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Melanoma: HELP
Articles by Anita Giobbie-Hurder
Based on 29 articles published since 2009
(Why 29 articles?)
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Between 2009 and 2019, Anita Giobbie-Hurder wrote the following 29 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Incidence of Programmed Cell Death 1 Inhibitor-Related Pneumonitis in Patients With Advanced Cancer: A Systematic Review and Meta-analysis. 2016

Nishino, Mizuki / Giobbie-Hurder, Anita / Hatabu, Hiroto / Ramaiya, Nikhil H / Hodi, F Stephen. ·Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Medical Oncology and Department of Medicine, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts. ·JAMA Oncol · Pubmed #27540850.

ABSTRACT: Importance: Programmed cell death 1 (PD-1) inhibitor-related pneumonitis is a rare but clinically serious and potentially life-threatening adverse event. Little is known about its incidence across different tumor types and treatment regimens. Objective: To compare the incidence of PD-1 inhibitor-related pneumonitis among different tumor types and therapeutic regimens. Data Sources: A PubMed search through November 10, 2015, and a review of references from relevant articles. For the PubMed search, the following keywords or corresponding Medical Subject Heading terms were used: nivolumab, pembrolizumab, and PD-1 inhibitor. Study Selection: Twenty-six original articles of PD-1 inhibitor trial results were identified. Among them, 20 studies of melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC) were eligible for a meta-analysis. Data Extraction and Synthesis: The data were extracted by 1 primary reviewer and then independently reviewed by 2 secondary reviewers following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Comparisons of the incidence were based on marginal, exact generalized linear models with generalized estimating equations. Main Outcomes and Measures: Incidence of all-grade and grade 3 or higher pneumonitis and pneumonitis-related deaths. Results: Twenty studies of single-tumor-type trials of PD-1 inhibitor (12 melanoma studies, 5 NSCLC studies, and 3 RCC studies) (a total of 4496 unique patients) were included in the meta-analysis. The overall incidence of pneumonitis during PD-1 inhibitor monotherapy was 2.7% (95% CI, 1.9%-3.6%) for all-grade and 0.8% (95% CI, 0.4%-1.2%) for grade 3 or higher pneumonitis. The incidence was higher in NSCLC for all-grade (4.1% vs 1.6%; P = .002) and grade 3 or higher pneumonitis (1.8% vs 0.2%; P < .001) compared with melanoma. The incidence in RCC was higher than in melanoma for all-grade pneumonitis (4.1% vs 1.6%; P < .001) but not for grade 3 or higher pneumonitis. Four pneumonitis-related deaths were observed in patients with NSCLC in the monotherapy group. Pneumonitis was more frequent during combination therapy than monotherapy for all-grade (6.6% vs 1.6%; P < .001) and grade 3 or higher pneumonitis (1.5% vs 0.2%; P = .001) in melanoma, with 1 pneumonitis-related death during combination therapy. Multivariable analyses demonstrated higher odds of pneumonitis in NSCLC for all-grade (odds ratio [OR], 1.43; 95% CI, 1.08-1.89; P = .005) and grade 3 or higher pneumonitis (OR, 2.85; 95% CI, 1.60-5.08; P < .001) and in RCC for all-grade pneumonitis (OR, 1.59; 95% CI, 1.32-1.92; P < .001) compared with melanoma. The combination therapy had significantly higher odds than monotherapy for all-grade (OR, 2.04; 95% CI, 1.69-2.50; P < .001) and grade 3 or higher pneumonitis (OR, 2.86; 95% CI, 1.79- 4.35; P < .001). Conclusions and Relevance: The incidence of PD-1 inhibitor-related pneumonitis was higher in NSCLC and RCC and during combination therapy. These findings contribute to enhance awareness among clinicians and support further investigations to meet the clinical needs.

2 Clinical Trial Results from phase II trial of HSP90 inhibitor, STA-9090 (ganetespib), in metastatic uveal melanoma. 2018

Shah, Shalin / Luke, Jason J / Jacene, Heather A / Chen, Tianqi / Giobbie-Hurder, Anita / Ibrahim, Nageatte / Buchbinder, Elizabeth L / McDermott, David F / Flaherty, Keith T / Sullivan, Ryan J / Lawrence, Donald P / Ott, Patrick A / Hodi, F Stephen. ·Department of Medicine, Medical University of South Carolina, Charleston, South Carolina. · Department of Medicine, University of Chicago, Chicago, Illinois. · Department of Radiology, Brigham and Women's Hospital. · Department of Biostatics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · Department of Medicine, Dana-Farber Cancer Institute. · Department of Medicine, Beth Israel Deaconess Medical Center. · Department of Medicine, Massachusetts General Hospital Cancer Center. ·Melanoma Res · Pubmed #30211813.

