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Melanoma: HELP
Articles by Mario Sznol
Based on 56 articles published since 2009
(Why 56 articles?)

Between 2009 and 2019, M. Sznol wrote the following 56 articles about Melanoma.
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Editorial Release the hounds! Activating the T-cell response to cancer. 2015

Sznol, Mario / Longo, Dan L. ·From the Section of Medical Oncology, Yale University School of Medicine, New Haven, CT (M.S.). ·N Engl J Med · Pubmed #25482238.

ABSTRACT: -- No abstract --

2 Editorial Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. 2010

Rubinstein, Jill C / Sznol, Mario / Pavlick, Anna C / Ariyan, Stephan / Cheng, Elaine / Bacchiocchi, Antonella / Kluger, Harriet M / Narayan, Deepak / Halaban, Ruth. ·Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA. ·J Transl Med · Pubmed #20630094.

ABSTRACT: Activating mutations in BRAF kinase are common in melanomas. Clinical trials with PLX4032, the mutant-BRAF inhibitor, show promising preliminary results in patients selected for the presence of V600E mutation. However, activating V600K mutation is the other most common mutation, yet patients with this variant are currently excluded from the PLX4032 trials. Here we present evidence that a patient bearing the BRAF V600K mutation responded remarkably to PLX4032, suggesting that clinical trials should include all patients with activating BRAF V600E/K mutations.

3 Editorial Melanoma: a model for testing new agents in combination therapies. 2010

Ascierto, Paolo A / Streicher, Howard Z / Sznol, Mario. ·Unit of Medical Oncology and Innovative Therapy, National Tumor Institute, Naples, Italy. paolo.ascierto@gmail.com ·J Transl Med · Pubmed #20406483.

ABSTRACT: Treatment for both early and advanced melanoma has changed little since the introduction of interferon and IL-2 in the early 1990s. Recent data from trials testing targeted agents or immune modulators suggest the promise of new strategies to treat patients with advanced melanoma. These include a new generation of B-RAF inhibitors with greater selectivity for the mutant protein, c-Kit inhibitors, anti-angiogenesis agents, the immune modulators anti-CTLA4, anti-PD-1, and anti-CD40, and adoptive cellular therapies. The high success rate of mutant B-RAF and c-Kit inhibitors relies on the selection of patients with corresponding mutations. However, although response rates with small molecule inhibitors are high, most are not durable. Moreover, for a large subset of patients, reliable predictive biomarkers especially for immunologic modulators have not yet been identified. Progress may also depend on identifying additional molecular targets, which in turn depends upon a better understanding of the mechanisms leading to response or resistance. More challenging but equally important will be understanding how to optimize the treatment of individual patients using these active agents sequentially or in combination with each other, with other experimental treatment, or with traditional anticancer modalities such as chemotherapy, radiation, or surgery. Compared to the standard approach of developing new single agents for licensing in advanced disease, the identification and validation of patient specific and multi-modality treatments will require increased involvement by several stakeholders in designing trials aimed at identifying, even in early stages of drug development, the most effective way to use molecularly guided approaches to treat tumors as they evolve over time.

4 Review Combination Strategies PD-1/PD-L1 Antagonists. 2018

Sznol, Mario. · ·Cancer J · Pubmed #29360729.

ABSTRACT: Despite the broad clinical antitumor activity of PD-1/PD-L1 antagonists, many patients who are treated with these agents either do not respond or achieve suboptimal responses. Improving overall outcome will require combinations with other agents to address potential innate or acquired mechanisms of resistance. Many combination trials have been initiated in patients with or without prior exposure to the PD-1/PD-L1 antagonists. In addition to the challenge of identifying optimal dose, schedule, and sequence for the combinations, current biomarker efforts lack the precision to identify optimal combination partners for the PD-1/PD-L1 antagonists in individual patients. For each possible combination, careful consideration of clinical trial design, biomarker strategies, and endpoints for early clinical development will be necessary to move the most promising regimens forward and therefore to accelerate the rate of clinical progress.

5 Review Challenges in Conducting Clinical Research on Patients With Advanced Melanoma. 2017

Sznol, Mario. ·From the Section of Medical Oncology, Yale University School of Medicine, New Haven, CT. ·Cancer J · Pubmed #28114259.

ABSTRACT: Unprecedented advances in the treatment of melanoma and the large number of investigational therapies entering clinical studies not only represent outstanding achievements, but also create major challenges for clinical research in melanoma. The challenges for accrual and for developing important new data in trials include the relatively low incidence of melanoma compared with other diseases, a shrinking pool of patients for trials because of the high efficacy of standard of care therapy, requirements for larger studies and longer duration of follow-up to detect signals of activity or establish efficacy, and suboptimal predictive biomarkers for the vast number of new combinations and new agents. The cost of new treatments remains a major concern, particularly because current standard of care involves doublets of targeted therapy or immune therapy, and clinically meaningful further increases in efficacy may require development of triplets or larger multidrug combinations. Toxicities of the current doublets, particularly for immune therapy, may limit development of some multidrug regimens or may require novel solutions such as sequencing or alternating schedules. The activity of first-line therapies may push development of new drugs or combinations into the second-line setting or into subgroups with suboptimal response to the first-line doublets as identified by predictive clinical variables or tissue biomarkers.

