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Melanoma: HELP
Articles by Omid A. Hamid
Based on 77 articles published since 2009
(Why 77 articles?)
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Between 2009 and 2019, O. Hamid wrote the following 77 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Review Oncolytic immunotherapy: unlocking the potential of viruses to help target cancer. 2017

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

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

2 Review Immunotherapy for melanoma using programmed death 1 checkpoint inhibitors. 2014

Hamid, Omid. ·The Angeles Clinic and Research Institute, Los Angeles, CA. ·Clin Adv Hematol Oncol · Pubmed #25674719.

ABSTRACT: -- No abstract --

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

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

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

4 Review Systemic treatment of metastatic melanoma: new approaches. 2011

Hamid, Omid / Boasberg, Peter D / Rosenthal, Katherine / O'Day, Steven J. ·The Angeles Clinic and Research Institute, Santa Monica, California, USA. ·J Surg Oncol · Pubmed #21858838.

ABSTRACT: The field of melanoma therapeutics has experienced a dramatic paradigm shift over the last 12 months through recent discoveries of novel therapeutics targeting known oncogenes and immunotherapeutic antibodies. In this article, we review these findings and provide a framework to understand these discoveries, their significance in melanoma therapy, and role in clinical care. As this understanding grows, enduring therapeutic success may be achieved through tailored use of molecular markers and immunotherapies in sequential or combinatorial methods.

5 Review Ipilimumab: unleashing the power of the immune system through CTLA-4 blockade. 2010

Boasberg, Peter / Hamid, Omid / O'Day, Steven. ·The Angeles Clinic & Research Institute, 2001 Santa Monica Blvd, Suite 560W, Santa Monica, CA 90404, USA. pboasberg@theangelesclinic.org ·Semin Oncol · Pubmed #21074058.

ABSTRACT: Malignant melanoma is rising faster in incidence than any other malignancy. Long-term remission or "cure" is rare and is almost exclusively limited to therapies that stimulate an immune antitumor response. Ipilimumab is a novel targeted human immunostimulatory monoclonal antibody that blocks cytotoxic T-lymphocyte antigen4 (CTLA-4), an immune-inhibitory site expressed on activated T cells. Ipilimumab is well tolerated as an outpatient infusion therapy. Multiple studies have confirmed significant antimelanoma activity. A randomized trial has documented a survival benefit when ipilimumab was compared to a gp-100 vaccine only arm. The unique mechanism of action of ipilimumab makes assessment of response by conventional criteria difficult. Benefit from ipilimumab can occur after what would be considered progression with World Health Oganization (WHO) or Response Evaluation Criteria in Solid Tumors (RECIST) criteria. New immune response criteria have been proposed. Therapeutic responses peak between 12 and 24 weeks, with slow responses continuing up to and beyond 12 months. The major drug- related adverse side effects (10%-15% grade 3 or above) are immune-related and consist most commonly of rash, colitis, hypophysitis, thyroiditis, and hepatitis. Colonic perforation can occur and patients with diarrhea have to be monitored carefully with strict adherence to treatment algorithms. Algorithms for the treatment of other adverse side effects have been developed. The treatment of immune-related side effects with immunosuppressive agents, such as corticosteroids, does not appear to impair antitumor response. With proper monitoring and management of side effects, ipilimumab is an extremely safe drug to administer. The benefits of ipilimumab will most certainly extend to other malignancies in the near future.

6 Clinical Trial Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma. 2019

Ribas, Antoni / Lawrence, Donald / Atkinson, Victoria / Agarwal, Sachin / Miller, Wilson H / Carlino, Matteo S / Fisher, Rosalie / Long, Georgina V / Hodi, F Stephen / Tsoi, Jennifer / Grasso, Catherine S / Mookerjee, Bijoyesh / Zhao, Qing / Ghori, Razi / Moreno, Blanca Homet / Ibrahim, Nageatte / Hamid, Omid. ·University of California, Los Angeles, Los Angeles, CA, USA. aribas@mednet.ucla.edu. · Massachusetts General Hospital, Boston, MA, USA. · Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, Queensland, Australia. · Indiana University Health Goshen Center for Cancer Care, Goshen, IN, USA. · Segal Cancer Centre, Montreal, Quebec, Canada. · Jewish General Hospital, Montreal, Quebec, Canada. · McGill University, Montreal, Quebec, Canada. · Westmead Hospital, Sydney, New South Wales, Australia. · Blacktown Hospital, Sydney, New South Wales, Australia. · The University of Sydney, Sydney, New South Wales, Australia. · Melanoma Institute Australia, Sydney, New South Wales, Australia. · Auckland District Health Board, Auckland, New Zealand. · Royal North Shore Hospital, Sydney, New South Wales, Australia. · Mater Hospital, Sydney, New South Wales, Australia. · Dana-Farber Cancer Institute, Boston, MA, USA. · University of California, Los Angeles, Los Angeles, CA, USA. · Novartis, East Hanover, NJ, USA. · Merck & Co., Inc., Kenilworth, NJ, USA. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. ·Nat Med · Pubmed #31171879.