ABSTRACT: Uveal melanoma (UM) is a rare form of melanoma without effective therapy. The biology of UM relies on several heat-shock protein 90 (Hsp90)-dependent molecules such as MET, MEK and AKT, making Hsp90 inhibition a rational approach. Patients with stage IV UM, measurable disease, and no previous chemotherapy were eligible. Patients received either ganetespib 200 mg weekly (cohort A) or 150 mg twice a week (cohort B). Primary endpoint response rate (RR) was assessed by RECIST. A total of 17 patients were accrued for this study, with seven in cohort A and 10 in cohort B. Liver metastases were present in 59%. Response outcomes included one partial response, four stable disease, 11 progressive disease, and one withdrawal for ORR: 5.9% and disease control rate of 29.4%. Progression-free survival was 1.6 months (cohort A) and 1.8 months (cohort B). Overall survival was 8.5 months (cohort A) and 4.9 months (cohort B). An overall 31% of adverse events were grade 3-4 and were mostly related to gastrointestinal toxicities. Early on-treatment (1 months) positron emission tomography showed reduction in metabolic activity in 24% of patients, suggesting a pharmacodynamic effect of Hsp90 inhibition. These early metabolic changes did not seem to be durable and/or clinically significant in relation to the 2-month response assessment. Hsp90 inhibition with ganetespib resulted in modest clinical benefit on two dosing schedules and was associated with significant, although manageable, gastrointestinal toxicity. Evidence of pharmacodynamic activity for Hsp90 inhibition was observed via positron emission tomography, which did not translate into clinical benefit, suggesting rapid development of resistance.

3 Clinical Trial An immunogenic personal neoantigen vaccine for patients with melanoma. 2017

Ott, Patrick A / Hu, Zhuting / Keskin, Derin B / Shukla, Sachet A / Sun, Jing / Bozym, David J / Zhang, Wandi / Luoma, Adrienne / Giobbie-Hurder, Anita / Peter, Lauren / Chen, Christina / Olive, Oriol / Carter, Todd A / Li, Shuqiang / Lieb, David J / Eisenhaure, Thomas / Gjini, Evisa / Stevens, Jonathan / Lane, William J / Javeri, Indu / Nellaiappan, Kaliappanadar / Salazar, Andres M / Daley, Heather / Seaman, Michael / Buchbinder, Elizabeth I / Yoon, Charles H / Harden, Maegan / Lennon, Niall / Gabriel, Stacey / Rodig, Scott J / Barouch, Dan H / Aster, Jon C / Getz, Gad / Wucherpfennig, Kai / Neuberg, Donna / Ritz, Jerome / Lander, Eric S / Fritsch, Edward F / Hacohen, Nir / Wu, Catherine J. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. · Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. · Harvard Medical School, Boston, Massachusetts 02215, USA. · Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. · Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. · Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. · Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. · Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, USA. · Center for Immuno-Oncology (CIO), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. · Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. · CuriRx, Inc., Wilmington, Massachusetts 01887, USA. · Oncovir, Inc., 3203 Cleveland Avenue, NW, Washington DC 20008, USA. · Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. ·Nature · Pubmed #28678778.

ABSTRACT: Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4

4 Clinical Trial Soluble PD-L1 as a Biomarker in Malignant Melanoma Treated with Checkpoint Blockade. 2017

Zhou, Jun / Mahoney, Kathleen M / Giobbie-Hurder, Anita / Zhao, Fengmin / Lee, Sandra / Liao, Xiaoyun / Rodig, Scott / Li, Jingjing / Wu, Xinqi / Butterfield, Lisa H / Piesche, Matthias / Manos, Michael P / Eastman, Lauren M / Dranoff, Glenn / Freeman, Gordon J / Hodi, F Stephen. ·Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. · Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. · Immunologic Monitoring and Cellular Products Laboratory, Hillman Cancer Center Research Pavilion, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. · Biomedical Research Laboratories, Medicine Faculty, Catholic University of Maule, Talca, Chile. · Novartis Institutes for BioMedical Research, Cambridge, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. stephen_hodi@dfci.harvard.edu. ·Cancer Immunol Res · Pubmed #28522460.