6 Review Therapeutic combinations of immune-modulating antibodies in melanoma and beyond. 2015

Cohen, Justine / Sznol, Mario. ·Division of Medical Oncology, Yale Comprehensive Cancer Center, Yale University, New Haven, CT. Electronic address: Justine.cohen@yale.edu. · Division of Medical Oncology, Yale Comprehensive Cancer Center, Yale University, New Haven, CT. ·Semin Oncol · Pubmed #25965368.

ABSTRACT: Immune-modulating antibodies demonstrate activity in increasing numbers of malignancies, and more will be developed in the coming decade. Although active as single agents, optimal outcomes will require combination therapies for many patients. Currently, most combinations are based on either PD-1/PD-L1 antagonists or anti-CTLA-4. The combination of anti-PD-1 with anti-CTLA-4 demonstrates promising activity in metastatic melanoma and metastatic renal cell carcinoma and will be tested in multipe other malignancies. Future combinations will likely involve two or more checkpoint inhibitors, a checkpoint inhibitor in combination with an agonist of costimulation, combinations of costimulatory agents or combinations with antibodies that alter lymphyocyte trafficking. Although opportunities for effective combinations are available, major challeneges include the potential for autoimmune toxicity and the selection of patients.

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

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

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

8 Review Advances in the systemic treatment of metastatic melanoma. 2013

Yushak, Melinda / Kluger, Harriet M / Sznol, Mario. ·Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut. ·Oncology (Williston Park) · Pubmed #25184258.

ABSTRACT: Prior to 2011, the only commercially available agents commonly used to treat metastatic melanoma-including dacarbazine, temozolomide (Temodar), fotemustine, carboplatin, paclitaxel, and interleukin-2-demonstrated limited efficacy, and no study involving these agents had shown an improvement in overall survival. The standard of care for the treatment of metastatic melanoma was radically changed by the subsequent approval of two agents, ipilimumab (Yervoy) and vemurafenib (Zelboraf), both of which improved survival in randomized phase III trials. Within the relatively short time that ipilimumab and vemurafenib have been commercially available, phase II data for the investigational agents nivolumab and MK-3475, for the combination of dabrafenib and trametinib, and for adoptive cell therapy strongly suggest even further improvements in treatment outcomes. Within this rich context of effective agents, the challenge for clinicians and investigators will be to develop predictive biomarkers of response, the optimal sequence of therapy for individual patients, and effective combinations. An additional challenge will be to find the appropriate venue and populations to test promising new agents arising from substantial advances in our understanding of molecular alterations in melanoma cells, of mechanisms of resistance to current agents, and of tumor-host immune interactions.

9 Review Molecular markers of response to treatment for melanoma. 2011

Sznol, Mario. ·Melanoma Program, Yale Cancer Center, New Haven, CT 06520, USA. mario.sznol@yale.edu ·Cancer J · Pubmed #21427556.

ABSTRACT: A large number of agents are currently in development for patients with metastatic melanoma. Potent small molecule inhibitors of mutant BRAF and the immunotherapy agent ipilimumab have demonstrated promising clinical activity and will likely change the standard of care in the future. However, only a fraction of patients currently receive durable benefit from immune therapies, and despite initial high response rates, resistance to the small molecule targeted agents eventually develops. Substantial opportunities exist for developing biomarkers that will lead to improved combinations and to choices for therapy after progression on a prior targeted agent. Development of clinically useful predictive biomarkers in tumor or blood has been particularly difficult for the immune therapies, owing to the complexity of interactions between tumor and host that impact on anti-tumor immune responses. In the setting of multiple active agents, and none capable of producing long-lasting benefit in most patients, it will be critical to develop assays to match individual patients with the treatment or treatments most likely to be effective to produce the greatest benefit in the overall population.

10 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.

11 Review Betting on immunotherapy for melanoma. 2009

Sznol, Mario. ·Yale Cancer Center, 333 Cedar Street, FMP #126, New Haven, CT 06525, USA. Mario.sznol@yale.edu ·Curr Oncol Rep · Pubmed #19679015.

