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Melanoma: HELP
Articles by Omid A. Hamid
Based on 70 articles published since 2008
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Between 2008 and 2019, O. Hamid wrote the following 70 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
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 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 .).

7 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.

8 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.

9 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.

10 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.

11 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.

12 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

13 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.

14 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.

15 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.

16 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.

17 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:

18 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.

19 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 .).

20 Clinical Trial Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. 2016

Schadendorf, Dirk / Dummer, Reinhard / Hauschild, Axel / Robert, Caroline / Hamid, Omid / Daud, Adil / van den Eertwegh, Alfons / Cranmer, Lee / O'Day, Steven / Puzanov, Igor / Schachter, Jacob / Blank, Christian / Salama, April / Loquai, Carmen / Mehnert, Janice M / Hille, Darcy / Ebbinghaus, Scot / Kang, S Peter / Zhou, Wei / Ribas, Antoni. ·University Hospital Essen, Hufelandstrasse 55, D-45147 Essen, Germany. Electronic address: dirk.schadendorf@uk-essen.de. · Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, 8091 Zurich, Switzerland. Electronic address: Reinhard.Dummer@usz.ch. · Department of Dermatology, Venereology, and Allergology, University Hospital Schleswig-Holstein, Kiel Campus, Arnold-Heller Strasse 3, 24105 Kiel, Germany. Electronic address: ahauschild@dermatology.uni-kiel.de. · Gustave Roussy Cancer Campus and Paris-Sud University, 114 Rue Edouard Vaillant, 94800 Villejuif, France. Electronic address: Caroline.Robert@gustaveroussyr.fr. · The Angeles Clinic and Research Institute, 2001 Santa Monica Blvd, Ste 560W, Santa Monica, CA 90404, USA. Electronic address: ohamid@theangelesclinic.org. · University of California, San Francisco School of Medicine, 1600 Divisadero St, NZ Bldg A, San Francisco, CA 94115, USA. Electronic address: Adil.Daud@ucsf.edu. · Department of Medical Oncology, VU University Medical Center Amsterdam, De Boelelaan 1118, 1081 HZ Amsterdam, The Netherlands. Electronic address: vandeneertwegh@VUMC.nl. · Department of Hematology/Oncology, University of Arizona Cancer Center at UMC North, 3838 N. Campbell Ave, Tucson, AZ 85724, USA. Electronic address: lcranmer@uacc.arizona.edu. · The Los Angeles Skin Cancer Institute, The Beverly Hills Cancer Center, 8900 Wilshire Blvd, Beverly Hills, CA 90211, USA. Electronic address: stevenjoday@gmail.com. · Vanderbilt-Ingram Cancer Center, 2220 Pierce Ave, 777 Preston Research Building, Nashville, TN 37232, USA. Electronic address: igor.puzanov@vanderbilt.edu. · Department of Oncology, Ella Institute for Melanoma, Sheba Medical Center, Derech Sheba 2, Tel-Hashomer, Ramat-Gan, Israel. Electronic address: Jacob.Schachter@sheba.health.gov.il. · Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Electronic address: c.blank@nki.nl. · Division of Medical Oncology, Duke Cancer Institute, Duke University Medical Center, Box 3198, 20 Duke Medicine Circle, Durham, NC 27710, USA. Electronic address: april.salama@duke.edu. · Skin Clinic, Universitätsmedizin Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. Electronic address: carmen.loquai@unimedizin-mainz.de. · Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA. Electronic address: mehnerja@cinj.rutgers.edu. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: darcy_hille@merck.com. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: scot_ebbinghaus@merck.com. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: s.peter.kang@merck.com. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: wei.zhou2@merck.com. · Department of Medicine, Division of Hematology-Oncology, Jonsson Comprehensive Cancer Center (JCCC) at the University of California, Los Angeles (UCLA), 10833 Le Conte Ave, Los Angeles, CA 90095, USA. Electronic address: aribas@mednet.ucla.edu. ·Eur J Cancer · Pubmed #27596353.