ABSTRACT: Blockade of the pathway including programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) has produced clinical benefits in patients with a variety of cancers. Elevated levels of soluble PD-L1 (sPD-L1) have been associated with worse prognosis in renal cell carcinoma and multiple myeloma. However, the regulatory roles and function of sPD-L1 particularly in connection with immune checkpoint blockade treatment are not fully understood. We identified four splice variants of PD-L1 in melanoma cells, and all of them are secreted. Secretion of sPD-L1 resulted from alternate splicing activities, cytokine induction, cell stress, cell injury, and cell death in melanoma cells. Pretreatment levels of sPD-L1 were elevated in stage IV melanoma patient sera compared with healthy donors. High pretreatment levels of sPD-L1 were associated with increased likelihood of progressive disease in patients treated by CTLA-4 or PD-1 blockade. Although changes in circulating sPD-L1 early after treatment could not distinguish responders from those with progressive disease, after five months of treatment by CTLA-4 or PD-1 blockade patients who had increased circulating sPD-L1 had greater likelihood of developing a partial response. Induction of sPD-L1 was associated with increased circulating cytokines after CTLA-4 blockade but not following PD-1 blockade. Circulating sPD-L1 is a prognostic biomarker that may predict outcomes for subgroups of patients receiving checkpoint inhibitors.

5 Clinical Trial Combined Anti-VEGF and Anti-CTLA-4 Therapy Elicits Humoral Immunity to Galectin-1 Which Is Associated with Favorable Clinical Outcomes. 2017

Wu, Xinqi / Li, Jingjing / Connolly, Erin M / Liao, Xiaoyun / Ouyang, Jing / Giobbie-Hurder, Anita / Lawrence, Donald / McDermott, David / Murphy, George / Zhou, Jun / Piesche, Matthias / Dranoff, Glenn / Rodig, Scott / Shipp, Margaret / Hodi, F Stephen. ·Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Center for Immuno-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Department of Biostatistics, Dana-Farber Cancer Institute, Boston, Massachusetts. · Massachusetts General Hospital Cancer Center, Boston, Massachusetts. · Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. · Biomedical Research Laboratories, Medicine Faculty, Catholic University of Maule, Talca, Chile. · Novartis Institutes for BioMedical Research, Cambridge, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. stephen_hodi@dfci.harvard.edu. ·Cancer Immunol Res · Pubmed #28473314.

ABSTRACT: The combination of anti-VEGF blockade (bevacizumab) with immune checkpoint anti-CTLA-4 blockade (ipilimumab) in a phase I study showed tumor endothelial activation and immune cell infiltration that were associated with favorable clinical outcomes in patients with metastatic melanoma. To identify potential immune targets responsible for these observations, posttreatment plasma from long-term responding patients were used to screen human protein arrays. We reported that ipilimumab plus bevacizumab therapy elicited humoral immune responses to galectin-1 (Gal-1), which exhibits protumor, proangiogenesis, and immunosuppressive activities in 37.2% of treated patients. Gal-1 antibodies purified from posttreatment plasma suppressed the binding of Gal-1 to CD45, a T-cell surface receptor that transduces apoptotic signals upon binding to extracellular Gal-1. Antibody responses to Gal-1 were found more frequently in the group of patients with therapeutic responses and correlated with improved overall survival. In contrast, another subgroup of treated patients had increased circulating Gal-1 protein instead, and they had reduced overall survival. Our findings suggest that humoral immunity to Gal-1 may contribute to the efficacy of anti-VEGF and anti-CTLA-4 combination therapy. Gal-1 may offer an additional therapeutic target linking anti-angiogenesis and immune checkpoint blockade.

6 Clinical Trial Adoptive Transfer of Invariant NKT Cells as Immunotherapy for Advanced Melanoma: A Phase I Clinical Trial. 2017

Exley, Mark A / Friedlander, Phillip / Alatrakchi, Nadia / Vriend, Lianne / Yue, Simon / Sasada, Tetsuro / Zeng, Wanyong / Mizukami, Yo / Clark, Justice / Nemer, David / LeClair, Kenneth / Canning, Christine / Daley, Heather / Dranoff, Glenn / Giobbie-Hurder, Anita / Hodi, F Stephen / Ritz, Jerome / Balk, Steven P. ·Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. mexley@partners.org sbalk@bidmc.harvard.edu. · Gastroenterology, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts. · University of Manchester, Manchester, United Kingdom. · Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. · Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. · Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, Massachusetts. · Biostatistics & Computational Biology, Dana Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts. ·Clin Cancer Res · Pubmed #28193627.