ABSTRACT: Oncogene-targeted therapy with B-Raf proto-oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors induces a high initial response rate in patients with BRAF

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

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

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

8 Clinical Trial Antitumour activity of pembrolizumab in advanced mucosal melanoma: a post-hoc analysis of KEYNOTE-001, 002, 006. 2018

Hamid, Omid / Robert, Caroline / Ribas, Antoni / Hodi, F Stephen / Walpole, Euan / Daud, Adil / Arance, Ana S / Brown, Ewan / Hoeller, Christoph / Mortier, Laurent / Schachter, Jacob / Long, Jianmin / Ebbinghaus, Scot / Ibrahim, Nageatte / Butler, Marcus. ·The Angeles Clinic and Research Institute, Los Angeles, CA, USA. ohamid@theangelesclinic.org. · Gustave Roussy and Paris-Sud University, Villejuif, France. · University of California, Los Angeles, Los Angeles, CA, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Princess Alexandra Hospital, Brisbane, Australia. · University of California, San Francisco, San Francisco, CA, USA. · Hospital Clinic de Barcelona, Barcelona, Spain. · Edinburgh Cancer Research Centre and Western General Hospital, Edinburgh, Scotland, UK. · Medical University of Vienna, Vienna, Austria. · Centre Hospitalier Régional Universitaire de Lille, Université Lille, Lille, France. · Ella Lemelbaum Institute for Melanoma, Sheba Medical Center, Tel Hashomer, Israel. · Merck & Co., Inc, Kenilworth, NJ, USA. · Princess Margaret Cancer Centre, Toronto, ON, Canada. ·Br J Cancer · Pubmed #30202085.

ABSTRACT: BACKGROUND: Mucosal melanoma is an aggressive melanoma with poor prognosis. We assessed efficacy of pembrolizumab in patients with advanced mucosal melanoma in KEYNOTE-001 (NCT01295827), -002 (NCT01704287), and -006 (NCT01866319). METHODS: Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) or 10 mg/kg Q2W or Q3W. Response was assessed by independent central review per RECIST v1.1. RESULTS: 1567 patients were treated and 84 (5%) had mucosal melanoma. Fifty-one of 84 were ipilimumab-naive. In patients with mucosal melanoma, the objective response rate (ORR) was 19% (95% CI 11-29%), with median duration of response (DOR) of 27.6 months (range 1.1 + to 27.6). Median progression-free survival (PFS) was 2.8 months (95% CI 2.7-2.8), with median overall survival (OS) of 11.3 months (7.7-16.6). ORR was 22% (95% CI 11-35%) and 15% (95% CI 5-32%) in ipilimumab-naive and ipilimumab-treated patients. CONCLUSION: Pembrolizumab provides durable antitumour activity in patients with advanced mucosal melanoma regardless of prior ipilimumab.

9 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 .).

10 Clinical Trial Durable Complete Response After Discontinuation of Pembrolizumab in Patients With Metastatic Melanoma. 2018

Robert, Caroline / Ribas, Antoni / Hamid, Omid / Daud, Adil / Wolchok, Jedd D / Joshua, Anthony M / Hwu, Wen-Jen / Weber, Jeffrey S / Gangadhar, Tara C / Joseph, Richard W / Dronca, Roxana / Patnaik, Amita / Zarour, Hassane / Kefford, Richard / Hersey, Peter / Zhang, Jin / Anderson, James / Diede, Scott J / Ebbinghaus, Scot / Hodi, F Stephen. ·Caroline Robert, Gustave Roussy Cancer Campus and Paris Sud University, Villejuif Paris-Sud, France · Antoni Ribas, University of California, Los Angeles · Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles · Adil Daud, University of California, San Francisco, San Francisco, CA · Jedd D. Wolchok, Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, NY · Anthony M. Joshua, The Princess Margaret Cancer Centre, Toronto, Ontario, Canada · Wen-Jen Hwu, The University of Texas MD Anderson Cancer Center, Houston · Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX · Jeffrey S. Weber, H Lee Moffitt Cancer Center, Tampa · Richard W. Joseph, Mayo Clinic Cancer Center-Florida, Jacksonville, FL · Tara C. Gangadhar, Abramson Cancer Center at the University of Pennsylvania, Philadelphia · Hassane Zarour, UPMC Hillman Cancer Center, Pittsburgh, PA · Roxana Dronca, Mayo Clinic, Rochester, MN · Richard Kefford, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead · Melanoma Institute Australia, Wollstonecraft · and Macquarie University, MQ Health, Health Sciences Centre · Peter Hersey, University of Sydney, Sydney, New South Wales, Australia · Jin Zhang, James Anderson, Scott J. Diede, and Scot Ebbinghaus, Merck & Co., Inc., Kenilworth, NJ · F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA. ·J Clin Oncol · Pubmed #29283791.