ABSTRACT: BACKGROUND: In KEYNOTE-002, pembrolizumab significantly prolonged progression-free survival and was associated with a better safety profile compared with chemotherapy in patients with advanced melanoma that progressed after ipilimumab. We present health-related quality of life (HRQoL) outcomes from KEYNOTE-002. METHODS: Patients were randomly assigned 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or investigator-choice chemotherapy. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 instrument. A constrained longitudinal data analysis model was implemented to assess between-arm differences in HRQoL scores. The study is registered with ClinicalTrials.gov, number NCT01704287. RESULTS: Of the 540 patients enrolled, 520 were included in the HRQoL analysis. Baseline global health status (GHS) was similar across treatment arms. Compliance rates at week 12 were 76.6% (n = 108), 82.3% (n = 121), and 86.4% (n = 133) for the control, pembrolizumab 2 mg/kg Q3W, and pembrolizumab 10 mg/kg Q3W arms, respectively. From baseline to week 12, GHS/HRQoL scores were maintained to a higher degree in the pembrolizumab arms compared with the chemotherapy arm (decrease of -2.6 for each pembrolizumab arm versus -9.1 for chemotherapy; P = 0.01 for each pembrolizumab arm versus chemotherapy). Fewer patients treated with pembrolizumab experienced deterioration in GHS at week 12 (31.8% for pembrolizumab 2 mg/kg, 26.6% for 10 mg/kg, and 38.3% for chemotherapy), with similar trends observed for the individual functioning and symptoms scales. CONCLUSIONS: HRQoL was better maintained with pembrolizumab than with chemotherapy in KEYNOTE-002, supporting the use of pembrolizumab in patients with ipilimumab-refractory melanoma.

21 Clinical Trial Talimogene Laherparepvec in Combination With Ipilimumab in Previously Untreated, Unresectable Stage IIIB-IV Melanoma. 2016

Puzanov, Igor / Milhem, Mohammed M / Minor, David / Hamid, Omid / Li, Ai / Chen, Lisa / Chastain, Michael / Gorski, Kevin S / Anderson, Abraham / Chou, Jeffrey / Kaufman, Howard L / Andtbacka, Robert H I. ·Igor Puzanov, Vanderbilt University, Nashville, TN · Mohammed M. Milhem, University of Iowa, Iowa City, IA · David Minor, California Pacific Melanoma Center, San Francisco · Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles · and Ai Li, Lisa Chen, Michael Chastain, Kevin S. Gorski, Abraham Anderson, and Jeffrey Chou, Amgen, Thousand Oaks, CA · Howard L. Kaufman, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ · and Robert H.I. Andtbacka, University of Utah, Salt Lake City, UT. ·J Clin Oncol · Pubmed #27298410.

ABSTRACT: PURPOSE: Combining immunotherapeutic agents with different mechanisms of action may enhance efficacy. We describe the safety and efficacy of talimogene laherparepvec (T-VEC; an oncolytic virus) in combination with ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 checkpoint inhibitor) in patients with advanced melanoma. METHODS: In this open-label, multicenter, phase Ib trial of T-VEC in combination with ipilimumab, T-VEC was administered intratumorally in week 1 (10(6) plaque-forming units/mL), then in week 4 and every 2 weeks thereafter (10(8) plaque-forming units/mL). Ipilimumab (3 mg/kg) was administered intravenously every 3 weeks for four infusions, beginning in week 6. The primary end point was incidence of dose-limiting toxicities. Secondary end points were objective response rate by immune-related response criteria and safety. RESULTS: Median duration of treatment with T-VEC was 13.3 weeks (range, 2.0 to 95.4 weeks). Median follow-up time for survival analysis was 20.0 months (1.0 to 25.4 months). Nineteen patients were included in the safety analysis. No dose-limiting toxicities occurred, and no new safety signals were detected. Grade 3/4 treatment-related adverse events (AEs) were seen in 26.3% of patients; 15.8% had AEs attributed to T-VEC, and 21.1% had AEs attributed to ipilimumab. The objective response rate was 50%, and 44% of patients had a durable response lasting ≥ 6 months. Eighteen-month progression-free survival was 50%; 18-month overall survival was 67%. CONCLUSION: T-VEC with ipilimumab had a tolerable safety profile, and the combination appeared to have greater efficacy than either T-VEC or ipilimumab monotherapy.

