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Melanoma: HELP
Articles by Michael B. Atkins
Based on 67 articles published since 2009
(Why 67 articles?)

Between 2009 and 2019, M. B. Atkins wrote the following 67 articles about Melanoma.
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Guideline The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. 2013

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

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

2 Review Surgical Management and Adjuvant Therapy for High-Risk and Metastatic Melanoma. 2016

van Akkooi, Alexander C J / Atkins, Michael B / Agarwala, Sanjiv S / Lorigan, Paul. ·From the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; St. Luke's University Hospital, Temple University, Allentown, PA; University of Manchester, The Christie NHS Foundation Trust, Manchester, United Kingdom. ·Am Soc Clin Oncol Educ Book · Pubmed #27249760.

ABSTRACT: Wide local excision is considered routine therapy after initial diagnosis of primary melanoma to reduce local recurrences, but it does not impact survival. Sentinel node staging is recommended for melanomas of intermediate thickness, but it has also not demonstrated any indisputable therapeutic effect on survival. The prognostic value of sentinel node staging has been long established and is therefore considered routine, especially in light of the eligibility criteria for adjuvant therapy (trials). Whether completion lymph node dissection after a positive sentinel node biopsy improves survival is the question of current trials. The MSLT-2 study is best powered to show a potential benefit, but it has not yet reported any data. Another study, the German DECOG study, presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting did not show any benefit but is criticized for the underpowered design and insufficient follow-up. There is no consensus on the use of adjuvant interferon in melanoma. This topic has been the focus of many studies with different regimens (low-, intermediate-, or high-dose and/or short- or long-term treatment). Adjuvant interferon has been shown to improve relapse-free survival but failed to improve overall survival. More recently, adjuvant ipilimumab has also demonstrated an improved relapse-free survival. Overall survival data have not yet been reported due to insufficient follow-up. Currently, studies are ongoing to analyze the use of adjuvant anti-PD-1 and molecular targeted therapies (vemurafenib, dabrafenib, and trametinib). In the absence of unambiguously positive approved agents, clinical trial participation remains a priority. This could change in the near future.

3 Review Advances in immunotherapy for melanoma. 2016

Redman, Jason M / Gibney, Geoffrey T / Atkins, Michael B. ·Georgetown Lombardi Comprehensive Cancer Center 3970 Reservoir Road, NW Research Building, Room E501, 20007, Washington DC, USA. jason.m.redman@gmail.com. · Department of Medicine, Georgetown University Medical Center, Washington DC, USA. jason.m.redman@gmail.com. · Georgetown Lombardi Comprehensive Cancer Center 3970 Reservoir Road, NW Research Building, Room E501, 20007, Washington DC, USA. geoffrey.t.gibney@gunet.georgetown.edu. · Department of Medicine, Georgetown University Medical Center, Washington DC, USA. geoffrey.t.gibney@gunet.georgetown.edu. · Georgetown Lombardi Comprehensive Cancer Center 3970 Reservoir Road, NW Research Building, Room E501, 20007, Washington DC, USA. mba41@georgetown.edu. · Department of Medicine, Georgetown University Medical Center, Washington DC, USA. mba41@georgetown.edu. ·BMC Med · Pubmed #26850630.

ABSTRACT: In recent years, the introduction and Federal Drug Administration approval of immune checkpoint inhibitor antibodies has dramatically improved the clinical outcomes for patients with advanced melanoma. These antagonist monoclonal antibodies are capable of unleashing dormant or exhausted antitumor immunity, which has led to durable complete and partial responses in a large number of patients. Ipilimumab targets the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) receptor. Nivolumab and pembrolizumab target programmed cell death protein 1 (PD-1) receptors and have proven to be superior to ipilimumab alone. The combination of ipilimumab and nivolumab has yielded higher response rates, greater tumor shrinkage, and longer progression-free survival than either monotherapy alone. As other promising immunotherapies for melanoma proceed through clinical trials, future goals include defining the role of immune checkpoint inhibitors as adjuvant therapy, identifying optimal combination strategies, and developing reliable predictive biomarkers to guide treatment selection for individual patients.

4 Review Immunotherapy Combined or Sequenced With Targeted Therapy in the Treatment of Solid Tumors: Current Perspectives. 2016

Atkins, Michael B / Larkin, James. ·Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC (MBA) · Royal Marsden Hospital, London, UK (JL). ·J Natl Cancer Inst · Pubmed #26839346.

ABSTRACT: The advent of newer immunotherapeutic and molecularly targeted agents has provided a number of effective options for cancer treatment but has also added much complexity in selecting the best initial treatment or treatment plan for each patient. Molecularly targeted agents offer selectivity and are the cornerstone for "precision medicine." While targeted agents are associated with high tumor response rates, patients inevitably develop resistance to these drugs. Immunotherapies exploit the endogenous immune system to eradicate cancer and can produce durable disease control that results in long-term, treatment-free survival in some patients. Guidelines for treatment selection in patients with specific tumor types and clinical features are routinely being reconsidered in order to accommodate the increasingly complex treatment landscapes. Here, we review current perspectives on the use of immunotherapeutic agents, particularly immune checkpoint inhibitors (nivolumab, pembrolizumab, and ipilimumab), in combination or in sequence with molecularly targeted agents in patients with advanced melanoma as well as other tumor types. We further discuss remaining unmet needs for patient selection and treatment with approved therapies.