ABSTRACT: Immunotherapy is an effective treatment option for a small percentage of patients with advanced melanoma or at high risk for recurrence after resection of the primary tumor. However, a long period of unsuccessful immune modulation trials involving new cytokines, antibodies, cancer vaccines, adoptive immunotherapy, and combinations generated doubts that benefit could be extended to a larger group of patients. Renewed optimism for the therapeutic potential of immune therapy is currently driven by key advances in tumor immunobiology, including the potential to manipulate and disrupt immune activation checkpoints and tumor defense mechanisms; newer approaches to antigen presentation for immune activation; refinements to procedures for antigen-specific T-cell expansions in vitro and preparative regimens to support their expansion and activity in vivo; gene transfer to alter lymphocyte specificity and function; and the potential for discovery of improved predictive biomarkers to select patients for individual treatments. Proof of concept is provided by durable remissions observed in patients with advanced melanoma enrolled in clinical trials of anti-CTLA-4 and in new studies of adoptively transferred tumor antigen-specific lymphocytes combined with lymphocyte ablation conditioning regimens. Many agents now being developed are predicted to produce broader, more potent, and more effective antitumor immune responses.

12 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.

13 Clinical Trial Long-Term Outcomes in Patients With BRAF V600-Mutant Metastatic Melanoma Who Received Dabrafenib Combined With Trametinib. 2018

Long, Georgina V / Eroglu, Zeynep / Infante, Jeffrey / Patel, Sapna / Daud, Adil / Johnson, Douglas B / Gonzalez, Rene / Kefford, Richard / Hamid, Omid / Schuchter, Lynn / Cebon, Jonathan / Sharfman, William / McWilliams, Robert / Sznol, Mario / Redhu, Suman / Gasal, Eduard / Mookerjee, Bijoyesh / Weber, Jeffrey / Flaherty, Keith T. ·Georgina V. Long, University of Sydney, and Royal North Shore Hospital · Richard Kefford, Macquarie University, Sydney, and Westmead Hospital, Westmead, New South Wales · Jonathan Cebon, Ludwig Institute for Cancer Research, Melbourne, Victoria, Australia · Zeynep Eroglu, Moffitt Cancer Center, Tampa, FL · Jeffrey Infante, Tennessee Oncology · Douglas B. Johnson, Vanderbilt-Ingram Cancer Center, Nashville, TN · Sapna Patel, The University of Texas MD Anderson Cancer Center, Houston, TX · Adil Daud, University of California, San Francisco, San Francisco · Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles, CA · Rene Gonzalez, University of Colorado, Denver, CO · Lynn Schuchter, University of Pennsylvania, Philadelphia, PA · William Sharfman, Sidney Kimmel Cancer Center, Baltimore, MD · Robert McWilliams, Mayo Clinic, Rochester, MN · Mario Sznol, Yale University, New Haven, CT · Suman Redhu, Eduard Gasal, and Bijoyesh Mookerjee, Novartis, East Hanover, NJ · Jeffrey Weber, New York University Langone Medical Center, New York, NY · and Keith T. Flaherty, Dana-Farber/Harvard Cancer Center, Boston, MA. ·J Clin Oncol · Pubmed #28991513.

ABSTRACT: Purpose To report 5-year landmark analysis efficacy and safety outcomes in patients with BRAF V600-mutant metastatic melanoma (MM) who received BRAF inhibitor dabrafenib (D) and MEK inhibitor trametinib (T) combination therapy versus D monotherapy in the randomized phase II BRF113220 study part C. Patients and Methods BRAF inhibitor-naive patients with BRAF V600-mutant MM were randomly assigned 1:1:1 to receive D 150 mg twice a day, D 150 mg twice a day plus T 1 mg once daily, or D 150 mg twice a day plus T 2 mg once daily (D + T 150/2). Patients who received D monotherapy could cross over to D + T 150/2 postprogression. Efficacy and safety were analyzed 4 and 5 years after initiation in patients with ≥ 5 years of follow-up. Results As of October 13, 2016, 18 patients who received D + T 150/2 remained in the study (13 [24%] of 54 enrolled at this dose plus five [11%] of 45 initially administered D who crossed over to D + T). With D + T 150/2, overall survival (OS; 4 years, 30%; 5 years, 28%) and progression-free survival (4 and 5 years, both 13%) appeared to stabilize with extended follow-up. Increased OS was observed in patients who received D + T with baseline normal lactate dehydrogenase (5 years, 45%) and normal lactate dehydrogenase with fewer than three organ sites with metastasis (5 years, 51%). With extended follow-up, one additional patient who received D + T 150/2 improved from a partial to a complete response. No new safety signals were observed. Conclusion This 5-year analysis represents the longest follow-up to date with BRAF + MEK inhibitor combination therapy in BRAF V600-mutant MM. Consistent with trends observed in landmark analyses with shorter follow-up, this therapy elicits durable plateaus of long-term OS and progression-free survival that last ≥ 5 years in some patients with MM.

