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Melanoma: HELP
Articles by Anna C. Pavlick
Based on 84 articles published since 2010
(Why 84 articles?)
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Between 2010 and 2020, A. Pavlick wrote the following 84 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Guideline An update on the Society for Immunotherapy of Cancer consensus statement on tumor immunotherapy for the treatment of cutaneous melanoma: version 2.0. 2018

Sullivan, Ryan J / Atkins, Michael B / Kirkwood, John M / Agarwala, Sanjiv S / Clark, Joseph I / Ernstoff, Marc S / Fecher, Leslie / Gajewski, Thomas F / Gastman, Brian / Lawson, David H / Lutzky, Jose / McDermott, David F / Margolin, Kim A / Mehnert, Janice M / Pavlick, Anna C / Richards, Jon M / Rubin, Krista M / Sharfman, William / Silverstein, Steven / Slingluff, Craig L / Sondak, Vernon K / Tarhini, Ahmad A / Thompson, John A / Urba, Walter J / White, Richard L / Whitman, Eric D / Hodi, F Stephen / Kaufman, Howard L. ·Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. · Georgetown University, Washington, DC, 20057, USA. · University of Pittsburgh, Pittsburgh, PA, 15213, USA. · St. Luke's Cancer Center and Temple University, Center Valley, PA, 18034, USA. · Loyola University Medical Center, Maywood, IL, 60153, USA. · Roswell Park Cancer Institute, Buffalo, NY, 14263, USA. · University of Michigan, Ann Arbor, MI, 48109, USA. · University of Chicago Medical Center, Chicago, IL, 60637, USA. · Cleveland Clinic, Cleveland, OH, 44195, USA. · Emory Winship Cancer Institute, Atlanta, GA, 30322, USA. · Mt. Sinai Medical Center, Miami Beach, FL, 33140, USA. · Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. · City of Hope, Duarte, CA, 91010, USA. · Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA. · New York University Cancer Institute, New York, NY, 10016, USA. · Lutheran General Hospital, Park Ridge, IL, 60068, USA. · The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 21231, USA. · Melanoma Research Foundation, Woodcliff Lake, NJ, 07077, USA. · University of Virginia, Charlottesville, VA, 22908, USA. · H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA. · Cleveland Clinic Taussig Cancer Center, Cleveland, OH, 44195, USA. · Seattle Cancer Care Alliance, Seattle, WA, 98109, USA. · Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, 97213, USA. · Carolinas Medical Center, Charlotte, NC, 28204, USA. · Carol G. Simon Cancer Center, Morristown, NJ, 07046, USA. · Dana-Farber Cancer Institute, Boston, MA, 02215, USA. · Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. howardkaufman6@gmail.com. ·J Immunother Cancer · Pubmed #29848375.

ABSTRACT: BACKGROUND: Cancer immunotherapy has been firmly established as a standard of care for patients with advanced and metastatic melanoma. Therapeutic outcomes in clinical trials have resulted in the approval of 11 new drugs and/or combination regimens for patients with melanoma. However, prospective data to support evidence-based clinical decisions with respect to the optimal schedule and sequencing of immunotherapy and targeted agents, how best to manage emerging toxicities and when to stop treatment are not yet available. METHODS: To address this knowledge gap, the Society for Immunotherapy of Cancer (SITC) Melanoma Task Force developed a process for consensus recommendations for physicians treating patients with melanoma integrating evidence-based data, where available, with best expert consensus opinion. The initial consensus statement was published in 2013, and version 2.0 of this report is an update based on a recent meeting of the Task Force and extensive subsequent discussions on new agents, contemporary peer-reviewed literature and emerging clinical data. The Academy of Medicine (formerly Institute of Medicine) clinical practice guidelines were used as a basis for consensus development with an updated literature search for important studies published between 1992 and 2017 and supplemented, as appropriate, by recommendations from Task Force participants. RESULTS: The Task Force considered patients with stage II-IV melanoma and here provide consensus recommendations for how they would incorporate the many immunotherapy options into clinical pathways for patients with cutaneous melanoma. CONCLUSION: These clinical guidleines provide physicians and healthcare providers with consensus recommendations for managing melanoma patients electing treatment with tumor immunotherapy.

2 Guideline The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. 2013

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

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

3 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.

4 Review Frontline Therapy for 2019

Pavlick, Anna C / Fecher, Leslie / Ascierto, Paolo A / Sullivan, Ryan J. ·1 New York University Perlmutter Cancer Center, New York, NY. · 2 University of Michigan Rogel Cancer Center, Ann Arbor, MI. · 3 From the Instituto Nazionale Tumori, Instituto di Ricovero e Cura a Carrattere Scientifico, Fondazione G. Pascale, Naples, Italy. · 4 Massachusetts General Hospital Cancer Center, Boston, MA. ·Am Soc Clin Oncol Educ Book · Pubmed #31099689.