5 Review Treatment of Melanoma CNS Metastases. 2016

Jang, Sekwon / Atkins, Michael B. ·Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., USA. · Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., USA. mba41@georgetown.edu. ·Cancer Treat Res · Pubmed #26601867.

ABSTRACT: The discovery of the BRAFV600 mutation and the development of targeted therapies directed against this mutation as well as effective immunotherapies with durable benefits have revolutionized the treatment of patients with melanoma. Nonetheless, the frequent occurrence of brain metastases in patients with advanced melanoma represents a significant obstacle to long-term, high quality survival. The application of stereotactic radiation therapy has provided an opportunity to control brain metastases in the majority of patients with metastatic melanoma reducing the impact of these lesions on morbidity and mortality and enabling patients to receive and potentially benefit from these novel systemic treatments. Encouragingly, several of these novel new therapies have shown antitumor activity against CNS metastases that approach that seen against extracranial disease. As a consequence, several effective treatment options are now available for patients with melanoma brain metastases. With these tools in hand, it is anticipated that further investigation into the optimal sequence and/or combination of systemic therapies and local therapies along with multidisciplinary team practice will continue to improve the outcome of patients with this previously life-limiting disease complication.

6 Review Immunotherapy Combinations With Checkpoint Inhibitors in Metastatic Melanoma: Current Approaches and Future Directions. 2015

Atkins, Michael. ·Deputy Director, Georgetown-Lombardi Comprehensive Cancer Center, Professor of Oncology and Medicine (Hematology/Oncology), Georgetown University School of Medicine, Washington, DC. Electronic address: Mba41@georgetown.edu. ·Semin Oncol · Pubmed #26598055.

ABSTRACT: Based on the complexity of the immune response to cancer and the mechanisms of tumor evasion, it is likely that therapeutic modulation of multiple immune-mediated pathways will be needed to maximally induce tumor regression in patients with advanced melanoma. The rationale of using combination checkpoint inhibitor-based regimens may include the concomitant effects on re-activation of T cells, increased trafficking of tumor reactive lymphocytes into the tumor tissue, and enhanced killing of cancer cells. The administration of nivolumab in combination with ipilimumab demonstrated increased response rates, tumor shrinkage, and median progression-free survival using combined therapy compared with either treatment alone. Although toxicity was also increased, this trial established proof of principle that combination immunotherapy could enhance the efficacy seen with single-agent programmed cell death protein-1 (PD-1) pathway blockade for the unselected patient. Current and future trials are evaluating alternative schedules and other combinations of immunotherapies to determine if they could provide similar efficacy with less toxicity. In addition, efforts are underway to determine how best to integrate combination immunotherapy with other treatment approaches for patients with advanced melanoma.

7 Review Immunotherapy or molecularly targeted therapy: what is the best initial treatment for stage IV BRAF-mutant melanoma? 2015

Gibney, Geoffrey T / Atkins, Michael B. ·Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC. ·Clin Adv Hematol Oncol · Pubmed #26353041.

ABSTRACT: The recent developments in BRAF-targeted therapy and checkpoint inhibitor immunotherapies for metastatic melanoma patients have led to better tolerability and markedly improved clinical outcomes, including higher objective response rates and longer survival. Treatment planning has become complex in patients with metastatic BRAF-mutant melanoma, with several options for BRAF- and/or MEK-targeted therapy (vemurafenib, dabrafenib, and trametinib) and immunotherapy (interleukin 2, ipilimumab, pembrolizumab, and nivolumab). Clinicians must weigh various patient factors, including the extent of disease (eg, symptomatic visceral metastases vs limited disease) and central nervous system involvement, as well as factors related to the therapeutic agent, such as rate of clinical response, durability of response, and impact on median and long-term survival. The combination regimen of dabrafenib plus trametinib has become a standard treatment strategy, and ipilimumab plus nivolumab is emerging as a promising treatment strategy. In this review, we discuss the benchmark trials leading to the approval of these new agents and provide emerging data on their use in sequence and impact on overall survival, with the goal of helping oncologists navigate treatment decisions for patients with metastatic BRAF-mutant melanoma.

8 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.

9 Review Treatment of BRAF-mutant melanoma: the role of vemurafenib and other therapies. 2014

Jang, S / Atkins, M B. ·1] Department of Medicine, Georgetown University School of Medicine, Washington, DC, USA [2] Hematology and Oncology, MedStar Washington Hospital Center, Washington, DC, USA. · 1] Division of Hematology and Oncology, Georgetown University School of Medicine, Washington, DC, USA [2] Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA. ·Clin Pharmacol Ther · Pubmed #24080641.