ABSTRACT:

7 Clinical Trial A phase I trial of panobinostat (LBH589) in patients with metastatic melanoma. 2016

Ibrahim, Nageatte / Buchbinder, Elizabeth I / Granter, Scott R / Rodig, Scott J / Giobbie-Hurder, Anita / Becerra, Carla / Tsiaras, Argyro / Gjini, Evisa / Fisher, David E / Hodi, F Stephen. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Currently at Merck & Co.,, Kenilworth, New Jersey. · Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. · Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts. ·Cancer Med · Pubmed #27748045.

ABSTRACT: Epigenetic alterations by histone/protein deacetylases (HDACs) are one of the many mechanisms that cancer cells use to alter gene expression and promote growth. HDAC inhibitors have proven to be effective in the treatment of specific malignancies, particularly in combination with other anticancer agents. We conducted a phase I trial of panobinostat in patients with unresectable stage III or IV melanoma. Patients were treated with oral panobinostat at a dose of 30 mg daily on Mondays, Wednesdays, and Fridays (Arm A). Three of the six patients on this dose experienced clinically significant thrombocytopenia requiring dose interruption. Due to this, a second treatment arm was opened and the dose was changed to 30 mg oral panobinostat three times a week every other week (Arm B). Six patients were treated on Arm A and 10 patients were enrolled to Arm B with nine patients treated. In nine patients treated on Arm B, the response rate was 0% (90% confidence interval [CI]: 0-28%) and the disease-control rate was 22% (90% CI: 4-55%). Among all 15 patients treated, the overall response rate was 0% (90% CI: 0-17%) and the disease-control rate was 27% (90% CI: 10-51%). There was a high rate of toxicity associated with treatment. Correlative studies suggest the presence of immune modifications after HDAC inhibition. Panobinostat is not active as a single agent in the treatment of melanoma. Further exploration of this agent in combination with other therapies may be warranted.

8 Clinical Trial VEGF Neutralization Plus CTLA-4 Blockade Alters Soluble and Cellular Factors Associated with Enhancing Lymphocyte Infiltration and Humoral Recognition in Melanoma. 2016

Wu, Xinqi / Giobbie-Hurder, Anita / Liao, Xiaoyun / Lawrence, Donald / McDermott, David / Zhou, Jun / Rodig, Scott / Hodi, F Stephen. ·Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Department of Biostatistics, Dana-Farber Cancer Institute, Boston, Massachusetts. · Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. · Massachusetts General Hospital Cancer Center, Boston, Massachusetts. · Beth Israel-Deaconess Medical Center, Boston, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. stephen_hodi@dfci.harvard.edu. ·Cancer Immunol Res · Pubmed #27549123.

ABSTRACT: Immune recognition of tumor targets by specific cytotoxic lymphocytes is essential for the effective rejection of tumors. A phase I clinical trial of ipilimumab (an antibody that blocks CTLA-4 function) in combination with bevacizumab (an antibody that inhibits angiogenesis) in patients with metastatic melanoma found favorable clinical outcomes were associated with increased tumor endothelial activation and lymphocyte infiltration. To better understand the underlying mechanisms, we sought features and factors that changed as a function of treatment in patients. Ipilimumab plus bevacizumab (Ipi-Bev) increased tumor vascular expression of ICAM1 and VCAM1. Treatment also altered concentrations of many circulating cytokines and chemokines, including increases of CXCL10, IL1α, TNFα, CXCL1, IFNα2, and IL8, with decreases in VEGF-A in most patients. IL1α and TNFα induced expression of E-selectin, CXCL1, and VCAM1 on melanoma tumor-associated endothelial cells (TEC) in vitro and promoted adhesion of activated T cells onto TEC. VEGFA inhibited TNFα-induced expression of ICAM1 and VCAM1 and T-cell adhesion, which was blocked by bevacizumab. CXCL10 promoted T-cell migration across TEC in vitro, was frequently expressed by melanoma cells, and was upregulated in a subset of tumors in treated patients. Robust upregulation of CXCL10 in tumors was accompanied by increased T-cell infiltration. Ipi-Bev also augmented humoral immune responses recognizing targets in melanoma, tumor endothelial, and tumor mesenchymal stem cells. Our findings suggest that Ipi-Bev therapy augments immune recognition in the tumor microenvironment through enhancing lymphocyte infiltration and antibody responses. IL1α, TNFα, and CXCL10, together with VEGF neutralization, contribute to Ipi-Bev-induced melanoma immune recognition. Cancer Immunol Res; 4(10); 858-68. ©2016 AACR.