14 Clinical Trial Overall Survival in Patients With Advanced Melanoma Who Received Nivolumab Versus Investigator's Choice Chemotherapy in CheckMate 037: A Randomized, Controlled, Open-Label Phase III Trial. 2018

Larkin, James / Minor, David / D'Angelo, Sandra / Neyns, Bart / Smylie, Michael / Miller, Wilson H / Gutzmer, Ralf / Linette, Gerald / Chmielowski, Bartosz / Lao, Christopher D / Lorigan, Paul / Grossmann, Kenneth / Hassel, Jessica C / Sznol, Mario / Daud, Adil / Sosman, Jeffrey / Khushalani, Nikhil / Schadendorf, Dirk / Hoeller, Christoph / Walker, Dana / Kong, George / Horak, Christine / Weber, Jeffrey. ·James Larkin, Royal Marsden NHS Foundation Trust, London · Paul Lorigan, The Christie National Health Service Foundation Trust, Manchester, United Kingdom · David Minor, California Pacific Medical Center Research Institute · Adil Daud, University of California San Francisco, San Francisco · Bartosz Chmielowski, University of California, Santa Monica, CA · Sandra D'Angelo, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College · Jeffrey Weber, Perlmutter Cancer Center at New York University-Langone Medical Center, New York · Nikhil Khushalani, Roswell Park Cancer Institute, Buffalo, NY · Gerald Linette, Washington University, St. Louis, MO · Christopher D. Lao, University of Michigan, Ann Arbor, MI · Kenneth Grossmann, Huntsman Cancer Institute, Salt Lake City, UT · Mario Sznol, Yale Comprehensive Cancer Center, New Haven, CT · Jeffrey Sosman, Northwestern University, Chicago, IL · Dana Walker, George Kong, and Christine Horak, Bristol-Myers Squibb, Princeton, NJ · Bart Neyns, University Hospital, Vrije Universiteit Brussel, Brussels, Belgium · Michael Smylie, Cross Cancer Institute, Edmonton, Alberta · Wilson H. Miller Jr, Jewish General Hospital and Segal Cancer Centre, McGill University, Montreal, Quebc, Canada · Ralf Gutzmer, Medizinische Hochschule Hannover, Hannover · Jessica C. Hassel, Nationale Centrum für Tumorerkrankungen Heidelberg, Heidelberg · Dirk Schadendorf, University Hospital Essen, Essen, Germany · and Christoph Hoeller, Medical University of Vienna, Wien, Austria. ·J Clin Oncol · Pubmed #28671856.

ABSTRACT: Purpose Until recently, limited options existed for patients with advanced melanoma who experienced disease progression while receiving treatment with ipilimumab. Here, we report the coprimary overall survival (OS) end point of CheckMate 037, which has previously shown that nivolumab resulted in more patients achieving an objective response compared with chemotherapy regimens in ipilimumab-refractory patients with advanced melanoma. Patients and Methods Patients were stratified by programmed death-ligand 1 expression, BRAF status, and best prior cytotoxic T-lymphocyte antigen-4 therapy response, then randomly assigned 2:1 to nivolumab 3 mg/kg intravenously every 2 weeks or investigator's choice chemotherapy (ICC; dacarbazine 1,000 mg/m

15 Clinical Trial Results from an Integrated Safety Analysis of Urelumab, an Agonist Anti-CD137 Monoclonal Antibody. 2017

Segal, Neil H / Logan, Theodore F / Hodi, F Stephen / McDermott, David / Melero, Ignacio / Hamid, Omid / Schmidt, Henrik / Robert, Caroline / Chiarion-Sileni, Vanna / Ascierto, Paolo A / Maio, Michele / Urba, Walter J / Gangadhar, Tara C / Suryawanshi, Satyendra / Neely, Jaclyn / Jure-Kunkel, Maria / Krishnan, Suba / Kohrt, Holbrook / Sznol, Mario / Levy, Ronald. ·Memorial Sloan Kettering Cancer Center, New York, New York. · Indiana University Simon Cancer Center, Indianapolis, Indiana. · Dana-Farber Cancer Institute, Boston, Massachusetts. · Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Clinica Universidad de Navarra, Pamplona, Spain. · The Angeles Clinic and Research Institute, Los Angeles, California. · Aarhus University Hospital, Aarhus, Denmark. · Gustave Roussy and Paris-Sud University Villejuif, Villejuif, France. · Istituto Oncologico Veneto, Padua, Italy. · Istituto Nazionale Tumori Fondazione "G. Pascale," Naples, Italy. · University Hospital of Siena, Siena, Italy. · Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon. · Abramson Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania. · Bristol-Myers Squibb, Princeton, New Jersey. · Stanford University School of Medicine, Stanford, California. · Yale Comprehensive Cancer Center, New Haven, Connecticut. · Stanford University School of Medicine, Stanford, California. levy@stanford.edu. ·Clin Cancer Res · Pubmed #27756788.