ABSTRACT: The discovery of activating BRAF mutations in melanomas has led to the investigation of small molecular inhibitors targeting BRAF mutation and MEK, a downstream protein within the mitogen-activated protein kinase (MAPK) pathway. This article reviews the role of mutant BRAF in melanoma and summarizes the results of clinical trials evaluating inhibitors of BRAF and MEK in BRAF-mutant melanoma. We further describe recent findings on the mechanisms of resistance to BRAF inhibitors and discuss ongoing efforts to combine BRAF inhibitors with other targeted agents. Finally, we review the results of immunotherapy in BRAF-mutant melanoma and address the current status of efforts to either combine or determine the optimal sequence of these two distinct treatment approaches. Although the recent advances in melanoma therapy have been dramatic, greater understanding of melanoma biology coupled with the successful development of several new treatments and combination regimens will further improve patient outcomes in the future.

10 Review Which drug, and when, for patients with BRAF-mutant melanoma? 2013

Jang, Sekwon / Atkins, Michael B. ·Department of Medicine, Georgetown University School of Medicine, Washington, DC, USA. ·Lancet Oncol · Pubmed #23369684.

ABSTRACT: Patients with metastatic melanoma had few treatment options until 2011, when two drugs-ipilimumab and vemurafenib-were approved following advances in the understanding of melanoma biology and tumour immunology. Almost 50% of melanomas harbour mutations in BRAF, mainly at codon 600, which result in constitutive activation of the MAPK pathway. The selective inhibitors of mutant BRAF Val600, vemurafenib and dabrafenib, showed major tumour responses, resulting in improved progression-free and overall survival in patients with metastatic disease, compared with chemotherapy. Antitumour activity was also recorded in brain metastases. The growth of cutaneous squamous-cell carcinomas is a unique side-effect of BRAF inhibitor therapy that is induced by the paradoxical activation of the MAPK pathway in cells with RAS mutations. Trametinib, which targets MEK downstream of BRAF, also produced an overall survival benefit compared with chemotherapy, although tumour responses were less frequent than they were with BRAF inhibitors. Despite this robust antitumour activity, most responses to these drugs are partial and disease progression is typically seen at a median of 5-7 months. Multiple resistance mechanisms have been identified, including those that lead to reactivation of the MAPK pathway and other pathways, such as the PI3K-AKT-mTOR and VEGF pathways. Some patients with BRAF Val600 mutant melanoma seem to also benefit from immunotherapies such as high-dose interleukin 2 and ipilimumab, which, by contrast with BRAF inhibitors, can produce durable complete responses. We review the available data to best guide initial treatment choice and the sequence of treatments for patients with BRAF Val600 mutant melanoma.

11 Review White paper on adoptive cell therapy for cancer with tumor-infiltrating lymphocytes: a report of the CTEP subcommittee on adoptive cell therapy. 2011

Weber, Jeffrey / Atkins, Michael / Hwu, Patrick / Radvanyi, Laszlo / Sznol, Mario / Yee, Cassian / Anonymous8120686. ·Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. jeffrey.weber@moffitt.org ·Clin Cancer Res · Pubmed #21325070.

ABSTRACT: Adoptive T-cell therapy (ACT) using expanded autologous tumor-infiltrating lymphocytes (TIL) and tumor antigen-specific T cell expanded from peripheral blood are complex but powerful immunotherapies directed against metastatic melanoma. A number of nonrandomized clinical trials using TIL combined with high-dose interleukin-2 (IL-2) have consistently found clinical response rates of 50% or more in metastatic melanoma patients accompanied by long progression-free survival. Recent studies have also established practical methods for the expansion of TIL from melanoma tumors with high success rates. These results have set the stage for randomized phase II/III clinical trials to determine whether ACT provides benefit in stage IV melanoma. Here, we provide an overview of the current state-of-the art in T-cell-based therapies for melanoma focusing on ACT using expanded TIL and address some of the key unanswered biological and clinical questions in the field. Different phase II/III randomized clinical trial scenarios comparing the efficacy of TIL therapy to high-dose IL-2 alone are described. Finally, we provide a roadmap describing the critical steps required to test TIL therapy in a randomized multicenter setting. We suggest an approach using centralized cell expansion facilities that will receive specimens and ship expanded TIL infusion products to participating centers to ensure maximal yield and product consistency. If successful, this approach will definitively answer the question of whether ACT can enter mainstream treatment for cancer.

12 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.

13 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 --

14 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.