9 Clinical Trial Phase 2 study of sunitinib in patients with metastatic mucosal or acral melanoma. 2015

Buchbinder, Elizabeth I / Sosman, Jeffrey A / Lawrence, Donald P / McDermott, David F / Ramaiya, Nikhil H / Van den Abbeele, Annick D / Linette, Gerald P / Giobbie-Hurder, Anita / Hodi, F Stephen. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Hematology-Oncology, Vanderbilt University, Nashville, Tennessee. · Hematology-Oncology, Massachusetts General Hospital, Boston, Massachusetts. · Hematology-Oncology, Beth Israel-Deaconess Medical Center, Boston, Massachusetts. · Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Imaging, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts. · Hematology-Oncology, Washington University in St. Louis, St. Louis, Missouri. · Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. ·Cancer · Pubmed #26264378.

ABSTRACT: BACKGROUND: Patients with mucosal and acral melanomas have limited treatment options and a poor prognosis. Mutations of the KIT oncogene in these melanoma subtypes provide a potential therapeutic target. METHODS: A multicenter phase 2 trial of sunitinib was conducted in patients with unresectable stage III or IV melanoma of a mucosal or acral primary origin. Patients were treated in 2 cohorts: cohort A received sunitinib at a dose of 50 mg daily for 4 weeks of a 6-week cycle, and cohort B received sunitinib at a dose of 37.5 mg daily on a continuous basis. Dose reductions were permitted for treatment-related toxicities, and tumor assessments were performed every 2 months. RESULTS: Fifty-two patients were enrolled: 21 in cohort A and 31 in cohort B. Four patients had confirmed partial responses, which lasted 5 to 10 months (1 with a KIT mutation). In both cohorts, the proportion of patients alive and progression-free at 2 months was 52% (95% confidence interval, 38%-66%); this was significantly larger than the hypothesized null of 5%. There was no significant difference in response or overall survival between the 25% of patients with a KIT mutation and those without one (response rate, 7.7% vs 9.7%; overall survival, 6.4 vs 8.6 months). The overall disease control rate was 44%, and a high rate of toxicity was associated with the treatment. CONCLUSIONS: Sunitinib showed activity in the treatment of mucosal and acral melanoma that was not dependent on the presence of a KIT mutation. However, the medication was poorly tolerated, and there were no prolonged responses. Cancer 2015;121:4007-4015. © 2015 American Cancer Society.

10 Clinical Trial A Phase I Trial of Bortezomib and Sorafenib in Advanced Malignant Melanoma. 2015

Sullivan, Ryan J / Ibrahim, Nageatte / Lawrence, Donald P / Aldridge, Julie / Giobbie-Hurder, Anita / Hodi, F Stephen / Flaherty, Keith T / Conley, Christine / Mier, James W / Atkins, Michael B / McDermott, David F. ·Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA; rsullivan7@partners.org. · Dana-Farber Cancer Institute, Boston, Massachusetts, USA; · Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA; · Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; · Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., USA. ·Oncologist · Pubmed #25986244.

ABSTRACT: LESSONS LEARNED: This study is a rare example of effective doses of both targeted agents being both administered and tolerated.This combination should not be used in melanoma. BACKGROUND: Sorafenib and bortezomib affect BCL family member expression. We previously demonstrated that bortezomib augmented sorafenib-mediated cytotoxicity in melanoma cell lines in vitro. We aimed to combine sorafenib 400 mg b.i.d. with increasing doses of weekly bortezomib. METHODS: Patients with metastatic melanoma were enrolled in dose-escalation cohorts to determine the maximum tolerated dose (MTD) of sorafenib (twice daily) in combination with bortezomib (weekly for 3 of 4 weeks). The MTD was defined as the highest dose level at which less than 33% of patients exhibited a dose-limiting toxicity (DLT). Efficacy, as measured by 6-month progression-free survival and response rate per RECIST, was documented. RESULTS: Eleven patients were enrolled at three dose levels. DLTs (fatigue and rash) were seen in two of three patients at the highest dose level. Five patients were enrolled for sorafenib 400 mg b.i.d. and bortezomib 1.0 mg/m(2) weekly for 3 of every 4 weeks; none had DLTs, and this dose level was defined as the MTD. Of 10 evaluable patients, no responses were seen. Two of 11 patients (18%) remained progression free for longer than 6 months. CONCLUSION: The combination of sorafenib and bortezomib is safe but not active in patients with melanoma.