ABSTRACT: Purpose Pembrolizumab provides durable antitumor activity in metastatic melanoma, including complete response (CR) in about 15% of patients. Data are limited on potential predictors of CR and patient disposition after pembrolizumab discontinuation after CR. We describe baseline characteristics and long-term follow-up in patients who experienced CR with pembrolizumab in the KEYNOTE-001 study ( ClinicalTrials.gov identifier: NCT01295827). Patients and Methods Patients with ipilimumab-naive or -treated advanced/metastatic melanoma received one of three dose regimens of pembrolizumab. Eligible patients who received pembrolizumab for ≥ 6 months and at least two treatments beyond confirmed CR could discontinue therapy. Response was assessed every 12 weeks by central Response Evaluation Criteria in Solid Tumors version 1.1. For this analysis, CR was defined per investigator assessment, immune-related response criteria, and potential predictors of CR were evaluated using univariate and multivariate analyses. Results Of 655 treated patients, 105 (16.0%) achieved CR after median follow-up of 43 months. At data cutoff, 92 patients (87.6%) had CR, with median follow-up of 30 months from first CR. Fourteen (13.3%) patients continued to receive treatment for a median of ≥ 40 months. Pembrolizumab was discontinued by 91 patients (86.7%), including 67 (63.8%) who proceeded to observation without additional anticancer therapy. The 24-month disease-free survival rate from time of CR was 90.9% in all 105 patients with CR and 89.9% in the 67 patients who discontinued pembrolizumab after CR for observation. Tumor size and programmed death-ligand 1 status were among the baseline factors independently associated with CR by univariate analysis. Conclusion Patients with metastatic melanoma can have durable complete remission after discontinuation of pembrolizumab, and the low incidence of relapse after median follow-up of approximately 2 years from discontinuation provides hope for a cure for some patients. The mechanisms underlying durable CR require further investigation.

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

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

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

12 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.

13 Clinical Trial Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma. 2018

Chesney, Jason / Puzanov, Igor / Collichio, Frances / Singh, Parminder / Milhem, Mohammed M / Glaspy, John / Hamid, Omid / Ross, Merrick / Friedlander, Philip / Garbe, Claus / Logan, Theodore F / Hauschild, Axel / Lebbé, Celeste / Chen, Lisa / Kim, Jenny J / Gansert, Jennifer / Andtbacka, Robert H I / Kaufman, Howard L. ·Jason Chesney, J. Graham Brown Cancer Center, University of Louisville, Louisville, KY · Igor Puzanov, Roswell Park Cancer Institute, Buffalo · Philip Friedlander, Mt Sinai School of Medicine, New York, NY · Frances Collichio, The University of North Carolina at Chapel Hill, Chapel Hill, NC · Parminder Singh, Mayo Clinic, Phoenix, AZ · Mohammed M. Milhem, University of Iowa Hospitals and Clinics, Iowa City, IA · John Glaspy, University of California Los Angeles School of Medicine · Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles · Lisa Chen, Jenny J. Kim, and Jennifer Gansert, Amgen, Thousand Oaks, CA · Merrick Ross, MD Anderson Cancer Center, Houston, TX · Claus Garbe, University Hospital Tuebingen, Tuebingen · Axel Hauschild, University of Kiel, Kiel, Germany · Theodore F. Logan, Indiana University Simon Cancer Center, Indianapolis, IN · Celeste Lebbé, Assistance Publique-Hôpital De Paris Dermatology and CIC Hôpital Saint Louis University Paris Diderot Sorbonne, Institut National de la Santé et de la Recherche Médicale U976, Paris, France · Robert H.I. Andtbacka, University of Utah, Salt Lake City, UT · and Howard L. Kaufman, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ. ·J Clin Oncol · Pubmed #28981385.

ABSTRACT: Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 10

14 Clinical Trial Vemurafenib treatment for patients with locally advanced, unresectable stage IIIC or metastatic melanoma and activating exon 15 BRAF mutations other than V600E. 2017

Hallmeyer, Sigrun / Gonzalez, Rene / Lawson, David H / Cranmer, Lee D / Linette, Gerald P / Puzanov, Igor / Taback, Bret / Cowey, C Lance / Ribas, Antoni / Daniels, Gregory A / Moore, Timothy / Gibney, Geoffrey T / Tawbi, Hussein / Whitman, Eric / Lee, Geraldine / Mun, Yong / Liu, Shiyao / Hamid, Omid. ·aDepartment of Internal Medicine, Advocate Medical Group - Oncology North, Park Ridge, Illinois bMelanoma Research Clinic, University of Colorado Cancer Center, Aurora, Colorado cDepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia dDepartment of Hematology and Oncology, The University of Arizona Cancer Center, Tucson, Arizona eDepartment of Medicine, Washington University School of Medicine, St Louis, Missouri fDepartment of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee gDepartment of Surgery, Columbia University Medical Center, New York, New York hDepartment of Medical Oncology, Texas Oncology, Dallas, Texas iDepartment of Medicine, Jonsson Comprehensive Cancer Center at University of California jDepartment of Immuno-Oncology, The Angeles Clinic and Research Institute, Los Angeles kDepartment of Oncology, Moores Cancer Center, University of California, San Diego, La Jolla lGenentech Inc., South San Francisco, California mMid Ohio Oncology and Hematology Inc., Columbus, Ohio nDepartment of Melanoma, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC oDepartment of Pathology, University of Pittsburgh Cancer Institute and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania pDepartment of Melanoma, Carol G. Simon Cancer Center, Atlantic Health System, Morristown, New Jersey, USA. ·Melanoma Res · Pubmed #29076950.

ABSTRACT: BRAF mutations are found in ~50% of metastatic melanomas, most commonly in codon V600. Vemurafenib improves progression-free survival and overall survival in patients with advanced BRAF-mutated melanoma. The results of a descriptive study evaluating vemurafenib in patients with advanced melanoma harbouring BRAF mutations other than V600E are reported. Eligible patients with stage IIIC or IV melanoma and non-V600E BRAF mutations received vemurafenib (960 mg, twice daily). End points included investigator-assessed best overall response rate (primary), time to response, duration of response, progression-free survival, overall survival and safety. Planned (V600K vs. non-V600K mutations) subgroup analyses were carried out. Thirty-one patients were enrolled; 13 (42%) had V600K mutations and 18 (58%) had other mutations. Investigator-assessed confirmed that the best overall response rate was 23% (95% confidence interval=10-41%) in the overall population, and was similar between patients with V600K mutations (23%; 95% confidence interval=5-54%) versus other mutations (22%; 95% confidence interval=6-48%). Responses were observed in patients with V600K (n=3), V600E2 (n=1), V600R (n=1), L597S (n=1) and D594G (n=1) mutations. No new safety signals were reported. Vemurafenib showed activity in patients with advanced melanoma with rarer BRAF mutations.