22 Clinical Trial Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. 2016

Ribas, Antoni / Hamid, Omid / Daud, Adil / Hodi, F Stephen / Wolchok, Jedd D / Kefford, Richard / Joshua, Anthony M / Patnaik, Amita / Hwu, Wen-Jen / Weber, Jeffrey S / Gangadhar, Tara C / Hersey, Peter / Dronca, Roxana / Joseph, Richard W / Zarour, Hassane / Chmielowski, Bartosz / Lawrence, Donald P / Algazi, Alain / Rizvi, Naiyer A / Hoffner, Brianna / Mateus, Christine / Gergich, Kevin / Lindia, Jill A / Giannotti, Maxine / Li, Xiaoyun Nicole / Ebbinghaus, Scot / Kang, S Peter / Robert, Caroline. ·Division of Hematology and Oncology, University of California-Los Angeles, Los Angeles. · Department of Hematology/Oncology, The Angeles Clinic and Research Institute, Los Angeles, California. · Department of Hematology/Oncology, University of California-San Francisco, San Francisco. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital and Melanoma Institute Australia, Sydney, Australia7Department of Clinical Medicine, Macquarie University, Sydney, Australia. · Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · Department of Clinical Research, South Texas Accelerated Research Therapeutics, San Antonio. · Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston. · Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida. · Division of Hematology and Oncology, Abramson Cancer Center at the University of Pennsylvania, Philadelphia. · Department of Medicine, University of Sydney, Sydney, Australia. · Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota. · Department of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida. · Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. · Department of Hematology/Oncology, Massachusetts General Hospital, Boston. · Department of Medical Oncology, Gustave-Roussy Cancer Campus and Paris Sud University, Villejuif Paris-Sud, France. · Department of Clinical Oncology, Merck & Co, Inc, Kenilworth, New Jersey. · BARDS, Merck & Co, Inc, Kenilworth, New Jersey. ·JAMA · Pubmed #27092830.

ABSTRACT: IMPORTANCE: The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab. OBJECTIVE: To characterize the association of pembrolizumab with tumor response and overall survival among patients with advanced melanoma. DESIGN, SETTINGS, AND PARTICIPANTS: Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013). Median duration of follow-up was 21 months. The study was performed in academic medical centers in Australia, Canada, France, and the United States. Eligible patients were aged 18 years and older and had advanced or metastatic melanoma. Data were pooled from 655 enrolled patients (135 from a nonrandomized cohort [n = 87 ipilimumab naive; n = 48 ipilimumab treated] and 520 from randomized cohorts [n = 226 ipilimumab naive; n = 294 ipilimumab treated]). Cutoff dates were April 18, 2014, for safety analyses and October 18, 2014, for efficacy analyses. EXPOSURES: Pembrolizumab 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks continued until disease progression, intolerable toxicity, or investigator decision. MAIN OUTCOMES AND MEASURES: The primary end point was confirmed objective response rate (best overall response of complete response or partial response) in patients with measurable disease at baseline per independent central review. Secondary end points included toxicity, duration of response, progression-free survival, and overall survival. RESULTS: Among the 655 patients (median [range] age, 61 [18-94] years; 405 [62%] men), 581 had measurable disease at baseline. An objective response was reported in 194 of 581 patients (33% [95% CI, 30%-37%]) and in 60 of 133 treatment-naive patients (45% [95% CI, 36% to 54%]). Overall, 74% (152/205) of responses were ongoing at the time of data cutoff; 44% (90/205) of patients had response duration for at least 1 year and 79% (162/205) had response duration for at least 6 months. Twelve-month progression-free survival rates were 35% (95% CI, 31%-39%) in the total population and 52% (95% CI, 43%-60%) among treatment-naive patients. Median overall survival in the total population was 23 months (95% CI, 20-29) with a 12-month survival rate of 66% (95% CI, 62%-69%) and a 24-month survival rate of 49% (95% CI, 44%-53%). In treatment-naive patients, median overall survival was 31 months (95% CI, 24 to not reached) with a 12-month survival rate of 73% (95% CI, 65%-79%) and a 24-month survival rate of 60% (95% CI, 51%-68%). Ninety-two of 655 patients (14%) experienced at least 1 treatment-related grade 3 or 4 adverse event (AE) and 27 of 655 (4%) patients discontinued treatment because of a treatment-related AE. Treatment-related serious AEs were reported in 59 patients (9%). There were no drug-related deaths. CONCLUSIONS AND RELEVANCE: Among patients with advanced melanoma, pembrolizumab administration was associated with an overall objective response rate of 33%, 12-month progression-free survival rate of 35%, and median overall survival of 23 months; grade 3 or 4 treatment-related AEs occurred in 14%. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01295827.