ABSTRACT: Genetic analysis of melanoma has allowed us to identify a population of patients who have more aggressive disease and harbor the driver mutation

5 Review Revolutionizing treatment of advanced melanoma with immunotherapy. 2019

Carreau, Nicole / Pavlick, Anna. ·NYU Perlmutter Cancer Center, NYU Langone Health, USA. · NYU Perlmutter Cancer Center, NYU Langone Health, USA. Electronic address: anna.pavlick@nyulangone.org. ·Surg Oncol · Pubmed #30691991.

ABSTRACT: Until immunotherapy was developed, a diagnosis of metastatic melanoma was most often fatal. Programmed death receptor-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibodies have been shown to work synergistically to treat metastatic disease throughout the body and brain. Today, over half of patients diagnosed with stage IV disease are alive after 3 years. In the adjuvant setting, 70% patients remain disease free with PD-1 blockade after 1 year. These treatments are generally safe and well tolerated. However, treatment-related endocrinopathies require long-term medications. With better therapies producing more durable responses, advanced cutaneous melanoma is dramatically more manageable now than ever before.

6 Review Nivolumab and ipilimumab: immunotherapy for treatment of malignant melanoma. 2019

Carreau, Nicole A / Pavlick, Anna C. ·Department of Medical Oncology, New York University Langone Medical Center, New York, NY 10016, USA. ·Future Oncol · Pubmed #30334646.

ABSTRACT: As recently as 10 years ago, a diagnosis of metastatic melanoma was considered fatal, with a prognosis of typically 6 months or less from diagnosis. The development of checkpoint inhibitors, such as ipilimumab and nivolumab, which modulate the effects of the CTLA-4 and PD-1, respectively, has revolutionized outcomes for these patients. Monotherapy improves metastatic disease survival, but dual therapy provides greater benefit with 58% of patients alive at 3 years. Combination immunotherapy is even active in brain metastases. In the adjuvant setting, data show that at 1 year over 70% patients remain disease-free with PD-1 blockade. Immunotherapy is generally safe and well tolerated. However, treatment-related endocrinopathies require long-term medications. Nowadays, advanced cutaneous melanoma is a more manageable disease.

7 Review Treatment Outcomes for Metastatic Melanoma of Unknown Primary in the New Era: A Single-Institution Study and Review of the Literature. 2017

Utter, Kierstin / Goldman, Chloe / Weiss, Sarah A / Shapiro, Richard L / Berman, Russell S / Wilson, Melissa Ann / Pavlick, Anna C / Osman, Iman. ·The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA. ·Oncology · Pubmed #28746931.

ABSTRACT: BACKGROUND: Metastatic melanoma of unknown primary (MUP) is uncommon, biologically ill defined, and clinically understudied. MUP outcomes are seldom reported in clinical trials. In this study, we analyze responses of MUP patients treated with systemic therapy in an attempt to inform treatment guidelines for this unique population. METHODS: New York University (NYU)'s prospective melanoma database was searched for MUP patients treated with systemic therapy. PubMed and Google Scholar were searched for MUP patients treated with immunotherapy or targeted therapy reported in the literature, and their response and survival data were compared to the MUP patient data from NYU. Both groups' response data were compared to those reported for melanoma of known primary (MKP). RESULTS: The MUP patients treated at NYU had better outcomes on immunotherapy but worse on targeted therapy than the MUP patients in the literature. The NYU MUP patients and those in the literature had worse outcomes than the majority-MKP populations in 10 clinical trial reports. CONCLUSIONS: Our study suggests that MUP patients might have poorer outcomes on systemic therapy as compared to MKP patients. Our cohort was small and limited data were available, highlighting the need for increased reporting of MUP outcomes and multi-institutional efforts to understand the mechanism behind the observed differences.

8 Review Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. 2017

Sznol, Mario / Postow, Michael A / Davies, Marianne J / Pavlick, Anna C / Plimack, Elizabeth R / Shaheen, Montaser / Veloski, Colleen / Robert, Caroline. ·Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA. Electronic address: mario.sznol@yale.edu. · Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. · Yale School of Nursing, West Haven, CT, USA. · New York University, New York, NY, USA. · Fox Chase Cancer Center, Temple Health, Philadelphia, PA, USA. · University of New Mexico, Albuquerque, NM, USA. · Gustave Roussy and Paris-Sud University, Villejuif, France. ·Cancer Treat Rev · Pubmed #28689073.

ABSTRACT: Agents that modulate immune checkpoint proteins, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death receptor-1 (PD-1), have become a mainstay in cancer treatment. The clinical benefit afforded by immune checkpoint inhibitors can be accompanied by immune-related adverse events (irAE) that affect the skin, gastrointestinal tract, liver, and endocrine system. The types of irAEs associated with immune checkpoint inhibitors are generally consistent across tumor types. Immune-related endocrine events can affect the pituitary, thyroid, and adrenal glands, as well as other downstream target organs. These events are unique when compared with other irAEs because the manifestations are often irreversible. Immune-related endocrine events are typically grade 1/2 in severity and often present with non-specific symptoms, making them difficult to diagnose. The mechanisms underlying immune-related target organ damage in select individuals remain mostly undefined. Management includes close patient monitoring, appropriate laboratory testing for endocrine function, replacement of hormones, and consultation with an endocrinologist when appropriate. An awareness of the symptoms and management of immune-related endocrine events may aid in the safe and appropriate use of immune checkpoint inhibitors in clinical practice.

