progressive disease, and one withdrawal for ORR: 5.9% and disease control rate of 29.4%. Progression-free survival was 1.6 months (cohort A) and 1.8 months (cohort B). Overall survival was 8.5 months (cohort A) and 4.9 months (cohort B). An overall 31% of adverse events were grade 3-4 and were mostly related to gastrointestinal toxicities. Early on-treatment (1 months) positron emission tomography showed reduction in metabolic activity in 24% of patients, suggesting a pharmacodynamic effect of Hsp90 inhibition. These early metabolic changes did not seem to be durable and/or clinically significant in relation to the 2-month response assessment. Hsp90 inhibition with ganetespib resulted in modest clinical benefit on two dosing schedules and was associated with significant, although manageable, gastrointestinal toxicity. Evidence of pharmacodynamic activity for Hsp90 inhibition was observed via positron emission tomography, which did not translate into clinical benefit, suggesting rapid development of resistance.

19 Clinical Trial Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic 2017

Delord, Jean-Pierre / Robert, Caroline / Nyakas, Marta / McArthur, Grant A / Kudchakar, Ragini / Mahipal, Amit / Yamada, Yasuhide / Sullivan, Ryan / Arance, Ana / Kefford, Richard F / Carlino, Matteo S / Hidalgo, Manuel / Gomez-Roca, Carlos / Michel, Daniela / Seroutou, Abdelkader / Aslanis, Vassilios / Caponigro, Giordano / Stuart, Darrin D / Moutouh-de Parseval, Laure / Demuth, Tim / Dummer, Reinhard. ·Institut Universitaire du Cancer, Toulouse, France. delord.jean-pierre@iuct-oncopole.fr. · Gustave Roussy and Paris-Sud University, Villejuif, France. · Oslo University Hospital, Norway. · Peter MacCallum Cancer Centre and the University of Melbourne, Australia. · Winship Cancer Institute of Emory University, Atlanta, Georgia. · Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. · National Cancer Center Hospital, Tokyo, Japan. · Massachusetts General Hospital, Boston, Massachusetts. · Department of Medical Oncology and Translational Genomics and Targeted Therapeutics in Solid Tumors, Hospital Clínic, Barcelona, Spain. · Crown Princess Mary Cancer Centre Westmead Hospital, Melanoma Institute Australia, University of Sydney, Sydney, New South Wales, Australia. · Macquarie University, Sydney, New South Wales, Australia. · Spanish National Cancer Research Centre (CNIO) and Centro Integral Oncologico Clara Campal, Madrid, Spain. · Institut Universitaire du Cancer, Toulouse, France. · Novartis Pharma AG, Basel, Switzerland. · Novartis Institutes for Biomedical Research, Cambridge, Massachusetts. · University Hospital Zurich, Zurich, Switzerland. ·Clin Cancer Res · Pubmed #28611198.

ABSTRACT:

20 Clinical Trial Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. 2016

Weber, Jeffrey S / Gibney, Geoff / Sullivan, Ryan J / Sosman, Jeffrey A / Slingluff, Craig L / Lawrence, Donald P / Logan, Theodore F / Schuchter, Lynn M / Nair, Suresh / Fecher, Leslie / Buchbinder, Elizabeth I / Berghorn, Elmer / Ruisi, Mary / Kong, George / Jiang, Joel / Horak, Christine / Hodi, F Stephen. ·New York University Langone Medical Center, New York, NY, USA; H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. · H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA. · Massachusetts General Hospital, Boston, MA, USA. · Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. · University of Virginia School of Medicine, Charlottesville, VA, USA. · Indiana University Simon Cancer Center, Indianapolis, IN, USA. · University of Pennsylvania, Philadelphia, PA, USA. · Lehigh Valley Health Network, Allentown, PA, USA. · Indiana University Simon Cancer Center, Indianapolis, IN, USA; University of Michigan, Ann Arbor, MI, USA. · Beth Israel Deaconess Medical Center, Boston, MA, USA. · Bristol-Myers Squibb, Princeton, NJ, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: stephen_hodi@dfci.harvard.edu. ·Lancet Oncol · Pubmed #27269740.