15 Clinical Trial Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. 2018

Tawbi, Hussein A / Forsyth, Peter A / Algazi, Alain / Hamid, Omid / Hodi, F Stephen / Moschos, Stergios J / Khushalani, Nikhil I / Lewis, Karl / Lao, Christopher D / Postow, Michael A / Atkins, Michael B / Ernstoff, Marc S / Reardon, David A / Puzanov, Igor / Kudchadkar, Ragini R / Thomas, Reena P / Tarhini, Ahmad / Pavlick, Anna C / Jiang, Joel / Avila, Alexandre / Demelo, Sheena / Margolin, Kim. ·From the University of Texas M.D. Anderson Cancer Center, Houston (H.A.T.) · Moffitt Cancer Center and Research Institute, Tampa, FL (P.A.F., N.I.K.) · University of California-San Francisco, San Francisco (A. Algazi), the Angeles Clinic and Research Institute, Los Angeles (O.H.), Stanford University Hospital, Palo Alto (R.P.T.), and the Department of Medical Oncology, City of Hope, Duarte (K.M.) - all in California · Dana-Farber Cancer Institute, Boston (F.S.H., D.A.R.) · University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (S.J.M.) · University of Colorado Comprehensive Cancer Center, Aurora (K.L.) · University of Michigan, Ann Arbor (C.D.L.) · Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (M.A.P.), Roswell Park Cancer Institute, Buffalo (M.S.E., I.P.), and New York University, Lake Success (A.C.P.) - all in New York · Georgetown-Lombardi Comprehensive Cancer Center, Washington DC (M.B.A.) · Winship Cancer Institute of Emory University, Atlanta (R.R.K.) · University of Pittsburgh Medical Center, Pittsburgh (A.T.) · Bristol-Myers Squibb, Princeton, NJ (J.J., A. Avila, S.D.) · and Cleveland Clinic-Taussig Cancer Institute, Cleveland (A.T.). ·N Engl J Med · Pubmed #30134131.

ABSTRACT: BACKGROUND: Brain metastases are a common cause of disabling neurologic complications and death in patients with metastatic melanoma. Previous studies of nivolumab combined with ipilimumab in metastatic melanoma have excluded patients with untreated brain metastases. We evaluated the efficacy and safety of nivolumab plus ipilimumab in patients with melanoma who had untreated brain metastases. METHODS: In this open-label, multicenter, phase 2 study, patients with metastatic melanoma and at least one measurable, nonirradiated brain metastasis (tumor diameter, 0.5 to 3 cm) and no neurologic symptoms received nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for up to four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks until progression or unacceptable toxic effects. The primary end point was the rate of intracranial clinical benefit, defined as the percentage of patients who had stable disease for at least 6 months, complete response, or partial response. RESULTS: Among 94 patients with a median follow-up of 14.0 months, the rate of intracranial clinical benefit was 57% (95% confidence interval [CI], 47 to 68); the rate of complete response was 26%, the rate of partial response was 30%, and the rate of stable disease for at least 6 months was 2%. The rate of extracranial clinical benefit was 56% (95% CI, 46 to 67). Treatment-related grade 3 or 4 adverse events were reported in 55% of patients, including events involving the central nervous system in 7%. One patient died from immune-related myocarditis. The safety profile of the regimen was similar to that reported in patients with melanoma who do not have brain metastases. CONCLUSIONS: Nivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases. (Funded by Bristol-Myers Squibb and the National Cancer Institute; CheckMate 204 ClinicalTrials.gov number, NCT02320058 .).

16 Clinical Trial Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study. 2018

Callahan, Margaret K / Kluger, Harriet / Postow, Michael A / Segal, Neil H / Lesokhin, Alexander / Atkins, Michael B / Kirkwood, John M / Krishnan, Suba / Bhore, Rafia / Horak, Christine / Wolchok, Jedd D / Sznol, Mario. ·Margaret K. Callahan, Michael A. Postow, Neil H. Segal, Alexander Lesokhin, and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College, New York, NY · Harriet Kluger and Mario Sznol, Yale University School of Medicine and Smilow Cancer Center, and Yale-New Haven Hospital, New Haven, CT · Michael B. Atkins, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC · John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, PA · and Suba Krishnan, Rafia Bhore, and Christine Horak, Bristol-Myers Squibb, Princeton, NJ. ·J Clin Oncol · Pubmed #29040030.

ABSTRACT: Purpose The clinical activity observed in a phase I dose-escalation study of concurrent therapy with nivolumab (NIVO) and ipilimumab (IPI) in patients with previously treated or untreated advanced melanoma led to subsequent clinical development, including randomized trials. Here, we report long-term follow-up data from study CA209-004, including 3-year overall survival (OS). Patients and Methods Concurrent cohorts 1, 2, 2a, and 3 received escalating doses of NIVO plus IPI once every 3 weeks for four doses, followed by NIVO once every 3 weeks for four doses, then NIVO plus IPI once every 12 weeks for eight doses. An expansion cohort (cohort 8) received concurrent NIVO 1 mg/kg plus IPI 3 mg/kg once every 3 weeks for four doses, followed by NIVO 3 mg/kg once every 2 weeks, which is the dose and schedule used in phase II and III studies and now approved for patients with unresectable or metastatic melanoma. Results Among all concurrent cohorts (N = 94) at a follow-up of 30.3 to 55.0 months, the 3-year OS rate was 63% and median OS had not been reached. Objective response rate by modified WHO criteria was 42%, and median duration of response was 22.3 months. Incidence of grade 3 and 4 treatment-related adverse events was 59%. The most common grade 3 and 4 treatment-related adverse events were increases in lipase (15%), alanine aminotransferase (12%), and aspartate aminotransferase (11%). One treatment-related death (1.1%) occurred in a patient who had multiorgan failure 70 days after the last dose of NIVO plus IPI. Conclusion This is the longest follow-up for NIVO plus IPI combination therapy in patients with advanced melanoma. The 3-year OS rate of 63% is the highest observed for this patient population and provides additional evidence for the durable clinical activity of immune checkpoint inhibitors in the treatment of advanced melanoma.