16 Clinical Trial Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. 2016

Goldberg, Sarah B / Gettinger, Scott N / Mahajan, Amit / Chiang, Anne C / Herbst, Roy S / Sznol, Mario / Tsiouris, Apostolos John / Cohen, Justine / Vortmeyer, Alexander / Jilaveanu, Lucia / Yu, James / Hegde, Upendra / Speaker, Stephanie / Madura, Matthew / Ralabate, Amanda / Rivera, Angel / Rowen, Elin / Gerrish, Heather / Yao, Xiaopan / Chiang, Veronica / Kluger, Harriet M. ·Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA. Electronic address: sarah.goldberg@yale.edu. · Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA. · New York Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, USA. · University of Connecticut Health Center, Farmington, CT, USA. ·Lancet Oncol · Pubmed #27267608.

ABSTRACT: BACKGROUND: Immunotherapy targeting the PD-1 axis has activity in several tumour types. We aimed to establish the activity and safety of the PD-1 inhibitor pembrolizumab in patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC). METHODS: In this non-randomised, open-label, phase 2 trial, we enrolled patients aged 18 years or older with melanoma or NSCLC with untreated brain metastases from the Yale Cancer Center. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in diameter without associated neurological symptoms or the need for corticosteroids. Patients with NSCLC had tumour tissue positive for PD-L1 expression; this was not required for patients with melanoma. Patients were given 10 mg/kg pembrolizumab every 2 weeks until progression. The primary endpoint was brain metastasis response assessed in all treated patients. The trial is ongoing and here we present an early analysis. The study is registered with ClinicalTrials.gov, number NCT02085070. FINDINGS: Between March 31, 2014, and May 31, 2015, we screened 52 patients with untreated or progressive brain metastases (18 with melanoma, 34 with NSCLC), and enrolled 36 (18 with melanoma, 18 with NSCLC). A brain metastasis response was achieved in four (22%; 95% CI 7-48) of 18 patients with melanoma and six (33%; 14-59) of 18 patients with NSCLC. Responses were durable, with all but one patient with NSCLC who responded showing an ongoing response at the time of data analysis on June 30, 2015. Treatment-related serious and grade 3-4 adverse events were grade 3 elevated aminotransferases (n=1 [6%]) in the melanoma cohort, and grade 3 colitis (n=1 [6%]), grade 3 pneumonitis (n=1 [6%]), grade 3 fatigue (n=1 [6%]), grade 4 hyperkalemia (n=1 [6%]), and grade 2 acute kidney injury (n=1 [6%]) in the NSCLC cohort. Clinically significant neurological adverse events included transient grade 3 cognitive dysfunction and grade 1-2 seizures (n=3 [17%]) in the melanoma cohort. INTERPRETATION: Pembrolizumab shows activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, which suggests that there might be a role for systemic immunotherapy in patients with untreated or progressive brain metastases. FUNDING: Merck and the Yale Cancer Center.

17 Clinical Trial Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. 2015

Larkin, James / Chiarion-Sileni, Vanna / Gonzalez, Rene / Grob, Jean Jacques / Cowey, C Lance / Lao, Christopher D / Schadendorf, Dirk / Dummer, Reinhard / Smylie, Michael / Rutkowski, Piotr / Ferrucci, Pier F / Hill, Andrew / Wagstaff, John / Carlino, Matteo S / Haanen, John B / Maio, Michele / Marquez-Rodas, Ivan / McArthur, Grant A / Ascierto, Paolo A / Long, Georgina V / Callahan, Margaret K / Postow, Michael A / Grossmann, Kenneth / Sznol, Mario / Dreno, Brigitte / Bastholt, Lars / Yang, Arvin / Rollin, Linda M / Horak, Christine / Hodi, F Stephen / Wolchok, Jedd D. ·From the Department of Medical Oncology, Royal Marsden Hospital, London (J.L.), and South West Wales Cancer Institute, Singleton Hospital, Swansea (J.W.) - both in the United Kingdom · Melanoma Oncology Unit, Veneto Region Oncology Research Institute, Padua (V.C.-S.), Oncology of Melanoma Unit, European Institute of Oncology, Milan (P.F.F.), University Hospital of Siena, Siena (M.M.), and Istituto Nazionale Tumori Fondazione Pascale, Naples (P.A.A.) - all in Italy · Division of Medical Oncology, University of Colorado, Denver, Denver (R.G.) · Aix-Marseille University, Hôpital de La Timone, Assitance Publique-Hôpitaux de Marseille, Marseille (J.J.G.), and Hôtel Dieu Place Alexis Ricordeau, Nantes (B.D.) - both in France · Baylor Charles A. Sammons Cancer Center, Dallas (C.L.C.) · Departments of Internal Medicine and Dermatology, University of Michigan, Ann Arbor (C.D.L.) · Department of Dermatology, University of Essen, Essen, Germany (D.S.) · University of Zürich Hospital, Zurich, Switzerland (R.D.) · Cross Cancer Institute, Edmonton, AB, Canada (M. Smylie) · Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland (P.R.) · Tasman Oncology Research, Southport Gold Coast, QLD (A.H.), and Westmead and Blacktown Hospitals (M.S.C.) and Melanoma Institute Australia (M.S.C., G.V.L.), University of Sydney, and the Mater Hospital (G.V.L.), Sydney, and Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (G.A.M.) - all in Australia · Division of Medical Oncology, the Netherlands Cancer Institute, Amsterdam (J.B.H.) · Servicio de Oncología Médica, Hospital General Universitario Gregorio Marañón, Madrid (I.M.-R.) · Ludwig Center, Memorial Sloan Kettering Cancer Center (M.K.C., M.A.P., J.D.W.) and Weill Cornell Medical College (M.K.C., M.A.P., J.D.W.) - both in New York · Huntsman Cancer Institute, University of Utah, Salt Lake City (K.G.) · Yale Cancer Center, Smilow Cancer Hospital of the Yale-New Haven Hospital, Yale University Sc ·N Engl J Med · Pubmed #26027431.