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

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

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

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

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

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

17 Clinical Trial Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). 2017

Schachter, Jacob / Ribas, Antoni / Long, Georgina V / Arance, Ana / Grob, Jean-Jacques / Mortier, Laurent / Daud, Adil / Carlino, Matteo S / McNeil, Catriona / Lotem, Michal / Larkin, James / Lorigan, Paul / Neyns, Bart / Blank, Christian / Petrella, Teresa M / Hamid, Omid / Zhou, Honghong / Ebbinghaus, Scot / Ibrahim, Nageatte / Robert, Caroline. ·Division of Oncology, Ella Lemelbaum Institute for Melanoma, Sheba Medical Center, Tel Hashomer, Israel. Electronic address: jacob.schachter@sheba.health.gov.il. · Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. · Department of Medical Oncology and Translational Research, Melanoma Institute Australia, The University of Sydney, Mater Hospital and Royal North Shore Hospital, Sydney, Australia. · Department of Medical Oncology, Hospital Clinic de Barcelona, Barcelona, Spain. · Department of Dermatology and Skin Cancer, Aix Marseille University, Hôpital de la Timone, Marseille, France. · Department of Dermatology, Université Lille, INSERM U1189, CHU Lille, F-59000, France. · Department of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA. · Department of Medical Oncology, Westmead and Blacktown Hospitals, Melanoma Institute Australia, and The University of Sydney, Sydney, Australia. · Department of Medical Oncology, Chris O'Brien Lifehouse, Royal Prince Alfred Hospital, and Melanoma Institute Australia, Camperdown, Australia. · Department of Melanoma and Cancer Immunotherapy, Sharett Institute of Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel. · Department of Medical Oncology, Royal Marsden Hospital, London, UK. · Department of Medical Oncology University of Manchester and the Christie NHS Foundation Trust, Manchester, UK. · Department of Medical Oncology, Universitair Ziekenhuis Brussel, Brussels, Belgium. · Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands. · Department of Medicine, Division of Medical Oncology/Hematology, Sunnybrook Health Sciences Center, Toronto, ON, Canada. · Department of Hematology/Oncology, The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Department of BARDS, Merck & Co, Kenilworth, NJ, USA. · Department of Clinical Oncology, Merck & Co, Kenilworth, NJ, USA. · Department of Oncology, Gustave Roussy and Paris-Sud University, Villejuif, France. ·Lancet · Pubmed #28822576.

ABSTRACT: BACKGROUND: Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis. METHODS: In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of pembrolizumab, or one regimen of ipilimumab, using a centralised, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3, 2015. This study was registered with ClinicalTrials.gov, number NCT01866319. FINDINGS: Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous pembrolizumab every 2 weeks (n=279), intravenous pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either pembrolizumab group and was 16·0 months with ipilimumab (hazard ratio [HR] 0·68, 95% CI 0·53-0·87 for pembrolizumab every 2 weeks vs ipilimumab; p=0·0009 and 0·68, 0·53-0·86 for pembrolizumab every 3 weeks vs ipilimumab; p=0·0008). 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group. INTERPRETATION: Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between pembrolizumab dosing schedules. These conclusions further support the use of pembrolizumab as a standard of care for advanced melanoma. FUNDING: Merck & Co.

18 Clinical Trial Liver Metastasis and Treatment Outcome with Anti-PD-1 Monoclonal Antibody in Patients with Melanoma and NSCLC. 2017

Tumeh, Paul C / Hellmann, Matthew D / Hamid, Omid / Tsai, Katy K / Loo, Kimberly L / Gubens, Matthew A / Rosenblum, Michael / Harview, Christina L / Taube, Janis M / Handley, Nathan / Khurana, Neharika / Nosrati, Adi / Krummel, Matthew F / Tucker, Andrew / Sosa, Eduardo V / Sanchez, Phillip J / Banayan, Nooriel / Osorio, Juan C / Nguyen-Kim, Dan L / Chang, Jeremy / Shintaku, I Peter / Boasberg, Peter D / Taylor, Emma J / Munster, Pamela N / Algazi, Alain P / Chmielowski, Bartosz / Dummer, Reinhard / Grogan, Tristan R / Elashoff, David / Hwang, Jimmy / Goldinger, Simone M / Garon, Edward B / Pierce, Robert H / Daud, Adil. ·University of California, Los Angeles, Los Angeles, California. · Memorial Sloan Kettering Cancer Center, New York, New York. · Angeles Clinic, Los Angeles, California. · University of California, San Francisco, San Francisco, California. · Johns Hopkins University, Baltimore, Maryland. · OncoSec Inc., San Diego, California. · University of California, San Francisco, San Francisco, California. adil.daud@ucsf.edu. ·Cancer Immunol Res · Pubmed #28411193.