17 Clinical Trial Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. 2017

Weber, Jeffrey / Mandala, Mario / Del Vecchio, Michele / Gogas, Helen J / Arance, Ana M / Cowey, C Lance / Dalle, Stéphane / Schenker, Michael / Chiarion-Sileni, Vanna / Marquez-Rodas, Ivan / Grob, Jean-Jacques / Butler, Marcus O / Middleton, Mark R / Maio, Michele / Atkinson, Victoria / Queirolo, Paola / Gonzalez, Rene / Kudchadkar, Ragini R / Smylie, Michael / Meyer, Nicolas / Mortier, Laurent / Atkins, Michael B / Long, Georgina V / Bhatia, Shailender / Lebbé, Celeste / Rutkowski, Piotr / Yokota, Kenji / Yamazaki, Naoya / Kim, Tae M / de Pril, Veerle / Sabater, Javier / Qureshi, Anila / Larkin, James / Ascierto, Paolo A / Anonymous7111184. ·From New York University Perlmutter Cancer Center, New York (J.W.) · Papa Giovanni XXIII Cancer Center Hospital, Bergamo (M. Mandala), Medical Oncology, National Cancer Institute, Milan (M.D.V.), Oncology Institute of Veneto Istituti di Ricovero e Cura a Carattere Scientifico, Padua (V.C.-S.), Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena (M. Maio), Ospedale Policlinico San Martino, Genoa (P.Q.), and Istituto Nazionale Tumori Fondazione Pascale, Naples (P.A.A.) - all in Italy · National and Kapodistrian University of Athens, Athens (H.J.G.) · Hospital Clinic de Barcelona, Barcelona (A.M.A.), and General University Hospital Gregorio Marañón, Madrid (I.M.-R.) - both in Spain · Texas Oncology-Baylor Cancer Center, Dallas (C.L.C.) · Hospices Civils de Lyon, Pierre Bénite (S.D.), Aix-Marseille University, Hospital de la Timone, Marseille (J.-J.G.), Institut Universitaire du Cancer de Toulouse and Centre Hospitalier Universitaire (CHU), Toulouse (N.M.), Université Lille, INSERM Unité 1189, CHU Lille, Lille (L.M.), and Assistance Publique-Hôpitaux de Paris, Dermatology and Centres d'Investigation Clinique, INSERM Unité 976, Hôpital Saint Louis, Université Paris Diderot, Paris (C.L.) - all in France · Oncology Center Sf. Nectarie, Craiova, Romania (M. Schenker) · Princess Margaret Cancer Centre, University of Toronto, Toronto (M.O.B.), and Cross Cancer Institute, Edmonton, AB (M. Smylie) - both in Canada · the Department of Oncology, University of Oxford, Oxford (M.R.M.), and Royal Marsden NHS Foundation Trust, London (J.L.) - both in the United Kingdom · Gallipoli Medical Research Foundation and University of Queensland, Queensland, VIC (V.A.), and Melanoma Institute Australia, University of Sydney, and Royal North Shore and Mater Hospitals, Sydney (G.V.L.) - all in Australia · University of Colorado, Denver (R.G.) · Winship Cancer Institute, Emory University School of Medicine, Atlanta (R.R.K.) · Georgetown-Lombardi Comprehensive Cancer Center, Washington DC (M.B.A.) · University of Washington, Seattle (S.B.) · Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.) · Nagoya University Graduate School of Medicine, Nagoya (K.Y.), and the National Cancer Center Hospital, Tokyo (N.Y.) - both in Japan · Seoul National University Hospital, Seoul, South Korea (T.M.K.) · and Bristol-Myers Squibb, Princeton, NJ (V.P, J.S., A.Q.). ·N Engl J Med · Pubmed #28891423.

ABSTRACT: BACKGROUND: Nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma. METHODS: In this randomized, double-blind, phase 3 trial, we randomly assigned 906 patients (≥15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence-free survival in the intention-to-treat population. RESULTS: At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment. CONCLUSIONS: Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 238 ClinicalTrials.gov number, NCT02388906 ; Eudra-CT number, 2014-002351-26 .).