ABSTRACT: BACKGROUND: Nivolumab (a programmed death 1 [PD-1] checkpoint inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] checkpoint inhibitor) have been shown to have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab plus ipilimumab was compared with ipilimumab alone in patients with metastatic melanoma. METHODS: We assigned, in a 1:1:1 ratio, 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone. Progression-free survival and overall survival were coprimary end points. Results regarding progression-free survival are presented here. RESULTS: The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group. CONCLUSIONS: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).

18 Clinical Trial Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. 2015

Weber, Jeffrey S / D'Angelo, Sandra P / Minor, David / Hodi, F Stephen / Gutzmer, Ralf / Neyns, Bart / Hoeller, Christoph / Khushalani, Nikhil I / Miller, Wilson H / Lao, Christopher D / Linette, Gerald P / Thomas, Luc / Lorigan, Paul / Grossmann, Kenneth F / Hassel, Jessica C / Maio, Michele / Sznol, Mario / Ascierto, Paolo A / Mohr, Peter / Chmielowski, Bartosz / Bryce, Alan / Svane, Inge M / Grob, Jean-Jacques / Krackhardt, Angela M / Horak, Christine / Lambert, Alexandre / Yang, Arvin S / Larkin, James. ·Moffitt Cancer Center, Tampa, FL, USA. Electronic address: jeffrey.weber@moffitt.org. · Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. · California Pacific Center for Melanoma Research, San Francisco, CA, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Medizinische Hochschule Hannover, Hannover, Germany. · Universitair Ziekenhuis Brussel, Brussels, Belgium. · Medical University of Vienna, Vienna, Austria. · Roswell Park Cancer Institute, Buffalo, NY, USA. · Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada. · University of Michigan, Ann Arbor, MI, USA. · Washington University, St Louis, MO, USA. · Centre Hospitalier Universitaire de Lyon, Lyon, France. · Christie Hospital, Manchester, UK. · Huntsman Cancer Institute, Salt Lake City, UT, USA. · German Cancer Research Centre University Hospital, Heidelberg, Germany. · Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. · Yale Cancer Center, New Haven, CT, USA. · Istituto Nazionale Tumori Fondazione G Pascale, Naples, Italy. · Elbe Kliniken Buxtehude, Buxtehude, Germany. · Department of Medicine, University of California, Los Angeles, CA, USA. · Department of Medicine, Mayo Clinic, Scottsdale, AZ, USA. · Department of Oncology, Herlev Hospital, Copenhagen, Denmark. · Aix-Marseille University, Hopital de la Timone, Marseille, France. · Technische Universität München School of Medicine, II Medical Department, Munich, Germany. · Bristol-Myers Squibb, Princeton, NJ, USA. · Bristol-Myers Squibb, Braine-I'Alleud, Belgium. · Royal Marsden Hospital, London, UK. ·Lancet Oncol · Pubmed #25795410.

ABSTRACT: BACKGROUND: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries. Eligible patients were 18 years or older, had unresectable or metastatic melanoma, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAF(V 600) mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m(2) every 3 weeks or paclitaxel 175 mg/m(2) combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used permuted blocks (block size of six) within each stratum. Primary endpoints were the proportion of patients who had an objective response and overall survival. Treatment was given open-label, but those doing tumour assessments were masked to treatment assignment. We assessed objective responses per-protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. The trial is closed and this is the first interim analysis, reporting the objective response primary endpoint. This study is registered with ClinicalTrials.gov, number NCT01721746. FINDINGS: Between Dec 21, 2012, and Jan 10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab and 133 to ICC. Confirmed objective responses were reported in 38 (31·7%, 95% CI 23·5-40·8) of the first 120 patients in the nivolumab group versus five (10·6%, 3·5-23·1) of 47 patients in the ICC group. Grade 3-4 adverse events related to nivolumab included increased lipase (three [1%] of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two [1%] each); for ICC, these included neutropenia (14 [14%] of 102), thrombocytopenia (six [6%]), and anaemia (five [5%]). We noted grade 3-4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths occurred. INTERPRETATION: Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need. FUNDING: Bristol-Myers Squibb.