9 Review Update on vaccines for high-risk melanoma. 2014

Weiss, Sarah A / Chandra, Sunandana / Pavlick, Anna C. ·New York University Cancer Institute, New York University School of Medicine, New York, NY, 10016, USA. ·Curr Treat Options Oncol · Pubmed #24788575.

ABSTRACT: The management of high-risk melanoma has historically included primary surgical resection with or without lymphadenectomy followed by an array of adjuvant options including radiation therapy or immunomodulatory therapies such as interferon-α, granulocyte macrophage colony-stimulating factor, and a multitude of vaccines. There has been a long-standing interest in the development of vaccines in high-risk and metastatic melanoma, and clinical trials have been ongoing for decades. Given that melanoma is identified as one of the most immunogenic solid tumors, there is continued hope that vaccine therapies will improve clinical outcomes. Despite intense interest in this field, few clinical trials to-date have demonstrated significant benefit from melanoma vaccines in high-risk disease. Several trials have even documented a detrimental effect on outcomes after vaccine administration. While the role of vaccines in the adjuvant setting of high-risk melanoma presently remains unclear, recent advances in immunotherapy for melanoma including development of cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) monoclonal antibodies have demonstrated meaningful clinical responses. With further study and focus on mechanisms of immune regulation, there remains promise for the role of vaccines in combination with other immune-stimulatory agents in high-risk melanoma.

10 Review Targeted therapies for metastatic melanoma. 2012

Chandra, Sunandana / Pavlick, Anna C. ·NYU School of Medicine, New York, NY 10016, USA. ·Dermatol Clin · Pubmed #22800555.

ABSTRACT: The next few years may show that when the novel therapeutics reviewed in this article are used in thoughtful combinations, a new standard of care for the treatment of advanced melanoma will emerge. As more understanding is gained on the different signaling pathways for tumor cell growth and mechanisms of action of the different classes of drugs, the ability to identify different subsets of patients with differentially dysregulated oncogenic signaling pathways may allow for more individualized treatments of advanced melanoma in the near future, which will ultimately translate into improved survival.

11 Review Mucosal melanomas: a case-based review of the literature. 2010

Seetharamu, Nagashree / Ott, Patrick A / Pavlick, Anna C. ·NYU Cancer Institute, 160E 34th Street, New York, New York 10016, USA. anna.pavlick@nyumc.org ·Oncologist · Pubmed #20571149.

ABSTRACT: Mucosal melanoma is a rare cancer that is clearly distinct from its cutaneous counterpart in biology, clinical course, and prognosis. Recent studies have shown important differences in the frequencies of various genetic alterations in different subtypes of melanoma. Activating mutations in the c-KIT gene are detected in a significant number of patients with mucosal melanoma. This observation has resulted in the initiation of several clinical trials aimed at exploring the role of receptor tyrosine kinases that inhibit c-KIT in this patient population. We herein present a comprehensive literature review of mucosal melanoma along with case vignettes of a number of pertinent cases. We further discuss melanomas of the head and neck, the female genital tract, and the anorectum, which are the three most common sites of mucosal melanoma, with a particular focus on the diagnostic, prognostic, and therapeutic data available in the literature.

12 Clinical Trial A phase 2 study of glembatumumab vedotin, an antibody-drug conjugate targeting glycoprotein NMB, in patients with advanced melanoma. 2019

Ott, Patrick A / Pavlick, Anna C / Johnson, Douglas B / Hart, Lowell L / Infante, Jeffrey R / Luke, Jason J / Lutzky, Jose / Rothschild, Neal E / Spitler, Lynn E / Cowey, C Lance / Alizadeh, Aaron R / Salama, April K / He, Yi / Hawthorne, Thomas R / Bagley, Rebecca G / Zhang, Joshua / Turner, Christopher D / Hamid, Omid. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Medical Oncology, New York University School of Medicine, New York, New York. · Department of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. · Florida Cancer Specialists and Research Institute, Fort Myers, Florida. · Tennessee Oncology, PLLC, Nashville, Tennessee. · Department of Hematology/Oncology, University of Chicago Medical Center, Chicago, Illinois. · Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida. · Florida Cancer Specialists, West Palm Beach, Florida. · St. Mary's Medical Center, San Francisco, California. · Northern California Melanoma Center, Baylor University Medical Center, Dallas, Texas. · Northside Hospital Cancer Institute, Decatur, Georgia. · Department of Medical Oncology, Duke University, Durham, North Carolina. · Celldex Therapeutics, Inc, Hampton, New Jersey. · The Angeles Clinic and Research Institute, Los Angeles, California. ·Cancer · Pubmed #30690710.