18 Clinical Trial Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. 2017

Long, Georgina V / Atkinson, Victoria / Cebon, Jonathan S / Jameson, Michael B / Fitzharris, Bernie M / McNeil, Catriona M / Hill, Andrew G / Ribas, Antoni / Atkins, Michael B / Thompson, John A / Hwu, Wen-Jen / Hodi, F Stephen / Menzies, Alexander M / Guminski, Alexander D / Kefford, Richard / Kong, Benjamin Y / Tamjid, Babak / Srivastava, Archana / Lomax, Anna J / Islam, Mohammed / Shu, Xinxin / Ebbinghaus, Scot / Ibrahim, Nageatte / Carlino, Matteo S. ·Melanoma Institute Australia, University of Sydney, Mater Hospital, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au. · Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, QLD, Australia; University of Queensland, Brisbane, QLD, Australia. · Olivia Newton-John Cancer Research Institute, Austin Health, School of Cancer Medicine, LaTrobe University, Heidelberg, VIC, Australia. · Regional Cancer Centre, Waikato Hospital, Hamilton, New Zealand. · Canterbury District Health Board, Christchurch Hospital, Christchurch, New Zealand. · Royal Prince Alfred Hospital, Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Chris O'Brien Lifehouse, Camperdown, NSW, Australia. · Tasman Oncology Research, Southport Gold Coast, QLD, Australia. · Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. · Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA. · Department of Medicine, University of Washington, Seattle, WA, USA. · University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Melanoma Institute Australia, University of Sydney, Mater Hospital, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia. · Westmead Hospital, Melanoma Institute Australia, Macquarie University, Sydney, NSW, Australia. · Westmead Hospital, Westmead, NSW, Australia; Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Blacktown Hospital, Blacktown, NSW, Australia. · Merck & Co, Kenilworth, NJ, USA. ·Lancet Oncol · Pubmed #28729151.

ABSTRACT: BACKGROUND: Reduced-dose nivolumab in combination with standard-dose ipilimumab improves objective response and progression-free survival compared with standard-dose ipilimumab alone, but increases toxicity. We assessed the safety and anti-tumour activity of standard-dose pembrolizumab in combination with reduced-dose ipilimumab. METHODS: In this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA. Eligible patients were aged at least 18 years, had advanced melanoma, had an Eastern Coooperative Oncology Group performance status of 0 or 1, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, had adequate organ function, had resolution of toxic effects of the most recent previous chemotherapy to grade 1 or less, had no active autoimmune disease requiring systemic steroids or immunosuppressive agents, had no active non-infectious pneumonitis, had no uncontrolled thyroid dysfunction or diabetes, had no active brain metastases, and had not received previous immune checkpoint inhibitor therapy. Patients received intravenous pembrolizumab 2 mg/kg plus intravenous ipilimumab 1 mg/kg every 3 weeks for four doses, followed by intravenous pembrolizumab 2 mg/kg every 3 weeks for up to 2 years or disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was safety and tolerability. The proportion of patients achieving an objective response assessed per RECIST version 1.1 by independent central review and overall survival were secondary endpoints. We also assessed progression-free survival. The primary endpoint was assessed in all patients who received at least one dose of combination therapy. Activity was assessed in all enrolled patients. This trial is registered with ClinicalTrials.gov, number NCT02089685. Enrolment into this cohort is closed, but patients are still being monitored for safety and anti-tumour activity. FINDINGS: Between Jan 13, 2015, and Sept 17, 2015, we enrolled and treated 153 patients. As of the Oct 17, 2016, cutoff date, median follow-up was 17·0 months (IQR 14·8-18·8). 110 (72%) of 153 patients received all four pembrolizumab plus ipilimumab doses; 64 (42%) remained on pembrolizumab monotherapy. 110 grade 3-4 treatment-related adverse events occurred in 69 (45%) patients. No treatment-related deaths occurred. Treatment-related adverse events led to discontinuation of pembrolizumab and ipilimumab in 22 (14%) patients, including 17 (11%) who discontinued both treatments for the same event and five (3%) who discontinued ipilimumab for one event and later discontinued pembrolizumab for another. 12 (8%) patients discontinued ipilimumab only and 14 (9%) discontinued pembrolizumab only because of treatment-related adverse events. 158 immune-mediated adverse events of any grade occurred in 92 (60%) patients, and 50 immune-mediated adverse events of grade 3-4 occurred in 42 (27%) patients; the most common immune-mediated adverse events were hypothyroidism (25 [16%]) and hyperthyroidism (17 [11%]). 93 (61% [95% CI 53-69]) patients achieved an objective response. Estimated 1 year progression-free survival was 69% (95% CI 60-75), and estimated 1 year overall survival was 89% (95% CI 83-93). INTERPRETATION: Standard-dose pembrolizumab given in combination with four doses of reduced-dose ipilimumab followed by standard-dose pembrolizumab has a manageable toxicity profile and provides robust anti-tumour activity in patients with advanced melanoma. These data suggest that standard-dose pembrolizumab plus reduced-dose ipilimumab might be a tolerable, efficacious treatment option for patients with advanced melanoma. A randomised phase 2 trial of alternative dosing strategies of this combination is underway. FUNDING: Merck & Co, Inc.