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

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

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

20 Clinical Trial Phase I/II study of the antibody-drug conjugate glembatumumab vedotin in patients with advanced melanoma. 2014

Ott, Patrick A / Hamid, Omid / Pavlick, Anna C / Kluger, Harriet / Kim, Kevin B / Boasberg, Peter D / Simantov, Ronit / Crowley, Elizabeth / Green, Jennifer A / Hawthorne, Thomas / Davis, Thomas A / Sznol, Mario / Hwu, Patrick. ·Patrick A. Ott and Anna C. Pavlick, New York University Cancer Institute, New York, NY · Omid Hamid and Peter D. Boasberg, The Angeles Clinic and Research Institute, Los Angeles, CA · Harriet Kluger and Mario Sznol, Yale Cancer Center, New Haven, CT · Kevin B. Kim and Patrick Hwu, University of Texas MD Anderson Cancer Center, Houston, TX · Ronit Simantov, Elizabeth Crowley, Jennifer A. Green, Thomas Hawthorne, and Thomas A. Davis, Celldex Therapeutics, Hampton, NJ. ·J Clin Oncol · Pubmed #25267741.

ABSTRACT: PURPOSE: The antibody-drug conjugate glembatumumab vedotin links a fully human immunoglobulin G2 monoclonal antibody against the melanoma-related glycoprotein NMB (gpNMB) to the potent cytotoxin monomethyl auristatin E. This study evaluated the safety and activity of glembatumumab vedotin in patients with advanced melanoma. PATIENTS AND METHODS: Patients received glembatumumab vedotin every 3 weeks (schedule 1) in a dose escalation and phase II expansion at the maximum-tolerated dose (MTD). Dosing during 2 of 3 weeks (schedule 2) and weekly (schedule 3) was also assessed. The primary end points were safety and pharmacokinetics. The secondary end points included antitumor activity, gpNMB expression, and immunogenicity. RESULTS: One hundred seventeen patients were treated using schedule 1 (n = 79), schedule 2 (n = 15), or schedule 3 (n = 23). The MTDs were 1.88, 1.5, and 1.0 mg/kg for schedules 1, 2, and 3, respectively. Grade 3/4 treatment-related toxicities that occurred in two or more patients included rash, neutropenia, fatigue, neuropathy, arthralgia, myalgia, and diarrhea. Three treatment-related deaths (resulting from pneumococcal sepsis, toxic epidermal necrolysis, and renal failure) occurred at doses exceeding the MTDs. In the schedule 1 phase II expansion cohort (n = 34), five patients (15%) had a partial response and eight patients (24%) had stable disease for ≥ 6 months. The objective response rate (ORR) was 2 of 6 (33%) for the schedule 2 MTD and 3 of 12 (25%) for the schedule 3 MTD. Rash was correlated with a greater ORR and improved progression-free survival. CONCLUSION: Glembatumumab vedotin is active in advanced melanoma. The schedule 1 MTD (1.88 mg/kg once every 3 weeks) was associated with a promising ORR and was generally well tolerated. More frequent dosing was potentially associated with a greater ORR but increased toxicity.

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

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

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

22 Clinical Trial Nivolumab plus ipilimumab in advanced melanoma. 2013

Wolchok, Jedd D / Kluger, Harriet / Callahan, Margaret K / Postow, Michael A / Rizvi, Naiyer A / Lesokhin, Alexander M / Segal, Neil H / Ariyan, Charlotte E / Gordon, Ruth-Ann / Reed, Kathleen / Burke, Matthew M / Caldwell, Anne / Kronenberg, Stephanie A / Agunwamba, Blessing U / Zhang, Xiaoling / Lowy, Israel / Inzunza, Hector David / Feely, William / Horak, Christine E / Hong, Quan / Korman, Alan J / Wigginton, Jon M / Gupta, Ashok / Sznol, Mario. ·Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. wolchokj@mskcc.org ·N Engl J Med · Pubmed #23724867.

ABSTRACT: BACKGROUND: In patients with melanoma, ipilimumab (an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab (an antibody against the programmed death 1 [PD-1] receptor) produced durable tumor regression in a phase 1 trial. On the basis of their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma. METHODS: We administered intravenous doses of nivolumab and ipilimumab in patients every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). The combined treatment was subsequently administered every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses. RESULTS: A total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment. The objective-response rate (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients. At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% of patients had an objective response, all with tumor reduction of 80% or more. Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among patients in the sequenced-regimen group, 18% had grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%. CONCLUSIONS: Concurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; ClinicalTrials.gov number, NCT01024231.).

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

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

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

24 Clinical Trial Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. 2012

Margolin, Kim / Ernstoff, Marc S / Hamid, Omid / Lawrence, Donald / McDermott, David / Puzanov, Igor / Wolchok, Jedd D / Clark, Joseph I / Sznol, Mario / Logan, Theodore F / Richards, Jon / Michener, Tracy / Balogh, Agnes / Heller, Kevin N / Hodi, F Stephen. ·University of Washington, Seattle, WA 98109, USA. kmargoli@seattlecca.org ·Lancet Oncol · Pubmed #22456429.