23 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.

24 Clinical Trial Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With Pembrolizumab. 2016

Hodi, F Stephen / Hwu, Wen-Jen / Kefford, Richard / Weber, Jeffrey S / Daud, Adil / Hamid, Omid / Patnaik, Amita / Ribas, Antoni / Robert, Caroline / Gangadhar, Tara C / Joshua, Anthony M / Hersey, Peter / Dronca, Roxana / Joseph, Richard / Hille, Darcy / Xue, Dahai / Li, Xiaoyun Nicole / Kang, S Peter / Ebbinghaus, Scot / Perrone, Andrea / Wolchok, Jedd D. ·F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA · Wen-Jen Hwu, The University of Texas MD Anderson Cancer Center, Houston · Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX · Richard Kefford, Westmead Hospital, Melanoma Institute Australia, and Macquarie University · Peter Hersey, University of Sydney, Sydney, Australia · Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa · Richard Joseph, Mayo Clinic, Jacksonville, FL · Adil Daud, University of California San Francisco, San Francisco · Omid Hamid, The Angeles Clinic and Research Institute · Antoni Ribas, University of California Los Angeles, Los Angeles, CA · Caroline Robert, Gustave-Roussy and Paris-Sud University, Villejuif-Paris-Sud, France · Tara C. Gangadhar, Abramson Cancer Center, Philadelphia, PA · Anthony M. Joshua, Princess Margaret Hospital, Toronto, Ontario, Canada · Roxana Dronca, Mayo Clinic, Rochester, MN · Darcy Hille, Dahai Xue, Xiaoyun Nicole Li, S. Peter Kang, Scot Ebbinghaus, and Andrea Perrone, Merck, Kenilworth, NJ · and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY. ·J Clin Oncol · Pubmed #26951310.

ABSTRACT: PURPOSE: We evaluated atypical response patterns and the relationship between overall survival and best overall response measured per immune-related response criteria (irRC) and Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) in patients with advanced melanoma treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). PATIENTS AND METHODS: Patients received pembrolizumab 2 or 10 mg/kg every 2 weeks or every 3 weeks. Atypical responses were identified by using centrally assessed irRC data in patients with ≥ 28 weeks of imaging. Pseudoprogression was defined as ≥ 25% increase in tumor burden at week 12 (early) or any assessment after week 12 (delayed) that was not confirmed as progressive disease at next assessment. Response was assessed centrally per irRC and RECIST v1.1. RESULTS: Of the 655 patients with melanoma enrolled, 327 had ≥ 28 weeks of imaging follow-up. Twenty-four (7%) of these 327 patients had atypical responses (15 [5%] with early pseudoprogression and nine [3%] with delayed pseudoprogression). Of the 592 patients who survived ≥ 12 weeks, 84 (14%) experienced progressive disease per RECIST v1.1 but nonprogressive disease per irRC. Two-year overall survival rates were 77.6% in patients with nonprogressive disease per both criteria (n = 331), 37.5% in patients with progressive disease per RECIST v1.1 but nonprogressive disease per irRC (n = 84), and 17.3% in patients with progressive disease per both criteria (n = 177). CONCLUSION: Atypical responses were observed in patients with melanoma treated with pembrolizumab. Based on survival analysis, conventional RECIST might underestimate the benefit of pembrolizumab in approximately 15% of patients; modified criteria that permit treatment beyond initial progression per RECIST v1.1 might prevent premature cessation of treatment.