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

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

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

20 Clinical Trial Immune Correlates of GM-CSF and Melanoma Peptide Vaccination in a Randomized Trial for the Adjuvant Therapy of Resected High-Risk Melanoma (E4697). 2017

Butterfield, Lisa H / Zhao, Fengmin / Lee, Sandra / Tarhini, Ahmad A / Margolin, Kim A / White, Richard L / Atkins, Michael B / Cohen, Gary I / Whiteside, Theresa L / Kirkwood, John M / Lawson, David H. ·University of Pittsburgh, Pittsburgh, Pennsylvania. butterfieldl@upmc.edu. · Dana Farber Cancer Institute - ECOG-ACRIN Biostatistics Center, Boston, Massachusetts. · University of Pittsburgh, Pittsburgh, Pennsylvania. · Seattle Cancer Care Alliance, Seattle, Washington. · Levine Cancer Institute, Carolinas Healthcare System, Charlotte, North Carolina. · Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Greater Baltimore Medical Center, Baltimore, Maryland. · Winship Cancer institute of Emory University, Atlanta, Georgia. ·Clin Cancer Res · Pubmed #28536308.


21 Clinical Trial Phase III Randomized Study of 4 Weeks of High-Dose Interferon-α-2b in Stage T2bNO, T3a-bNO, T4a-bNO, and T1-4N1a-2a (microscopic) Melanoma: A Trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E1697). 2017

Agarwala, Sanjiv S / Lee, Sandra J / Yip, Waiki / Rao, Uma N / Tarhini, Ahmad A / Cohen, Gary I / Reintgen, Douglas S / Evans, Terry L / Brell, Joanna M / Albertini, Mark R / Atkins, Michael B / Dakhil, Shaker R / Conry, Robert M / Sosman, Jeffrey A / Flaherty, Lawrence E / Sondak, Vernon K / Carson, William E / Smylie, Michael G / Pappo, Alberto S / Kefford, Richard F / Kirkwood, John M. ·Sanjiv S. Agarwala, Saint Luke's University Hospital, Easton · Uma N. Rao, Ahmad A. Tarhini, Terry L. Evans, and John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, PA · Sandra J. Lee, and Waiki Yip, Dana Farber Cancer Institute-ECOG-ACRIN Biostatistics Center, Boston, MA · Gary I. Cohen, Greater Baltimore Medical Center, Baltimore, MD · Douglas S. Reintgen, Lakeland Regional Cancer Center, Lakeland · Vernon K. Sondak, H. Lee Moffitt Cancer Center, Tampa, FL · Joanna M. Brell, MetroHealth Medical Center, Cleveland · William E. Carson, The Ohio State University Comprehensive Cancer Center, Columbus, OH · Mark R. Albertini, University of Wisconsin Hospital, Madison, WI · Michael B. Atkins, Georgetown Medical Center, Washington, DC · Shaker R. Dakhil, Cancer Center of Kansas, Wichita, KS · Robert M. Conry, University of Alabama at Birmingham, Birmingham, AL · Jeffrey A. Sosman, Vanderbilt University, Nashville · Alberto S. Pappo, Saint Jude Children's Research Hospital Oncology, Memphis, TN · Lawrence E. Flaherty, Wayne State University/Karmanos Cancer Institute, Detroit, MI · Michael G. Smylie, Cross Cancer Institute, Edmonton, Canada · and Richard F. Kefford, Sydney West Area Health Service, Westmead, Australia. ·J Clin Oncol · Pubmed #28135150.

ABSTRACT: Purpose To test the efficacy of 4 weeks of intravenous (IV) induction with high-dose interferon (IFN) as part of the Eastern Cooperative Oncology Group regimen compared with observation (OBS) in patients with surgically resected intermediate-risk melanoma. Patients and Methods In this intergroup international trial, eligible patients had surgically resected cutaneous melanoma in the following categories: (1) T2bN0, (2) T3a-bN0, (3) T4a-bN0, and (4) T1-4N1a-2a (microscopic). Patients were randomly assigned to receive IFN α-2b at 20 MU/m

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

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

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

23 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.

24 Clinical Trial Southwest Oncology Group S0008: a phase III trial of high-dose interferon Alfa-2b versus cisplatin, vinblastine, and dacarbazine, plus interleukin-2 and interferon in patients with high-risk melanoma--an intergroup study of cancer and leukemia Group B, Children's Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. 2014

Flaherty, Lawrence E / Othus, Megan / Atkins, Michael B / Tuthill, Ralph J / Thompson, John A / Vetto, John T / Haluska, Frank G / Pappo, Alberto S / Sosman, Jeffrey A / Redman, Bruce G / Moon, James / Ribas, Antoni / Kirkwood, John M / Sondak, Vernon K. ·Lawrence E. Flaherty, Wayne State University, Detroit · Bruce G. Redman, University of Michigan, Ann Arbor, MI · Megan Othus, James Moon, Southwest Oncology Group Statistical Center · John A. Thompson, Seattle Cancer Care Alliance, Seattle, WA · Michael B. Atkins, Georgetown University Hospital, Washington DC · Ralph J. Tuthill, Cleveland Clinic Foundation, Cleveland, OH · John T. Vetto, Oregon Health & Science University/Knight Cancer Institute, Portland, OR · Frank G. Haluska, Tufts-New England Medical Center, Boston, MA · Alberto S. Pappo, Texas Children's Cancer Center, Houston, TX · Jeffrey A. Sosman, Vanderbilt University School of Medicine Nashville, TN · Antoni Ribas, University of California Los Angeles, Los Angeles, CA · John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, PA · Vernon K. Sondak, H. Lee Moffitt Cancer Center, Tampa, FL. ·J Clin Oncol · Pubmed #25332243.