ABSTRACT: BACKGROUND: Concurrent administration of the immune checkpoint inhibitors nivolumab and ipilimumab has shown greater efficacy than either agent alone in patients with advanced melanoma, albeit with more high-grade adverse events. We assessed whether sequential administration of nivolumab followed by ipilimumab, or the reverse sequence, could improve safety without compromising efficacy. METHODS: We did this randomised, open-label, phase 2 study at nine academic medical centres in the USA. Eligible patients (aged ≥18 years) with unresectable stage III or IV melanoma (treatment-naive or who had progressed after no more than one previous systemic therapy, with an Eastern Cooperative Oncology Group performance status of 0 or 1) were randomly assigned (1:1) to induction with intravenous nivolumab 3 mg/kg every 2 weeks for six doses followed by a planned switch to intravenous ipilimumab 3 mg/kg every 3 weeks for four doses, or the reverse sequence. Randomisation was done by an independent interactive voice response system with a permuted block schedule (block size four) without stratification factors. After induction, both groups received intravenous nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary endpoint was treatment-related grade 3-5 adverse events until the end of the induction period (week 25), analysed in the as-treated population. Secondary endpoints were the proportion of patients who achieved a response at week 25 and disease progression at weeks 13 and 25. Overall survival was a prespecified exploratory endpoint. This study is registered with ClinicalTrials.gov, number NCT01783938, and is ongoing but no longer enrolling patients. FINDINGS: Between April 30, 2013, and July 21, 2014, 140 patients were enrolled and randomly assigned to nivolumab followed by ipilimumab (n=70) or to the reverse sequence of ipilimumab followed by nivolumab (n=70), of whom 68 and 70 patients, respectively, received at least one dose of study drug and were included in the analyses. The frequencies of treatment-related grade 3-5 adverse events up to week 25 were similar in the nivolumab followed by ipilimumab group (34 [50%; 95% CI 37·6-62·4] of 68 patients) and in the ipilimumab followed by nivolumab group (30 [43%; 31·1-55·3] of 70 patients). The most common treatment-related grade 3-4 adverse events during the whole study period were colitis (ten [15%]) in the nivolumab followed by ipilimumab group vs 14 [20%] in the reverse sequence group), increased lipase (ten [15%] vs 12 [17%]), and diarrhoea (eight [12%] vs five [7%]). No treatment-related deaths occurred. The proportion of patients with a response at week 25 was higher with nivolumab followed by ipilimumab than with the reverse sequence (28 [41%; 95% CI 29·4-53·8] vs 14 [20%; 11·4-31·3]). Progression was reported in 26 (38%; 95% CI 26·7-50·8) patients in the nivolumab followed by ipilimumab group and 43 (61%; 49·0-72·8) patients in the reverse sequence group at week 13 and in 26 (38%; 26·7-50·8) and 42 (60%; 47·6-71·5) patients at week 25, respectively. After a median follow-up of 19·8 months (IQR 12·8-25·7), median overall survival was not reached in the nivolumab followed by ipilimumab group (95% CI 23·7-not reached), whereas over a median follow-up of 14·7 months (IQR 5·6-23·9) in the ipilimumab followed by nivolumab group, median overall survival was 16·9 months (95% CI 9·2-26·5; HR 0·48 [95% CI 0·29-0·80]). A higher proportion of patients in the nivolumab followed by ipilimumab group achieved 12-month overall survival than in the ipilimumab followed by nivolumab group (76%; 95% CI 64-85 vs 54%; 42-65). INTERPRETATION: Nivolumab followed by ipilimumab appears to be a more clinically beneficial option compared with the reverse sequence, albeit with a higher frequency of adverse events. FUNDING: Bristol-Myers Squibb.

21 Clinical Trial Clinical, Molecular, and Immune Analysis of Dabrafenib-Trametinib Combination Treatment for BRAF Inhibitor-Refractory Metastatic Melanoma: A Phase 2 Clinical Trial. 2016

Chen, Guo / McQuade, Jennifer L / Panka, David J / Hudgens, Courtney W / Amin-Mansour, Ali / Mu, Xinmeng Jasmine / Bahl, Samira / Jané-Valbuena, Judit / Wani, Khalida M / Reuben, Alexandre / Creasy, Caitlyn A / Jiang, Hong / Cooper, Zachary A / Roszik, Jason / Bassett, Roland L / Joon, Aron Y / Simpson, Lauren M / Mouton, Rosalind D / Glitza, Isabella C / Patel, Sapna P / Hwu, Wen-Jen / Amaria, Rodabe N / Diab, Adi / Hwu, Patrick / Lazar, Alexander J / Wargo, Jennifer A / Garraway, Levi A / Tetzlaff, Michael T / Sullivan, Ryan J / Kim, Kevin B / Davies, Michael A. ·Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston. · Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston. · Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Departments of Pathology and Translational and Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston. · Broad Institute, Cambridge, Massachusetts. · Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston7Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston. · Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston. · Massachusetts General Hospital, Boston. · California Pacific Medical Center Research Institute, San Francisco. · Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston11Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston. ·JAMA Oncol · Pubmed #27124486.