ABSTRACT: We explored the association between liver metastases, tumor CD8

19 Clinical Trial Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. 2017

Ascierto, Paolo A / Del Vecchio, Michele / Robert, Caroline / Mackiewicz, Andrzej / Chiarion-Sileni, Vanna / Arance, Ana / Lebbé, Céleste / Bastholt, Lars / Hamid, Omid / Rutkowski, Piotr / McNeil, Catriona / Garbe, Claus / Loquai, Carmen / Dreno, Brigitte / Thomas, Luc / Grob, Jean-Jacques / Liszkay, Gabriella / Nyakas, Marta / Gutzmer, Ralf / Pikiel, Joanna / Grange, Florent / Hoeller, Christoph / Ferraresi, Virginia / Smylie, Michael / Schadendorf, Dirk / Mortier, Laurent / Svane, Inge Marie / Hennicken, Delphine / Qureshi, Anila / Maio, Michele. ·Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. Electronic address: paolo.ascierto@gmail.com. · Medical Oncology, National Cancer Institute, Milan, Italy. · Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. · Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, Poznan Medical University, Poznan, Poland. · IOV-IRCCS, Melanoma Oncology Unit, Padova, Italy. · Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain. · AP-HP Dermatology CIC Departments, Saint-Louis Hospital, INSERM U976, Université Paris Diderot, Paris, France. · Odense University Hospital, Odense, Denmark. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland. · Chris O'Brien Lifehouse and Royal Prince Alfred Hospital, Camperdown, NSW, Australia; Melanoma Institute Australia, Sydney, NSW, Australia. · Eberhard Karls University, Tübingen, Germany. · University Medical Center, Mainz, Germany. · Department of Oncodermatology, INSERM Research Unit 892, Nantes University Hospital, Nantes, France. · Department of Dermatology, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France. · Hospital de la Timone, Marseille, France. · National Institute of Oncology, Budapest, Hungary. · Oslo University Hospital, Oslo, Norway. · Medizinische Hochschule Hannover, Hannover, Germany. · Wojewodzkie Centrum Oncologii, Gdańsk, Poland. · Department of Dermatology, Reims University Hospital, Reims, France. · Medical University of Vienna, Vienna, Austria. · Istituti Fisioterapici Ospitalieri, Rome, Italy. · Cross Cancer Institute, Edmonton, AB, Canada. · University Hospital Essen, Essen, Germany. · Hôspital Claude Huriez, Lille, France. · Herlev Hospital, University of Copenhagen, Herlev, Denmark. · Bristol-Myers Squibb, Princeton, NJ, USA. · University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. ·Lancet Oncol · Pubmed #28359784.

ABSTRACT: BACKGROUND: A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3-4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit-risk profile of ipilimumab 10 mg/kg versus 3 mg/kg. METHODS: This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov, number NCT01515189. FINDINGS: Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6-42·3) for the ipilimumab 10 mg/kg group and 11·2 months (4·9-29·4) for the ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6-17·8) for ipilimumab 10 mg/kg compared with 11·5 months (9·9-13·3) for ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70-0·99; p=0·04). The most common grade 3-4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (<1%) patients died from treatment-related adverse events. INTERPRETATION: In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment. FUNDING: Bristol-Myers Squibb.

20 Clinical Trial Evaluation of clinicopathological factors in PD-1 response: derivation and validation of a prediction scale for response to PD-1 monotherapy. 2017

Nosrati, Adi / Tsai, Katy K / Goldinger, Simone M / Tumeh, Paul / Grimes, Barbara / Loo, Kimberly / Algazi, Alain P / Nguyen-Kim, Thi Dan Linh / Levesque, Mitchell / Dummer, Reinhard / Hamid, Omid / Daud, Adil. ·Division of Hematology-Oncology, Department of Medicine, University of California, San Francisco, Mount Zion A-743, 1600 Divisadero Street, San Francisco, CA 94143, USA. · Department of Dermatology, University Hospital of Zurich (USZ), University of Zurich, Gloriastrasse 31, Zürich 8091, Switzerland. · Division of Dermatology, Department of Medicine, University of California Los Angeles (UCLA), 200 Medical Plaza Driveway, Los Angeles, CA 90024, USA. · Department of Epidemiology & Biostatistics, University of California, San Francisco, 550 16th Street, San Francisco, CA 94158, USA. · Department of Interventional Radiology, University of Zurich, Rämistrasse 100, Zürich, 8091, Switzerland. · The Angeles Clinic and Research Institute (TACRI), 11818 Wilshire Boulevard #200, Los Angeles, CA 90025, USA. ·Br J Cancer · Pubmed #28324889.

ABSTRACT: BACKGROUND: Anti-PD-1 therapy has shown significant clinical activity in advanced melanoma. We developed and validated a clinical prediction scale for response to anti- PD-1 monotherapy. METHODS: A total of 315 patients with advanced melanoma treated with pembrolizumab (2 or 10 mg kg RESULTS: The developed clinical prediction scale included elevated LDH (1 point), age <65 years (1 point), female sex (1 point), history of ipilimumab treatment (2 points) and the presence of liver metastasis (2 points). The scale had an area under the receiver-operating curve (AUC) of 0.73 (95% CI 0.67, 0.80) in predicting response to therapy. The predictive performance of the score was maintained in the validation cohort (AUC 0.70 (95% CI 0.58, 0.81)) and the goodness-to-fit model demonstrated good calibration. CONCLUSIONS: Based on a large cohort of patients, we developed and validated a simple five-factor prediction scale for the clinical activity of PD-1 antibodies in advanced melanoma patients. This scale can be used to stratify patients participating in clinical trials.