ABSTRACT: BACKGROUND: Glembatumumab vedotin is an antibody-drug conjugate that produced preliminary clinical activity against advanced melanoma in a phase 1 dose-escalation trial. The objective of the current study was to investigate further the antitumor activity of glembatumumab vedotin at the recommended phase 2 dose in heavily pretreated patients with melanoma. METHODS: This single-arm, phase 2 study enrolled patients with stage IV melanoma who were refractory to checkpoint inhibition and to B-raf proto-oncogene, serine/threonine kinase (BRAF)/mitogen-activated protein kinase kinase (MEK) inhibition (in the presence of a BRAF valine mutation at codon 600). Patients received 1.9 mg/kg glembatumumab vedotin intravenously every 3 weeks until they developed disease progression or intolerance. The primary endpoint was objective response rate (ORR), which was determined according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included progression-free survival (PFS), duration of response, overall survival (OS), safety, and clinical efficacy versus tumor glycoprotein NMB (gpNMB) expression. Tumor expression of gpNMB was assessed using immunohistochemistry. RESULTS: In total, 62 patients received treatment. The ORR was 11% and the median response duration was 6.0 months (95% confidence interval [CI], 4.1 months to not reached). The median PFS was 4.4 months (95% CI, 2.6-5.5 months), and the median OS was 9.0 months (95% CI, 6.1-11.7 months). For patients who developed rash during the first cycle versus those who did not, the ORR was 21% versus 7%, respectively, and there was an overall improvement in PFS (hazard ratio, 0.43; P = .013) and OS (hazard ratio, 0.43; P = .017). The most frequent adverse events were alopecia, neuropathy, rash, fatigue, and neutropenia. With one exception, all evaluable tumors were positive for gpNMB, and 46 of 59 tumors (76%) had 100% gpNMB-positive epithelial cells. CONCLUSIONS: Glembatumumab vedotin had modest activity and an acceptable safety profile in patients with advanced melanoma who were refractory to checkpoint inhibitors and MEK/BRAF inhibition. Treatment-related rash may be associated with response.

13 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 .).

14 Clinical Trial MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma. 2018

Rodig, Scott J / Gusenleitner, Daniel / Jackson, Donald G / Gjini, Evisa / Giobbie-Hurder, Anita / Jin, Chelsea / Chang, Han / Lovitch, Scott B / Horak, Christine / Weber, Jeffrey S / Weirather, Jason L / Wolchok, Jedd D / Postow, Michael A / Pavlick, Anna C / Chesney, Jason / Hodi, F Stephen. ·Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. srodig@bwh.harvard.edu stephen_hodi@dfci.harvard.edu. · Department of Pathology, Brigham and Women's Hospital, Boston, MA 20115, USA. · Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. · Bristol-Myers Squibb, Princeton, NJ 08540, USA. · Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. · Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA. · Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. · James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA. · Melanoma Disease Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA. srodig@bwh.harvard.edu stephen_hodi@dfci.harvard.edu. ·Sci Transl Med · Pubmed #30021886.

ABSTRACT: Combination anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) and anti-programmed cell death protein 1 (PD-1) therapy promotes antitumor immunity and provides superior benefit to patients with advanced-stage melanoma compared with either therapy alone. T cell immunity requires recognition of antigens in the context of major histocompatibility complex (MHC) class I and class II proteins by CD8

15 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.

16 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.

17 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.

18 Clinical Trial A phase I dose-escalation study of TAK-733, an investigational oral MEK inhibitor, in patients with advanced solid tumors. 2017

Adjei, Alex A / LoRusso, Patricia / Ribas, Antoni / Sosman, Jeffrey A / Pavlick, Anna / Dy, Grace K / Zhou, Xiaofei / Gangolli, Esha / Kneissl, Michelle / Faucette, Stephanie / Neuwirth, Rachel / Bózon, Viviana. ·Department of Oncology, Mayo Clinic, 200 First St, SW, Rochester, MN, 55905, USA. Adjei.Alex@Mayo.edu. · Roswell Park Cancer Institute, Buffalo, NY, USA. Adjei.Alex@Mayo.edu. · Yale University, New Haven, CT, USA. · University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. · Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. · New York University Langone Medical Center, New York, NY, USA. · Roswell Park Cancer Institute, Buffalo, NY, USA. · Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA. · AstraZeneca Pharmaceuticals, Waltham, MA, USA. · Present address: Array BioPharma Inc., Boulder, CO, USA. ·Invest New Drugs · Pubmed #27650277.

ABSTRACT: Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1-21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1. Results Fifty-one patients received TAK-733 0.2-22 mg. Primary diagnoses included uveal melanoma (24 %), colon cancer (22 %), and cutaneous melanoma (10 %). Four patients had dose-limiting toxicities of dermatitis acneiform, plus fatigue and pustular rash in one patient, and stomatitis in one patient. The maximum tolerated dose was 16 mg. Common drug-related AEs included dermatitis acneiform (51 %), diarrhea (29 %), and increased blood creatine phosphokinase (20 %); grade ≥ 3 AEs were reported in 27 (53 %) patients. Median T