ABSTRACT: IMPORTANCE: Combined treatment with dabrafenib and trametinib (CombiDT) achieves clinical responses in only about 15% of patients with BRAF inhibitor (BRAFi)-refractory metastatic melanoma in contrast to the higher response rate observed in BRAFi-naïve patients. Identifying correlates of response and mechanisms of resistance in this population will facilitate clinical management and rational therapeutic development. OBJECTIVE: To determine correlates of benefit from CombiDT therapy in patients with BRAFi-refractory metastatic melanoma. DESIGN, SETTING, AND PARTICIPANTS: Single-center, single-arm, open-label phase 2 trial of CombiDT treatment in patients with BRAF V600 metastatic melanoma resistant to BRAFi monotherapy conducted between September 2012 and October 2014 at the University of Texas MD Anderson Cancer Center. Key eligibility criteria for participants included BRAF V600 metastatic melanoma, prior BRAFi monotherapy, measurable disease (RECIST 1.1), and tumor accessible for biopsy. INTERVENTIONS: Patients were treated with dabrafenib (150 mg, twice daily) and trametinib (2 mg/d) continuously until disease progression or intolerance. All participants underwent a mandatory baseline biopsy, and optional biopsy specimens were obtained on treatment and at disease progression. Whole-exome sequencing, reverse transcription polymerase chain reaction analysis for BRAF splicing, RNA sequencing, and immunohistochemical analysis were performed on tumor samples, and blood was analyzed for levels of circulating BRAF V600. MAIN OUTCOMES AND MEASURES: The primary end point was overall response rate (ORR). Progression-free survival (PFS) and overall survival (OS) were secondary clinical end points. RESULTS: A total of 28 patients were screened, and 23 enrolled. Among evaluable patients, the confirmed ORR was 10%; disease control rate (DCR) was 45%, and median PFS was 13 weeks. Clinical benefit was associated with duration of prior BRAFi therapy greater than 6 months (DCR, 73% vs 11% for ≤6 months; P = .02) and decrease in circulating BRAF V600 at day 8 of cycle 1 (DCR, 75% vs 18% for no decrease; P = .02) but not with pretreatment mitogen-activated protein kinase (MAPK) pathway mutations or activation. Biopsy specimens obtained during treatment demonstrated that CombiDT therapy failed to achieve significant MAPK pathway inhibition or immune infiltration in most patients. CONCLUSIONS AND RELEVANCE: The baseline presence of MAPK pathway alterations was not associated with benefit from CombiDT in patients with BRAFi-refractory metastatic melanoma. Failure to inhibit the MAPK pathway provides a likely explanation for the limited clinical benefit of CombiDT in this setting. Circulating BRAF V600 is a promising early biomarker of clinical response. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01619774.

22 Clinical Trial A Phase I Trial of Bortezomib and Sorafenib in Advanced Malignant Melanoma. 2015

Sullivan, Ryan J / Ibrahim, Nageatte / Lawrence, Donald P / Aldridge, Julie / Giobbie-Hurder, Anita / Hodi, F Stephen / Flaherty, Keith T / Conley, Christine / Mier, James W / Atkins, Michael B / McDermott, David F. ·Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA; rsullivan7@partners.org. · Dana-Farber Cancer Institute, Boston, Massachusetts, USA; · Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA; · Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; · Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., USA. ·Oncologist · Pubmed #25986244.

ABSTRACT: LESSONS LEARNED: This study is a rare example of effective doses of both targeted agents being both administered and tolerated.This combination should not be used in melanoma. BACKGROUND: Sorafenib and bortezomib affect BCL family member expression. We previously demonstrated that bortezomib augmented sorafenib-mediated cytotoxicity in melanoma cell lines in vitro. We aimed to combine sorafenib 400 mg b.i.d. with increasing doses of weekly bortezomib. METHODS: Patients with metastatic melanoma were enrolled in dose-escalation cohorts to determine the maximum tolerated dose (MTD) of sorafenib (twice daily) in combination with bortezomib (weekly for 3 of 4 weeks). The MTD was defined as the highest dose level at which less than 33% of patients exhibited a dose-limiting toxicity (DLT). Efficacy, as measured by 6-month progression-free survival and response rate per RECIST, was documented. RESULTS: Eleven patients were enrolled at three dose levels. DLTs (fatigue and rash) were seen in two of three patients at the highest dose level. Five patients were enrolled for sorafenib 400 mg b.i.d. and bortezomib 1.0 mg/m(2) weekly for 3 of every 4 weeks; none had DLTs, and this dose level was defined as the MTD. Of 10 evaluable patients, no responses were seen. Two of 11 patients (18%) remained progression free for longer than 6 months. CONCLUSION: The combination of sorafenib and bortezomib is safe but not active in patients with melanoma.

23 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.