21 Clinical Trial Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. 2017

Coens, Corneel / Suciu, Stefan / Chiarion-Sileni, Vanna / Grob, Jean-Jacques / Dummer, Reinhard / Wolchok, Jedd D / Schmidt, Henrik / Hamid, Omid / Robert, Caroline / Ascierto, Paolo A / Richards, Jon M / Lebbé, Celeste / Ferraresi, Virginia / Smylie, Michael / Weber, Jeffrey S / Maio, Michele / Bottomley, Andrew / Kotapati, Srividya / de Pril, Veerle / Testori, Alessandro / Eggermont, Alexander M M. ·EORTC Headquarters, Brussels, Belgium. Electronic address: corneel.coens@eortc.be. · EORTC Headquarters, Brussels, Belgium. · IOV-IRCCS, Melanoma Oncology Unit, Padova, Italy. · Hôpital de la Timone, Marseille, France. · University of Zürich Hospital, Zürich, Switzerland. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Aarhus University Hospital, Aarhus, Denmark. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. · Istituto Nazionale Tumori Fondazione "G. Pascale", Naples, Italy. · Oncology Specialists S C, Park Ridge, IL, USA. · Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Paris. · Istituti Fisioterapici Ospitalieri, Rome, Italy. · Cross Cancer Institute, Edmonton, AB, Canada. · H Lee Moffitt Cancer Center, Tampa, FL, USA. · University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. · Bristol-Myers Squibb, Wallingford, CT, USA. · Bristol-Myers Squibb, Braine-l'Alleud, Belgium. · European Institute of Oncology, Milan, Italy. ·Lancet Oncol · Pubmed #28162999.

ABSTRACT: BACKGROUND: The EORTC 18071 phase 3 trial compared adjuvant ipilimumab with placebo in patients with stage III melanoma. The primary endpoint, recurrence-free survival, was significantly longer in the ipilimumab group than in the placebo group. Investigator-reported toxic effects of ipilimumab consisted mainly of skin, gastrointestinal, endocrine, and hepatic immune-related adverse events. Adjuvant treatment with ipilimumab in this setting was approved in October, 2014, by the US Food and Drug Administration based on the results of the primary outcome of this trial. Here, we report the results of the secondary endpoint, health-related quality of life (HRQoL), of this trial. METHODS: EORTC 18071 was a multinational, double-blind, randomised, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) in 19 countries worldwide. Participants were randomly assigned (1:1) centrally by an interactive voice response system, to receive either ipilimumab 10 mg/kg or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. HRQoL was assessed with the EORTC QLQ-C30 quality-of-life instrument at baseline, weeks 4, 7, 10, and 24, and every 12 weeks thereafter up to 2 years, irrespective of disease progression. Results were summarised by timepoint and in a longitudinal manner in the intention-to-treat population. Two summary scores were calculated for each HRQoL scale: the average score reported during induction (ipilimumab or placebo at a dose of 10 mg/kg, administered as one single dose at the start of days 1, 22, 43, and 64-ie, four doses in 3 weeks), and the average score reported after induction. A predefined threshold of a 10 point difference between arms was considered clinically relevant. The primary HRQoL endpoint was the global health scale, with the predefined hypothesis of no clinically relevant differences after induction between groups. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. FINDINGS: Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to treatment: 475 in the ipilimumab group and 476 in the placebo group. Compliance with completing the HRQoL questionnaire was 893 (94%) of 951 patients at baseline, 693 (75%) of 924 at week 24, and 354 (51%) of 697 at week 108. Patient mean global health scores during (77·32 [SD 17·36] vs 72·96 [17·82]; p=0·00011) and after induction (76·48 [17·52] vs 72·32 [18·60]; p=0·00067) were statistically significantly different between groups but were not clinically relevant. Mean global health scores differed most between the groups at week 7 (77 [SD 19] in the placebo group vs 72 [22] in the ipilimumab group) and week 10 (77 [20] vs 70 [23]). Mean HRQoL scores differed by more than 10 points at week 10 between treatment groups for diarrhoea (7·67 [SD 17·05] for placebo vs 18·17 [28·35] for ipilimumab) and insomnia (15·17 [22·53] vs 25·60 [29·19]). INTERPRETATION: Despite increased toxicity, which led to treatment discontinuation for most patients during the induction phase of ipilimumab administration, overall HRQoL, as measured by the EORTC QLQ-C30, was similar between groups, as no clinically relevant differences (10 points or more) in global health status scores were observed during or after induction. Clinically relevant deterioration for some symptoms was observed at week 10, but after induction, no clinically relevant differences remained. Together with the primary analysis, results from this trial show that treatment with ipilimumab results in longer recurrence-free survival compared with that for treatment with placebo, with little impairment in HRQoL despite grade 3-4 investigator-reported adverse events. FUNDING: Bristol-Myers Squibb.