19 Clinical Trial Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. 2016

Hodi, F Stephen / Chesney, Jason / Pavlick, Anna C / Robert, Caroline / Grossmann, Kenneth F / McDermott, David F / Linette, Gerald P / Meyer, Nicolas / Giguere, Jeffrey K / Agarwala, Sanjiv S / Shaheen, Montaser / Ernstoff, Marc S / Minor, David R / Salama, April K / Taylor, Matthew H / Ott, Patrick A / Horak, Christine / Gagnier, Paul / Jiang, Joel / Wolchok, Jedd D / Postow, Michael A. ·Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: stephen_hodi@dfci.harvard.edu. · University of Louisville, Louisville, KY, USA. · New York University, New York, NY, USA. · Gustave Roussy, INSERM U981, Paris, France. · Huntsman Cancer Institute, Salt Lake City, UT, USA. · Beth Israel Deaconess Medical Center, Boston, MA, USA. · Washington University School of Medicine, St Louis, MO, USA. · Institut Universitaire du Cancer, Toulouse, France. · Greenville Health System Cancer Institute, Greenville, SC, USA. · St Luke's Cancer Center and Temple University, Bethlehem, PA, USA. · University of New Mexico, Albuquerque, NM, USA. · Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA. · California Pacific Center for Melanoma Research, San Francisco, CA, USA. · Duke University Medical Center, Durham, NC, USA. · Oregon Health & Science University, Portland, OR, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Bristol-Myers Squibb, Princeton, NJ, USA. · Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. ·Lancet Oncol · Pubmed #27622997.

ABSTRACT: BACKGROUND: Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma. METHODS: In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAF FINDINGS: Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24·5 months (IQR 9·1-25·7), 2-year overall survival was 63·8% (95% CI 53·3-72·6) for those assigned to nivolumab plus ipilimumab and 53·6% (95% CI 38·1-66·8) for those assigned to ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0·74, 95% CI 0·43-1·26; p=0·26). Treatment-related grade 3-4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received ipilimumab alone. The most common treatment-related grade 3-4 adverse events were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten [11%]) in the combination group and diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]) in the ipilimumab alone group. Serious grade 3-4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus ipilimumab (including colitis in ten [11%] of 94 patients, and diarrhoea in five [5%]) compared with four (9%) of 46 patients who received ipilimumab alone (including diarrhoea in two [4%] of 46 patients, colitis in one [2%], and hypophysitis in one [2%]). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis. INTERPRETATION: Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients. FUNDING: Bristol-Myers Squibb.

20 Clinical Trial A phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with metastatic melanoma. 2016

Bhatia, Shailender / Pavlick, Anna C / Boasberg, Peter / Thompson, John A / Mulligan, George / Pickard, Michael D / Faessel, Hélène / Dezube, Bruce J / Hamid, Omid. ·Department of Medicine/Medical Oncology, University of Washington Medical Center/Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, 825 Eastlake Ave W, G4-830, Seattle, WA, 98109-1023, USA. sbhatia@uw.edu. · Departments of Medicine (Perlmutter Cancer Center) and Dermatology, NYU Langone Medical Center, New York, NY, USA. · The Angeles Clinic and Research Institute, Translational Research & Cutaneous Oncology, Los Angeles, CA, USA. · Department of Medicine/Medical Oncology, University of Washington Medical Center/Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, 825 Eastlake Ave W, G4-830, Seattle, WA, 98109-1023, USA. · Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA. ·Invest New Drugs · Pubmed #27056178.

ABSTRACT: Purpose The therapeutic index of proteasome inhibitors may be improved through selective inhibition of a sub-component of the ubiquitin-proteasome system, such as the NEDD8-conjugation pathway. This multicenter, phase I, dose-escalation study assessed safety and the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of pevonedistat, an investigational NEDD8-activating enzyme (NAE) inhibitor, in patients with metastatic melanoma. Methods Patients received intravenous pevonedistat on Days 1, 4, 8, 11 (schedule A) or 1, 8, 15 (schedule B) of 21-day cycles. Results 26 patients received pevonedistat 50-278 mg/m(2) on schedule A; 11 patients received pevonedistat 157 mg/m(2) on schedule B. The schedule A MTD was 209 mg/m(2): dose-limiting toxicities (DLTs) included grade 3 hypophosphatemia and grade 3 increased blood creatinine (associated with grade 3 hyperbilirubinemia). Two schedule A patients experienced acute organ failure toxicities, one of whom experienced grade 5 acute renal failure. Dose escalation did not occur in schedule B: DLTs included grade 3 myocarditis, grade 2 acute renal failure, and grade 2 hyperbilirubinemia in a single patient. Pevonedistat pharmacokinetics were approximately dose-proportional across the dose range studied, with a biphasic disposition profile characterized by a short elimination half-life (~10 h). Pharmacodynamic studies showed increases in NAE-regulated transcripts post-treatment; all post-dose biopsy samples were positive for pevonedistat-NEDD8 adduct. One schedule A patient achieved a partial response; 15 patients had stable disease (4 lasting ≥6.5 months). Conclusions Pevonedistat was generally well tolerated at the MTD. Anticipated pharmacodynamic effects of NAE inhibition were observed with single-agent pevonedistat in peripheral blood and tumor tissue.