11 Clinical Trial Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition. 2015

Carvajal, Richard D / Lawrence, Donald P / Weber, Jeffrey S / Gajewski, Thomas F / Gonzalez, Rene / Lutzky, Jose / O'Day, Steven J / Hamid, Omid / Wolchok, Jedd D / Chapman, Paul B / Sullivan, Ryan J / Teitcher, Jerrold B / Ramaiya, Nikhil / Giobbie-Hurder, Anita / Antonescu, Cristina R / Heinrich, Michael C / Bastian, Boris C / Corless, Christopher L / Fletcher, Jonathan A / Hodi, F Stephen. ·Memorial Sloan Kettering Cancer Center, New York, New York. Weill Medical College of Cornell University, New York, New York. · Massachusetts General Hospital, Boston, Massachusetts. · H. Lee Moffitt Cancer Center, Tampa, Florida. · The University of Chicago, Chicago, Illinois. · The University of Colorado Cancer Center, Aurora, Colorado. · Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida. · Beverly Hills Cancer Center, Beverly Hills, California. · Angeles Clinic and Research Institute, Los Angeles, California. · Memorial Sloan Kettering Cancer Center, New York, New York. · Dana Farber Cancer Institute, Boston, Massachusetts. · Oregon Health and Science University, Portland, Oregon. · The University of California San Francisco, San Francisco, California. · Dana Farber Cancer Institute, Boston, Massachusetts. Stephen_hodi@dfci.harvard.edu. ·Clin Cancer Res · Pubmed #25695690.

ABSTRACT: PURPOSE: Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown. EXPERIMENTAL DESIGN: We conducted a phase II study of nilotinib 400 mg twice a day in two cohorts of patients with melanomas harboring KIT mutations or amplification: (A) those refractory or intolerant to a prior KIT inhibitor; and (B) those with brain metastases. The primary endpoint was 4-month disease control rate. Secondary endpoints included response rate, time-to-progression (TTP), and overall survival (OS). A Simon two-stage and a single-stage design was planned to assess for the primary endpoint in cohorts A and B, respectively. RESULTS: Twenty patients were enrolled and 19 treated (11 in cohort A; 8 in cohort B). Three patients on cohort A [27%; 95% confidence interval (CI), 8%-56%] and 1 on cohort B (12.5%; 90% CI, 0.6%-47%) achieved the primary endpoint. Two partial responses were observed in cohort A (18.2%; 90% CI, 3%-47%); none were observed in cohort B. The median TTP and OS was 3.3 (90% CI, 2.1-3.9 months) and 9.1 months (90% CI, 4.3-14.2 months), respectively, in all treated patients. CONCLUSIONS: Nilotinib may achieve disease control in patients with melanoma harboring KIT alterations and whose disease progressed after imatinib therapy. The efficacy of this agent in KIT-altered melanoma with brain metastasis is limited.

12 Clinical Trial Metabolic response by FDG-PET to imatinib correlates with exon 11 KIT mutation and predicts outcome in patients with mucosal melanoma. 2014

Zukotynski, Katherine / Yap, Jeffrey T / Giobbie-Hurder, Anita / Weber, Jeffrey / Gonzalez, Rene / Gajewski, Thomas F / O'Day, Steven / Kim, Kevin / Hodi, F Stephen / Van den Abbeele, Annick D. · ·Cancer Imaging · Pubmed #25609545.