22 Clinical Trial Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study. 2017

McArthur, G A / Maio, M / Arance, A / Nathan, P / Blank, C / Avril, M-F / Garbe, C / Hauschild, A / Schadendorf, D / Hamid, O / Fluck, M / Thebeau, M / Schachter, J / Kefford, R / Chamberlain, M / Makrutzki, M / Robson, S / Gonzalez, R / Margolin, K. ·Department of Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne and University of Melbourne, Parkville, Australia. · AOU Senese Policlinico Santa Maria Alle Scotte, Siena, Italy. · Department of Medical Oncology, Hospital Clínic Barcelona, Spain. · Mount Vernon Hospital, Centre for Cancer Treatment, Northwood, UK. · The Netherlands Cancer Institute, Amsterdam, The Netherlands. · University Paris Descartes, Hospital Cochin, APHP, Paris, France. · Department of Dermatology, University Hospital Tuebingen, Tuebingen. · Department of Dermatology, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel. · Department of Dermatology, Comprehensive Cancer Center, University Hospital Essen, Essen, Germany. · Angeles Clinic and Research Institute, Los Angeles, USA. · Fachklinik Hornheide, Munster, Germany. · Moffitt Cancer Center, Tampa, USA. · Chaim Sheba Medical Centre, Oncology Institute, Ramat-Gan, Israel. · Crown Princess Cancer Centre Westmead Hospital and Department of Clinical Medicine, Macquarie University, Sydney NSW, Australia. · Seattle Cancer Care Alliance, Seattle, USA. · F. Hoffmann-La Roche Ltd, Basel, Switzerland. · University of Colorado Cancer Center, Aurora. · City of Hope, Duarte, USA. ·Ann Oncol · Pubmed #27993793.

ABSTRACT: Background: Vemurafenib has shown activity in patients with BRAFV600 mutated melanoma with brain metastases (BM). This phase 2 study evaluated vemurafenib in patients with/without prior treatment for BM. Methods: Patients with BRAFV600 mutated melanoma with BM were enrolled into cohort 1 (previously untreated BM) and cohort 2 (previously treated BM) and received vemurafenib (960 mg BID) until disease progression (PD) or intolerance. Primary endpoint was best overall response rate (BORR) in the brain in cohort 1 that was evaluated using modified RECIST 1.1 criteria using lesions ≥0.5 cm to assess response. Results: 146 patients were treated (cohort 1 n = 90; cohort 2 n = 56), 62% of whom were male. Median (range) time since diagnosis of BM: 1.0 (0-9) month in cohort 1 and 4.2 (1-68) months in cohort 2. Median duration of treatment was 4.1 months (range 0.3-34.5) in cohort 1 and 4.1 months (range 0.2-27.6) in cohort 2. Intracranial BORR in cohort 1 by an independent review committee (IRC) was 18% (2 CRs, 14 PRs). Extracranial BORR by IRC was 33% in cohort 1 and 23% in cohort 2. Median PFS (brain only, investigator-assessed) was 3.7 months (range 0.03-33.4; IQR 1.9-5.6) in cohort 1 and 4.0 months (range 0.3-27.4; IQR 2.2-7.4) in cohort 2. Median OS was 8.9 months (range 0.6-34.5; IQR 4.9-17.0) in cohort 1 and 9.6 months (range 0.7-34.3; IQR 4.5-18.4) in cohort 2. Adverse events (AEs) were similar in type, grade and frequency to other studies of single-agent vemurafenib. Grade 3/4 AEs occurred in 59 (66%) patients in cohort 1 and 36 (64%) in cohort 2. Overall, 84% of patients died during the study (86% in cohort 1 and 80% in cohort 2), mainly due to disease progression. Conclusions: The study demonstrates clinically meaningful response rates of melanoma BM to vemurafenib, which was well tolerated and without significant CNS toxicity.

23 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.

ABSTRACT:

24 Clinical Trial Programmed Death-Ligand 1 Expression and Response to the Anti-Programmed Death 1 Antibody Pembrolizumab in Melanoma. 2016

Daud, Adil I / Wolchok, Jedd D / Robert, Caroline / Hwu, Wen-Jen / Weber, Jeffrey S / Ribas, Antoni / Hodi, F Stephen / Joshua, Anthony M / Kefford, Richard / Hersey, Peter / Joseph, Richard / Gangadhar, Tara C / Dronca, Roxana / Patnaik, Amita / Zarour, Hassane / Roach, Charlotte / Toland, Grant / Lunceford, Jared K / Li, Xiaoyun Nicole / Emancipator, Kenneth / Dolled-Filhart, Marisa / Kang, S Peter / Ebbinghaus, Scot / Hamid, Omid. ·Adil I. Daud, University of California, San Francisco, San Francisco · Antoni Ribas, University of California, Los Angeles · Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles · Charlotte Roach and Grant Toland, Dako North America, Carpinteria, CA · Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY · Wen-Jen Hwu, The University of Texas MD Anderson Cancer Center, Houston · Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX · Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa · Richard Joseph, Mayo Clinic, Jacksonville, FL · F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA · Tara C. Gangadhar, Abramson Cancer Center at the University of Pennsylvania, Philadelphia · Hassane Zarour, University of Pittsburgh, Pittsburgh, PA · Roxana Dronca, Mayo Clinic, Rochester, MN · Jared K. Lunceford, Xiaoyun Nicole Li, Kenneth Emancipator, Marisa Dolled-Filhart, S. Peter Kang, and Scot Ebbinghaus, Merck & Co, Kenilworth, NJ · Caroline Robert, Gustave Roussy and Paris-Sud University, Villejuif, France · Anthony M. Joshua, Princess Margaret Cancer Centre, Toronto, ON, Canada · Richard Kefford, Crown Princess Mary Cancer Centre, Westmead Hospital and Melanoma Institute Australia · Richard Kefford, Macquarie University · and Richard Kefford and Peter Hersey, University of Sydney, Sydney, NSW, Australia. ·J Clin Oncol · Pubmed #27863197.