ABSTRACT: PURPOSE: High-dose interferon (IFN) for 1 year (HDI) is the US Food and Drug Administration-approved adjuvant therapy for patients with high-risk melanoma. Efforts to modify IFN dose and schedule have not improved efficacy. We sought to determine whether a shorter course of biochemotherapy would be more effective. PATIENTS AND METHODS: S0008 (S0008: Chemotherapy Plus Biological Therapy in Treating Patients With Melanoma) was an Intergroup phase III trial that enrolled high-risk patients (stage IIIA-N2a through IIIC-N3), randomly assigning them to receive either HDI or biochemotherapy consisting of dacarbazine, cisplatin, vinblastine, interleukin-2, IFN alfa-2b (IFN-α-2b) and granulocyte colony-stimulating factor given every 21 days for three cycles. Coprimary end points were relapse-free survival (RFS) and overall survival (OS). RESULTS: In all, 432 patients were enrolled. Grade 3 and 4 adverse events occurred in 57% and 7% of HDI patients and 36% and 40% of biochemotherapy patients, respectively. At a median follow-up of 7.2 years, biochemotherapy improved RFS (hazard ratio [HR], 0.75; 95% CI, 0.58 to 0.97; P = .015), with a median RFS of 4.0 years (95% CI, 1.9 years to not reached [NR]) versus 1.9 years for HDI (95% CI, 1.2 to 2.8 years) and a 5-year RFS of 48% versus 39%. Median OS was not different (HR, 0.98; 95% CI, 0.74 to 1.31; P = .55), with a median OS of 9.9 years (95% CI, 4.62 years to NR) for biochemotherapy versus 6.7 years (95% CI, 4.5 years to NR) for HDI and a 5-year OS of 56% for both arms. CONCLUSION: Biochemotherapy is a shorter, alternative adjuvant treatment for patients with high-risk melanoma that provides statistically significant improvement in RFS but no difference in OS and more toxicity compared with HDI.

25 Clinical Trial Bevacizumab plus ipilimumab in patients with metastatic melanoma. 2014

Hodi, F Stephen / Lawrence, Donald / Lezcano, Cecilia / Wu, Xinqi / Zhou, Jun / Sasada, Tetsuro / Zeng, Wanyong / Giobbie-Hurder, Anita / Atkins, Michael B / Ibrahim, Nageatte / Friedlander, Philip / Flaherty, Keith T / Murphy, George F / Rodig, Scott / Velazquez, Elsa F / Mihm, Martin C / Russell, Sara / DiPiro, Pamela J / Yap, Jeffrey T / Ramaiya, Nikhil / Van den Abbeele, Annick D / Gargano, Maria / McDermott, David. ·Authors' Affiliations: Departments of Medical Oncology, Stephen_Hodi@dfci.harvard.edu. · Massachusetts General Hospital Cancer Center; Departments of. · University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; · Authors' Affiliations: Departments of Medical Oncology. · Biostatistics, and. · Lombardi Cancer Center Georgetown University, Washington, District of Columbia; and. · Mount Sinai Medical Center, New York, New York. · Pathology and. · Tufts University; Miraca Life Sciences, Newton, Massachusetts; · Surgery, Brigham and Women's Hospital; · Imaging, Dana-Farber Cancer Institute; · Beth Israel-Deaconess Medical Center, Boston; ·Cancer Immunol Res · Pubmed #24838938.

ABSTRACT: Ipilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopathy. Besides promoting angiogenesis, vascular endothelial growth factor (VEGF) suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. This study investigated the combination of CTLA4 blockade with ipilimumab and VEGF inhibition with bevacizumab. Patients with metastatic melanoma were treated in four dosing cohorts of ipilimumab (3 or 10 mg/kg) with four doses at 3-week intervals and then every 12 weeks, and bevacizumab (7.5 or 15 mg/kg) every 3 weeks. Forty-six patients were treated. Inflammatory events included giant cell arteritis (n = 1), hepatitis (n = 2), and uveitis (n = 2). On-treatment tumor biopsies revealed activated vessel endothelium with extensive CD8(+) and macrophage cell infiltration. Peripheral blood analyses demonstrated increases in CCR7(+/-)/CD45RO(+) cells and anti-galectin antibodies. Best overall response included 8 partial responses, 22 instances of stable disease, and a disease-control rate of 67.4%. Median survival was 25.1 months. Bevacizumab influences changes in tumor vasculature and immune responses with ipilimumab administration. The combination of bevacizumab and ipilimumab can be safely administered and reveals VEGF-A blockade influences on inflammation, lymphocyte trafficking, and immune regulation. These findings provide a basis for further investigating the dual roles of angiogenic factors in blood vessel formation and immune regulation, as well as future combinations of antiangiogenesis agents and immune checkpoint blockade.