ABSTRACT: BACKGROUND: Brain metastases commonly develop in patients with melanoma and are a frequent cause of death of patients with this disease. Ipilimumab improves survival in patients with advanced melanoma. We aimed to investigate the safety and activity of this drug specifically in patients with brain metastases. METHODS: Between July 31, 2008, and June 3, 2009, we enrolled patients with melanoma and brain metastases from ten US centres who were older than 16 years into two parallel cohorts. Patients in cohort A were neurologically asymptomatic and were not receiving corticosteroid treatment at study entry; those in cohort B were symptomatic and on a stable dose of corticosteroids. Patients were to receive four doses of 10 mg/kg intravenous ipilimumab, one every 3 weeks. Individuals who were clinically stable at week 24 were eligible to receive 10 mg/kg intravenous ipilimumab every 12 weeks. The primary endpoint was the proportion of patients with disease control, defined as complete response, partial response, or stable disease after 12 weeks, assessed with modified WHO criteria. Analyses of safety and efficacy included all treated patients. This trial is registered with ClinicalTrials.gov, number NCT00623766. FINDINGS: We enrolled 72 patients: 51 into cohort A and 21 into cohort B. After 12 weeks, nine patients in cohort A exhibited disease control (18%, 95% CI 8-31), as did one patient in cohort B (5%, 0·1-24). When the brain alone was assessed, 12 patients in cohort A (24%, 13-38) and two in cohort B (10%, 1-30) achieved disease control. We noted disease control outside of the brain in 14 patients (27%, 16-42) in cohort A and in one individual (5%, 0·1-24) in cohort B. The most common grade 3 adverse events in cohort A were diarrhoea (six patients [12%]) and fatigue (six [12%]); in cohort B, they were dehydration (two individuals [10%]), hyperglycaemia (two [10%]), and increased concentrations of serum aspartate aminotransferase (two [10%]). One patient in each cohort had grade 4 confusion. The most common grade 3 immune-related adverse events were diarrhoea (six patients [12%]) and rash (one [2%]) in cohort A, and rash (one individual [5%]) and increased concentrations of serum aspartate aminotransferase (two [10%]) in cohort B. One patient in cohort A died of drug-related complications of immune-related colitis. INTERPRETATION: Ipilimumab has activity in some patients with advanced melanoma and brain metastases, particularly when metastases are small and asymptomatic. The drug has no unexpected toxic effects in this population. FUNDING: Bristol-Myers Squibb.

25 Clinical Trial A phase 2 trial of dasatinib in advanced melanoma. 2011

Kluger, Harriet M / Dudek, Arkadiuz Z / McCann, Carrie / Ritacco, Jean / Southard, Nadine / Jilaveanu, Lucia B / Molinaro, Annette / Sznol, Mario. ·Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA. harriet.kluger@yale.edu ·Cancer · Pubmed #21523734.

ABSTRACT: BACKGROUND: Inhibiting src kinases (non-receptor tyrosine kinase signaling intermediates) reduces melanoma cell proliferation and invasion. Dasatinib inhibits c-kit, PDGFβR, and EPHA2 and src kinases c-src, c-Yes, Lck, and Fyn. A phase 2 trial of dasatinib in melanoma was conducted to assess response rate (RR), progression-free survival (PFS), and toxicity. METHODS: Adults with stage 3/4 chemotherapy-naïve unresectable melanoma were eligible. Dasatinib was initially administered at 100 mg twice daily continuously to 17 patients. Due to toxicity, the starting dosage was decreased to 70 mg twice daily. Tumor assessments occurred every 8 weeks. RESULTS: Thirty-nine patients were enrolled, 36 of whom were evaluable for activity and toxicity. Five, 4, and 3 patients had acral-lentiginous, ocular, or mucosal primaries, respectively. Two patients had confirmed partial responses lasting 64 and 24 weeks (RR 5%). Three patients had minor responses lasting 136, 64, and 28 weeks, and 1 patient who was responding discontinued due to noncompliance. The median PFS was 8 weeks; the 6-month PFS rate was 13%. One patient with an exon-13 c-kit mutation had a partial response, whereas disease in another patient with an exon-11 c-kit mutation progressed. Common toxicities were fatigue, dyspnea, and pleural effusion. CONCLUSIONS: Daily dasatinib has minimal activity in unselected melanoma patients, excluding those with c-kit mutations. The study did not meet the prespecified endpoints of 30% response rate or 6-month PFS. Dasatinib was poorly tolerated overall, often requiring dose reduction or interruption. Because activity was observed in a small subset without c-kit mutations, identifying predictive biomarkers is important for future development of dasatinib in melanoma alone or in combination trials.