ABSTRACT: Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 (PD-1). This study explored the relationship between anti-PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks. Tumor response was assessed every 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent central review. Primary outcome was objective response rate. Secondary outcomes included progression-free survival (PFS) and overall survival (OS). Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique melanoma (MEL) scale of 0 to 5 by one of three pathologists who were blinded to clinical outcome; a score ≥ 2 (membranous staining in ≥ 1% of cells) was considered positive. Results Of 451 patients with evaluable PD-L1 expression, 344 (76%) had PD-L1-positive tumors. Demographic and staging variables were equally distributed among PD-L1-positive and -negative patients. An association between higher MEL score and higher response rate and longer PFS (hazard ratio, 0.76; 95% CI, 0.71 to 0.82) and OS (hazard ratio, 0.76; 95% CI, 0.69 to 0.83) was observed ( P < .001 for each). Objective response rate was 8%, 12%, 22%, 43%, 57%, and 53% for MEL 0, 1, 2, 3, 4, and 5, respectively. Conclusion PD-L1 expression in pretreatment tumor biopsy samples was correlated with response rate, PFS, and OS; however, patients with PD-L1-negative tumors may also achieve durable responses.

25 Clinical Trial Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. 2016

Eggermont, Alexander M M / Chiarion-Sileni, Vanna / Grob, Jean-Jacques / Dummer, Reinhard / Wolchok, Jedd D / Schmidt, Henrik / Hamid, Omid / Robert, Caroline / Ascierto, Paolo A / Richards, Jon M / Lebbé, Céleste / Ferraresi, Virginia / Smylie, Michael / Weber, Jeffrey S / Maio, Michele / Bastholt, Lars / Mortier, Laurent / Thomas, Luc / Tahir, Saad / Hauschild, Axel / Hassel, Jessica C / Hodi, F Stephen / Taitt, Corina / de Pril, Veerle / de Schaetzen, Gaetan / Suciu, Stefan / Testori, Alessandro. ·From Gustave Roussy Cancer Campus Grand Paris, Villejuif (A.M.M.E., C.R.), Aix-Marseille University, Hôpital de La Timone, Marseille (J.-J.G.), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris (C.L.), University Lille, INSERM Unité-1189, Centre Hospitalier Universitaire (CHU) Lille, Service de Dermatologie, Lille (L.M.), and CHU Lyon, Lyon (L.T.) - all in France · the Oncology Institute of Veneto-Istituto di Ricovero e Cura a Carattere Scientifico, Padua (V.C.-S.), Istituto Nazionale Tumori Fondazione G. Pascale, Naples (P.A.A.), Istituti Fisioterapici Ospitalieri, Rome (V.F.), University Hospital of Siena, Istituto Toscano Tumori, Siena (M.M.), and the European Institute of Oncology, Milan (A.T.) - all in Italy · University of Zurich Hospital, Zurich, Switzerland (R.D.) · Memorial Sloan Kettering Cancer Center, New York (J.D.W.) · Aarhus University Hospital, Aarhus (H.S.), and Odense University Hospital, Odense (L.B.) - both in Denmark · the Angeles Clinic and Research Institute, Los Angeles (O.H.) · Oncology Specialists, Park Ridge, IL (J.M.R.) · Cross Cancer Institute, Edmonton, AB, Canada (M.S.) · H. Lee Moffitt Cancer Center, Tampa, FL (J.S.W.) · Broomfield Hospital, Chelmsford, United Kingdom (S.T.) · Universitätsklinikum Schleswig-Holstein, Kiel (A.H.), and University Hospital Heidelberg, Heidelberg (J.C.H.) - both in Germany · Dana-Farber Cancer Institute, Boston (F.S.H.) · Bristol-Myers Squibb, Princeton, NJ (C.T., V.P.) · and the European Organization for Research and Treatment of Cancer, Brussels (G.S., S.S.). ·N Engl J Med · Pubmed #27717298.

ABSTRACT: BACKGROUND: On the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma. METHODS: After patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred. Recurrence-free survival was the primary end point. Secondary end points included overall survival, distant metastasis-free survival, and safety. RESULTS: At a median follow-up of 5.3 years, the 5-year rate of recurrence-free survival was 40.8% in the ipilimumab group, as compared with 30.3% in the placebo group (hazard ratio for recurrence or death, 0.76; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). The rate of overall survival at 5 years was 65.4% in the ipilimumab group, as compared with 54.4% in the placebo group (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P=0.001). The rate of distant metastasis-free survival at 5 years was 48.3% in the ipilimumab group, as compared with 38.9% in the placebo group (hazard ratio for death or distant metastasis, 0.76; 95.8% CI, 0.64 to 0.92; P=0.002). Adverse events of grade 3 or 4 occurred in 54.1% of the patients in the ipilimumab group and in 26.2% of those in the placebo group. Immune-related adverse events of grade 3 or 4 occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. In the ipilimumab group, 5 patients (1.1%) died owing to immune-related adverse events. CONCLUSIONS: As adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis-free survival than placebo. There were more immune-related adverse events with ipilimumab than with placebo. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00636168 , and EudraCT number, 2007-001974-10 .).

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