21 Clinical Trial Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. 2015

Ribas, Antoni / Puzanov, Igor / Dummer, Reinhard / Schadendorf, Dirk / Hamid, Omid / Robert, Caroline / Hodi, F Stephen / Schachter, Jacob / Pavlick, Anna C / Lewis, Karl D / Cranmer, Lee D / Blank, Christian U / O'Day, Steven J / Ascierto, Paolo A / Salama, April K S / Margolin, Kim A / Loquai, Carmen / Eigentler, Thomas K / Gangadhar, Tara C / Carlino, Matteo S / Agarwala, Sanjiv S / Moschos, Stergios J / Sosman, Jeffrey A / Goldinger, Simone M / Shapira-Frommer, Ronnie / Gonzalez, Rene / Kirkwood, John M / Wolchok, Jedd D / Eggermont, Alexander / Li, Xiaoyun Nicole / Zhou, Wei / Zernhelt, Adriane M / Lis, Joy / Ebbinghaus, Scot / Kang, S Peter / Daud, Adil. ·University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: aribas@mednet.ucla.edu. · Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. · University of Zürich, Zürich, Switzerland. · University Hospital Essen, Essen, Germany. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Gustave Roussy and Paris-Sud University, Villejuif, France. · Dana-Farber Cancer Institute, Boston, MA, USA. · Sheba Medical Center, Tel Hashomer, Israel. · New York University Cancer Institute, New York, NY, USA. · University of Colorado Denver, Aurora, CO, USA. · University of Arizona Cancer Center, Tucson, AZ, USA. · Netherlands Cancer Institute, Amsterdam, Netherlands. · Beverly Hills Cancer Center, Beverly Hills, CA, USA. · Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, Italy. · Duke Cancer Institute, Durham, NC, USA. · Seattle Cancer Care Alliance/University of Washington, Seattle, WA, USA. · University Medical Center, Mainz, Germany. · Universitätsklinikum Tübingen, Tübingen, Germany. · Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA. · Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, and Melanoma Institute Australia, Westmead, NSW, Australia. · St Luke's Cancer Center, Bethlehem, PA, USA; Temple University, Philadelphia, PA, USA. · University of North Carolina, Chapel Hill, NC, USA. · University of Pittsburgh, Pittsburgh, PA, USA. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Merck & Co, Kenilworth, NJ, USA. · University of California, San Francisco, San Francisco, CA, USA. ·Lancet Oncol · Pubmed #26115796.

ABSTRACT: BACKGROUND: Patients with melanoma that progresses on ipilimumab and, if BRAF(V600) mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma. METHODS: We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF(V600) mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0-1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAF(V600) mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients. FINDINGS: Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45-0·73; p<0·0001) and those assigned to pembrolizumab 10 mg/kg (0·50, 0·39-0·64; p<0·0001) compared with those assigned to chemotherapy. 6-month progression-free survival was 34% (95% CI 27-41) in the pembrolizumab 2 mg/kg group, 38% (31-45) in the 10 mg/kg group, and 16% (10-22) in the chemotherapy group. Treatment-related grade 3-4 adverse events occurred in 20 (11%) patients in the pembrolizumab 2 mg/kg group, 25 (14%) in the pembrolizumab 10 mg/kg group, and 45 (26%) in the chemotherapy group. The most common treatment-related grade 3-4 adverse event in the pembrolizumab groups was fatigue (two [1%] of 178 patients in the 2 mg/kg group and one [<1%] of 179 patients in the 10 mg/kg group, compared with eight [5%] of 171 in the chemotherapy group). Other treatment-related grade 3-4 adverse events include generalised oedema and myalgia (each in two [1%] patients) in those given pembrolizumab 2 mg/kg; hypopituitarism, colitis, diarrhoea, decreased appetite, hyponatremia, and pneumonitis (each in two [1%]) in those given pembrolizumab 10 mg/kg; and anaemia (nine [5%]), fatigue (eight [5%]), neutropenia (six [4%]), and leucopenia (six [4%]) in those assigned to chemotherapy. INTERPRETATION: These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma. FUNDING: Merck Sharp & Dohme.

22 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.

23 Clinical Trial Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. 2014

Ribas, Antoni / Gonzalez, Rene / Pavlick, Anna / Hamid, Omid / Gajewski, Thomas F / Daud, Adil / Flaherty, Lawrence / Logan, Theodore / Chmielowski, Bartosz / Lewis, Karl / Kee, Damien / Boasberg, Peter / Yin, Ming / Chan, Iris / Musib, Luna / Choong, Nicholas / Puzanov, Igor / McArthur, Grant A. ·Jonsson Comprehensive Cancer Center at University of California, Los Angeles, CA, USA. · University of Colorado Comprehensive Cancer Center, Aurora, CO, USA. · New York University Medical Center, New York, NY, USA. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · University of Chicago, Chicago, IL, USA. · Hematology/Oncology Division, University of California, San Francisco, CA, USA. · Karmanos Cancer Institute, Detroit, MI, USA. · Indiana University, Indianapolis, IN, USA. · Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. · Genentech, South San Francisco, CA, USA. · Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. · Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Electronic address: grant.mcarthur@petermac.org. ·Lancet Oncol · Pubmed #25037139.