24 Clinical Trial Clinical profiling of BCL-2 family members in the setting of BRAF inhibition offers a rationale for targeting de novo resistance using BH3 mimetics. 2014

Frederick, Dennie T / Salas Fragomeni, Roberto A / Schalck, Aislyn / Ferreiro-Neira, Isabel / Hoff, Taylor / Cooper, Zachary A / Haq, Rizwan / Panka, David J / Kwong, Lawrence N / Davies, Michael A / Cusack, James C / Flaherty, Keith T / Fisher, David E / Mier, James W / Wargo, Jennifer A / Sullivan, Ryan J. ·Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts, United States of America. · Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America. · Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States of America. · Department of Surgical Oncology and Genomic Medicine, University of Texas, M.D.Anderson Cancer Center, Houston, Texas, United States of America. · Harvard Medical School, Boston, Massachusetts, United States of America; Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States of America. · Harvard Medical School, Boston, Massachusetts, United States of America; Division of Hematology Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America. · Harvard Medical School, Boston, Massachusetts, United States of America; Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, United States of America. ·PLoS One · Pubmed #24983357.

ABSTRACT: While response rates to BRAF inhibitiors (BRAFi) are high, disease progression emerges quickly. One strategy to delay the onset of resistance is to target anti-apoptotic proteins such as BCL-2, known to be associated with a poor prognosis. We analyzed BCL-2 family member expression levels of 34 samples from 17 patients collected before and 10 to 14 days after treatment initiation with either vemurafenib or dabrafenib/trametinib combination. The observed changes in mRNA and protein levels with BRAFi treatment led us to hypothesize that combining BRAFi with a BCL-2 inhibitor (the BH3-mimetic navitoclax) would improve outcome. We tested this hypothesis in cell lines and in mice. Pretreatment mRNA levels of BCL-2 negatively correlated with maximal tumor regression. Early increases in mRNA levels were seen in BIM, BCL-XL, BID and BCL2-W, as were decreases in MCL-1 and BCL2A. No significant changes were observed with BCL-2. Using reverse phase protein array (RPPA), significant increases in protein levels were found in BIM and BID. No changes in mRNA or protein correlated with response. Concurrent BRAF (PLX4720) and BCL2 (navitoclax) inhibition synergistically reduced viability in BRAF mutant cell lines and correlated with down-modulation of MCL-1 and BIM induction after PLX4720 treatment. In xenograft models, navitoclax enhanced the efficacy of PLX4720. The combination of a selective BRAF inhibitor with a BH3-mimetic promises to be an important therapeutic strategy capable of enhancing the clinical efficacy of BRAF inhibition in many patients that might otherwise succumb quickly to de novo resistance. Trial registrations: ClinicalTrials.gov NCT01006980; ClinicalTrials.gov NCT01107418; ClinicalTrials.gov NCT01264380; ClinicalTrials.gov NCT01248936; ClinicalTrials.gov NCT00949702; ClinicalTrials.gov NCT01072175.

25 Clinical Trial MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. 2014

Wagle, Nikhil / Van Allen, Eliezer M / Treacy, Daniel J / Frederick, Dennie T / Cooper, Zachary A / Taylor-Weiner, Amaro / Rosenberg, Mara / Goetz, Eva M / Sullivan, Ryan J / Farlow, Deborah N / Friedrich, Dennis C / Anderka, Kristin / Perrin, Danielle / Johannessen, Cory M / McKenna, Aaron / Cibulskis, Kristian / Kryukov, Gregory / Hodis, Eran / Lawrence, Donald P / Fisher, Sheila / Getz, Gad / Gabriel, Stacey B / Carter, Scott L / Flaherty, Keith T / Wargo, Jennifer A / Garraway, Levi A. ·1Department of Medical Oncology, Dana-Farber Cancer Institute; 2Department of Medicine, Brigham and Women's Hospital; 3Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston; 4Broad Institute of Harvard and MIT; and 5Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts. ·Cancer Discov · Pubmed #24265154.

ABSTRACT: Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP-ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-seq) on pretreatment and drug-resistant tumors from five patients with acquired resistance to dabrafenib/trametinib. In three of these patients, we identified additional mitogen-activated protein kinase (MAPK) pathway alterations in the resistant tumor that were not detected in the pretreatment tumor, including a novel activating mutation in MEK2 (MEK2(Q60P)). MEK2(Q60P) conferred resistance to combined RAF/MEK inhibition in vitro, but remained sensitive to inhibition of the downstream kinase extracellular signal-regulated kinase (ERK). The continued MAPK signaling-based resistance identified in these patients suggests that alternative dosing of current agents, more potent RAF/MEK inhibitors, and/or inhibition of the downstream kinase ERK may be needed for durable control of BRAF-mutant melanoma.

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