25 Clinical Trial Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib. 2016

Long, Georgina V / Weber, Jeffrey S / Infante, Jeffrey R / Kim, Kevin B / Daud, Adil / Gonzalez, Rene / Sosman, Jeffrey A / Hamid, Omid / Schuchter, Lynn / Cebon, Jonathan / Kefford, Richard F / Lawrence, Donald / Kudchadkar, Ragini / Burris, Howard A / Falchook, Gerald S / Algazi, Alain / Lewis, Karl / Puzanov, Igor / Ibrahim, Nageatte / Sun, Peng / Cunningham, Elizabeth / Kline, Amy S / Del Buono, Heather / McDowell, Diane Opatt / Patel, Kiran / Flaherty, Keith T. ·Georgina V. Long, Melanoma Institute Australia · The University of Sydney · Richard F. Kefford, Melanoma Institute Australia · The University of Sydney · Macquarie University, Sydney · Westmead Hospital, Westmead · Jonathan Cebon, Austin Health, Melbourne, Victoria, Australia · Jeffrey S. Weber and Ragini Kudchadkar, Moffitt Cancer Center, Tampa, FL · Jeffrey R. Infante and Howard A. Burris III, Sarah Cannon Research Institute/Tennessee Oncology · Kevin B. Kim, California Pacific Medical Center · Adil Daud, Alain Algazi, University of California, San Francisco, San Francisco · Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles, CA · Rene Gonzalez, Karl Lewis, University of Colorado · Gerald S. Falchook, Sarah Cannon Research Institute at HealthONE, Denver, CO · Jeffrey A. Sosman, Igor Puzanov, Vanderbilt University Medical Center, Nashville, TN · Lynn Schuchter, University of Pennsylvania Abramson Cancer Center · Nageatte Ibrahim, Elizabeth Cunningham, Merck · Peng Sun, Amy S. Kline, Heather Del Buono, Diane Opatt McDowell, GlaxoSmithKline, Philadelphia, PA · Donald Lawrence and Kiran Patel, Incyte Corporation, Wilmington, DE · and Keith T. Flaherty, Massachusetts General Hospital Cancer Center, Boston, MA. ·J Clin Oncol · Pubmed #26811525.

ABSTRACT: PURPOSE: To report the overall survival (OS) and clinical characteristics of BRAF inhibitor-naive long-term responders and survivors treated with dabrafenib plus trametinib in a phase I and II study of patients with BRAF V600 mutation-positive metastatic melanoma. METHODS: BRAF inhibitor-naive patients treated with dabrafenib 150 mg twice daily plus trametinib 2 mg daily (the 150/2 group) from the non-randomly assigned (part B) and randomly assigned (part C) cohorts of the study were analyzed for progression-free and OS separately. Baseline characteristics and factors on treatment were analyzed for associations with durable responses and OS. RESULTS: For BRAF inhibitor-naive patients in the 150/2 groups (n = 78), the progression-free survival at 1, 2, and 3 years was 44%, 22%, and 18%, respectively, for part B (n = 24) and 41%, 25%, and 21%, respectively, for part C (n = 54). Median OS was 27.4 months in part B and 25 months in part C. OS at 1, 2, and 3 years was 72%, 60%, and 47%, respectively, for part B and 80%, 51%, and 38%, respectively, for part C. Prolonged survival was associated with metastases in fewer than three organ sites and lower baseline lactate dehydrogenase. OS at 3 years was 62% in patients with normal baseline lactate dehydrogenase and 63% in patients with a complete response. CONCLUSION: Dabrafenib plus trametinib results in a median OS of more than 2 years in BRAF inhibitor-naive patients with BRAF V600 mutation-positive metastatic melanoma, and approximately 20% were progression free at 3 years. Durable responses occurred in patients with good prognostic features at baseline, which may be predictive.

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