ABSTRACT: BACKGROUND: Addition of a MEK inhibitor to a BRAF inhibitor enhances tumour growth inhibition, delays acquired resistance, and abrogates paradoxical activation of the MAPK pathway in preclinical models of BRAF-mutated melanoma. We assessed the safety and efficacy of combined BRAF inhibition with vemurafenib and MEK inhibition with cobimetinib in patients with advanced BRAF-mutated melanoma. METHODS: We undertook a phase 1b study in patients with advanced BRAF(V600)-mutated melanoma. We included individuals who had either recently progressed on vemurafenib or never received a BRAF inhibitor. In the dose-escalation phase of our study, patients received vemurafenib 720 mg or 960 mg twice a day continuously and cobimetinib 60 mg, 80 mg, or 100 mg once a day for either 14 days on and 14 days off (14/14), 21 days on and 7 days off (21/7), or continuously (28/0). The primary endpoint was safety of the drug combination and to identify dose-limiting toxic effects and the maximum tolerated dose. Efficacy was a key secondary endpoint. All patients treated with vemurafenib and cobimetinib were included in safety and efficacy analyses (intention-to-treat). The study completed accrual and all analyses are final. This study is registered with ClinicalTrials.gov, number NCT01271803. FINDINGS: 129 patients were treated at ten dosing regimens combining vemurafenib and cobimetinib: 66 had recently progressed on vemurafenib and 63 had never received a BRAF inhibitor. Dose-limiting toxic effects arose in four patients. One patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 80 mg once a day 14/14 had grade 3 fatigue for more than 7 days; one patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg once a day 21/7 had a grade 3 prolongation of QTc; and two patients on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg 28/0 had dose-limiting toxic effects-one developed grade 3 stomatitis and fatigue and one developed arthralgia and myalgia. The maximum tolerated dose was established as vemurafenib 960 mg twice a day in combination with cobimetinib 60 mg 21/7. Across all dosing regimens, the most common adverse events were diarrhoea (83 patients, 64%), non-acneiform rash (77 patients, 60%), liver enzyme abnormalities (64 patients, 50%), fatigue (62 patients, 48%), nausea (58 patients, 45%), and photosensitivity (52 patients, 40%). Most adverse events were mild-to-moderate in severity. The most common grade 3 or 4 adverse events were cutaneous squamous-cell carcinoma (12 patients, 9%; all grade 3), raised amounts of alkaline phosphatase (11 patients, 9%]), and anaemia (nine patients, 7%). Confirmed objective responses were recorded in ten (15%) of 66 patients who had recently progressed on vemurafenib, with a median progression-free survival of 2·8 months (95% CI 2·6-3·4). Confirmed objective responses were noted in 55 (87%) of 63 patients who had never received a BRAF inhibitor, including six (10%) who had a complete response; median progression-free survival was 13·7 months (95% CI 10·1-17·5). INTERPRETATION: The combination of vemurafenib and cobimetinib was safe and tolerable when administered at the respective maximum tolerated doses. The combination has promising antitumour activity and further clinical development is warranted in patients with advanced BRAF(V600)-mutated melanoma, particularly in those who have never received a BRAF inhibitor; confirmatory clinical testing is ongoing. FUNDING: F Hoffmann-La Roche/Genentech.

24 Clinical Trial Dose selection, pharmacokinetics, and pharmacodynamics of BRAF inhibitor dabrafenib (GSK2118436). 2014

Falchook, Gerald S / Long, Georgina V / Kurzrock, Razelle / Kim, Kevin B / Arkenau, H-Tobias / Brown, Michael P / Hamid, Omid / Infante, Jeffrey R / Millward, Michael / Pavlick, Anna / Chin, Melvin T / O'Day, Steven J / Blackman, Samuel C / Curtis, C Martin / Lebowitz, Peter / Ma, Bo / Ouellet, Daniele / Kefford, Richard F. ·Division of Cancer Medicine, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. gerald.falchook@scresearch.net georgina.long@sydney.edu.au. · Melanoma Institute Australia and University of Sydney, New South Wales, Australia. Westmead Institute for Cancer Research, Westmead Millennium Institute, and Department of Medical Oncology, Westmead Hospital, Sydney, New South Wales, Australia. gerald.falchook@scresearch.net georgina.long@sydney.edu.au. · Moores Cancer Center, University of California San Diego, La Jolla, California. · Division of Cancer Medicine, Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · GlaxoSmithKline Medicines Research Unit, Prince of Wales Hospital, Randwick, New South Wales, Australia. · Cancer Clinical Trials Unit, Royal Adelaide Hospital and University of Adelaide, Adelaide, South Australia, Australia. · Experimental Therapeutics/Immunotherapy, The Angeles Clinic and Research Institute, Los Angeles, California. · Drug Development Unit, Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, Tennessee. · Cancer Council Trials and Sir Charles Gairdner Hospital and University of Western Australia, Perth, Western Australia, Australia. · Division of Medical Oncology, New York University School of Medicine, New York, New York. · Prince of Wales Clinical School, University of New South Wales, Randwick, Australia. · GlaxoSmithKline Research and Development, Philadelphia, Pennsylvania and Research Triangle Park, North Carolina. · Melanoma Institute Australia and University of Sydney, New South Wales, Australia. Westmead Institute for Cancer Research, Westmead Millennium Institute, and Department of Medical Oncology, Westmead Hospital, Sydney, New South Wales, Australia. ·Clin Cancer Res · Pubmed #24958809.