ABSTRACT: BACKGROUND: In patients with metastatic melanoma and KIT amplifications and/or mutations, therapy with imatinib mesylate may prolong survival. 18F-labeled 2-fluoro-2-deoxy-D-glucose (18F-FDG) PET/CT may be used to assess metabolic response. We investigated associations of metabolic response, mutational status, progression-free survival and overall survival in this population. METHODS: Baseline and 4-week follow-up 18F-FDG-PET/CT were evaluated in 17 patients with metastatic melanoma and KIT amplifications and/or mutations treated with imatinib in a multicenter phase II clinical trial. The maximum standardized uptake values (SUVmax) were measured in up to 10 lesions on each scan. Metabolic response was classified using modified EORTC criteria. Each patient had a diagnostic CT or MR at baseline, after 6 weeks of therapy and then at intervals of 2 months and anatomic response was classified using RECIST 1.0. Median follow-up was 9.8 months. RESULTS: Partial metabolic response (PMR), stable metabolic disease (SMD) and progressive metabolic disease (PMD) was seen in 5 (29%), 5 (29%), and 7 (41%) patients respectively. Five patients (29%) had a KIT mutation in exon 11, four of whom (80%) had PMR while 1 (20%) had SMD. Twelve patients (71%) did not have a KIT mutation in exon 11, and only 1 (8%) had PMR, 4 (33%) had SMD and 7 (58%) had PMD. There was agreement of metabolic and anatomic classification in 12 of 17 patients (71%). Four of 17 patients (24%) had PR on both metabolic and anatomic imaging and all had a KIT mutation in exon 11. Survival of patients with PMD was lower than with SMD or PMR. CONCLUSIONS: Metabolic response by 18F-FDG-PET/CT is associated with mutational status in metastatic melanoma patients treated with imatinib. 18F-FDG-PET/CT may be a predictor of outcome, although a larger study is needed to verify this. CLINICAL TRIAL REGISTRATION: NCT00424515.

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

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

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

14 Clinical Trial Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. 2013

Hodi, F Stephen / Corless, Christopher L / Giobbie-Hurder, Anita / Fletcher, Jonathan A / Zhu, Meijun / Marino-Enriquez, Adrian / Friedlander, Philip / Gonzalez, Rene / Weber, Jeffrey S / Gajewski, Thomas F / O'Day, Steven J / Kim, Kevin B / Lawrence, Donald / Flaherty, Keith T / Luke, Jason J / Collichio, Frances A / Ernstoff, Marc S / Heinrich, Michael C / Beadling, Carol / Zukotynski, Katherine A / Yap, Jeffrey T / Van den Abbeele, Annick D / Demetri, George D / Fisher, David E. ·F. Stephen Hodi, Anita Giobbie-Hurder, Philip Friedlander, Jason J. Luke, Katherine A. Zukotynski, Jeffrey T. Yap, Annick D. Van den Abbeele, and George D. Demetri, Dana-Farber Cancer Institute · Jonathan A. Fletcher, Meijun Zhu, and Adrian Marino-Enriquez, Brigham and Women's Hospital · Donald Lawrence, Keith T. Flaherty, and David E. Fisher, Massachusetts General Hospital, Boston, MA · Christopher L. Corless, Michael C. Heinrich, and Carol Beadling, Portland Veterans Administration Medical Center and Oregon Health & Science University, Portland, OR · Philip Friedlander, Mount Sinai Medical Center, New York, NY · Rene Gonzalez, University of Colorado Cancer Center, Aurora, CO · Jeffrey S. Weber, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL · Thomas F. Gajewski, University of Chicago, Chicago, IL · Steven J. O'Day, Beverly Hills Cancer Center, Beverly Hills, CA · Kevin B. Kim, The University of Texas MD Anderson Cancer Center, Houston, TX · Frances A. Collichio, The University of North Carolina at Chapel Hill, Chapel Hill, NC · and Marc S. Ernstoff, Geisel School of Medicine and Norris Cotton Cancer Center, Hanover, NH. ·J Clin Oncol · Pubmed #23775962.

ABSTRACT: PURPOSE: Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities. PATIENTS AND METHODS: We conducted a multicenter phase II trial of imatinib in metastatic mucosal, acral, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations. Patients received imatinib 400 mg once per day or 400 mg twice per day if there was no initial response. Dose reductions were permitted for treatment-related toxicities. Additional oncogene mutation screening was performed by mass spectroscopy. RESULTS: Twenty-five patients were enrolled (24 evaluable). Eight patients (33%) had tumors with KIT mutations, 11 (46%) with KIT amplifications, and five (21%) with both. Median follow-up was 10.6 months (range, 3.7 to 27.1 months). Best overall response rate (BORR) was 29% (21% excluding nonconfirmed responses) with a two-stage 95% CI of 13% to 51%. BORR was significantly greater than the hypothesized null of 5% and statistically significantly different by mutation status (7 of 13 or 54% KIT mutated v 0% KIT amplified only). There were no statistical differences in rates of progression or survival by mutation status or by melanoma site. The overall disease control rate was 50% but varied significantly by KIT mutation status (77% mutated v 18% amplified). Four patients harbored pretreatment NRAS mutations, and one patient acquired increased KIT amplification after treatment. CONCLUSION: Melanomas that arise on mucosal, acral, or CSD skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.