ABSTRACT: PURPOSE: Dabrafenib is a selective, potent ATP-competitive inhibitor of the BRAFV600-mutant kinase that has demonstrated efficacy in clinical trials. We report the rationale for dose selection in the first-in-human study of dabrafenib, including pharmacokinetics, tissue pharmacodynamics, 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) pharmacodynamics, and dose-response relationship. EXPERIMENTAL DESIGN: Dabrafenib was administered orally once, twice (BID), or three times daily (TID). Selected dose cohorts were expanded to collect adequate data on safety, pharmacokinetics, or pharmacodynamics. A recommended phase II dose (RP2D) was chosen based on safety, pharmacokinetic, pharmacodynamic, and response data. RESULTS: One hundred and eighty-four patients were enrolled and treated with doses ranging from 12 mg once daily to 300 mg BID in 10 cohorts. Pharmacokinetic assessment of dabrafenib demonstrated a less-than-dose-proportional increase in exposure after repeat dosing above 150 mg BID. Similar to parent drug concentrations, exposure for all metabolites demonstrated less-than-dose-proportional increases. Predicted target inhibition of pERK (>80%) was achieved at 150 mg BID, with a similar magnitude of inhibition at higher doses in BRAFV600 mutation melanoma biopsy samples. Although there was large variability between patients, FDG uptake decreased with higher daily doses in patients with BRAFV600 mutation-positive melanoma. A favorable activity and tolerability profile was demonstrated at 150 mg BID. There was no improvement with TID dosing compared with BID dosing, based on FDG-PET and tumor response analyses in patients with melanoma. CONCLUSION: The RP2D of dabrafenib was determined to be 150 mg BID after considering multiple factors, including pharmacokinetics, tissue pharmacodynamics, FDG-PET pharmacodynamics, and the dose-response relationship. A maximum tolerated dose for dabrafenib was not determined.

25 Clinical Trial A phase 2 randomised study of ramucirumab (IMC-1121B) with or without dacarbazine in patients with metastatic melanoma. 2014

Carvajal, Richard D / Wong, Michael K / Thompson, John A / Gordon, Michael S / Lewis, Karl D / Pavlick, Anna C / Wolchok, Jedd D / Rojas, Patrick B / Schwartz, Jonathan D / Bedikian, Agop Y. ·Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Electronic address: carvajar@mskcc.org. · USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA. · Seattle Cancer Care Alliance, Seattle, WA, USA. · Pinnacle Oncology Hematology, Scottsdale, AZ, USA. · University of Colorado Denver, Aurora, CO, USA. · New York University, New York, NY, USA. · Memorial Sloan-Kettering Cancer Center, New York, NY, USA. · ImClone Systems LLC, a wholly-owned subsidiary of Eli Lilly and Company, Bridgewater, NJ, USA. · MD Anderson Cancer Center, Houston, TX, USA. ·Eur J Cancer · Pubmed #24930625.

ABSTRACT: BACKGROUND: To evaluate the efficacy and safety of ramucirumab (IMC-1121B; LY3009806), a fully human monoclonal antibody targeting the vascular endothelial growth factor receptor-2, alone and in combination with dacarbazine in chemotherapy-naïve patients with metastatic melanoma (MM). METHODS: Eligible patients received ramucirumab (10mg/kg) + dacarbazine (1000 mg/m(2)) (Arm A) or ramucirumab only (10mg/kg) (Arm B) every 3 weeks. The primary end-point was progression-free survival (PFS); secondary end-points included overall survival (OS), overall response and safety. FINDINGS: Of 106 randomised patients, 102 received study treatment (Arm A, N=52; Arm B, N=50). Baseline characteristics were similar in both arms. Median PFS was 2.6 months (Arm A) and 1.7 months (Arm B); median 6-month PFS rates were 30.7% and 17.9% and 12-month PFS rates were 23.7% and 15.6%, respectively. In Arm A, 9 (17.3%) patients had partial response (PR) and 19 (36.5%), stable disease (SD); PR and SD in Arm B were 2 (4.0%) and 21 (42.0%), respectively. Median OS was 8.7 months in Arm A and 11.1 months in Arm B. Patients in both arms tolerated the treatment with limited Grade 3/4 toxicities. INTERPRETATION: Ramucirumab alone or in combination with dacarbazine was associated with an acceptable safety profile in patients with MM. Although the study was not powered for comparison between treatment arms, PFS appeared greater with combination therapy. Sustained disease control was observed on both study arm.

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