15 Article Immunity to X-linked inhibitor of apoptosis protein (XIAP) in malignant melanoma and check-point blockade. 2019

Zhou, Jun / Li, Jingjing / Guleria, Indira / Chen, Tianqi / Giobbie-Hurder, Anita / Stevens, Jonathan / Gupta, Meghna / Wu, Xinqi / Brennick, Ryan C / Manos, Michael P / Hodi, F Stephen. ·Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. · Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. · Center for Immuno-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. · Tissue Typing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. · Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. stephen_hodi@dfci.harvard.edu. · Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. stephen_hodi@dfci.harvard.edu. · Center for Immuno-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. stephen_hodi@dfci.harvard.edu. · Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA. stephen_hodi@dfci.harvard.edu. ·Cancer Immunol Immunother · Pubmed #31317218.

ABSTRACT: Expression of inhibitors of apoptosis protein (IAP) family members is associated with poor prognosis in cancer patients. Immunity to ML-IAP (livin) and survivin has been well studied in patients with a variety of tumors. XIAP, the most potent inhibitor of apoptosis, is widely expressed in melanoma. To better define its potential role as an immunogenic target, cellular and humoral responses to XIAP were investigated in patients with advanced melanoma. An overlapping peptide library covering the full length of the XIAP protein was used to screen T cell responses of peripheral blood mononuclear cells (PBMC) from stage-IV melanoma patients treated with or without anti-CTLA4 (ipilimumab). The screen identified an array of peptides that predominantly induced CD4

16 Article Clinical experience with combination BRAF/MEK inhibitors for melanoma with brain metastases: a real-life multicenter study. 2019

Drago, Joshua Z / Lawrence, Donald / Livingstone, Elisabeth / Zimmer, Lisa / Chen, Tianqi / Giobbie-Hurder, Anita / Amann, Valerie C / Mangana, Joanna / Siano, Marco / Zippelius, Alfred / Dummer, Reinhard / Goldinger, Simone M / Sullivan, Ryan J. ·Massachusetts General Hospital Cancer Center. · Department of Dermatology, Essen University Hospital, Essen, Germany. · Dana Farber Cancer Institute, Boston, USA. · Department of Dermatology, University Hospital Zurich, Zurich. · Department of Dermatology, University Hospital of Basel, Basel, Switzerland. · Department of Medical Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen. · Department of Biomedicine. ·Melanoma Res · Pubmed #30376465.

ABSTRACT: BRAF and MEK kinase inhibitors can be highly effective in treating BRAF-mutant melanomas, but their safety and activity in patients with active/symptomatic brain metastases are unclear. We sought to shed light on this open clinical question. We conducted a multicenter retrospective study on real-life patients with melanoma and active brain metastases treated with combination BRAF/MEK inhibitors. A total of 65 patients were included (38 men and 27 women; median age: 49 years). Of them, 53 patients received dabrafenib/trametinib, 10 received vemurafenib/cobimetinib, one received encorafenib/binimetinib, and one received vemurafenib/trametinib. We did not observe any unexpected treatment-related safety signals in our cohort. Overall, 17 patients continued on therapy through the cutoff date. After initiation of therapy, steroid dose could be decreased in 22 of 33 patients (11 tapered off entirely), anticonvulsants were stopped in four of 21, and narcotics were stopped in four of 12. Median progression-free survival from the start of therapy was 5.3 months (95% confidence interval: 3.6-6.1), and median overall survival was 9.5 months (95% confidence interval: 7.7-13.5). A total of 20 patients were surviving at the cutoff date. Univariate analysis of age, sex, ulceration status, thickness, stage, location, or lactate dehydrogenase did not reveal significant predictors of progression-free survival or overall survival within our cohort, but multivariate analysis suggested that older age, lower risk location of original lesion, and nodular melanoma are poor prognostic indicators. Combination therapy with BRAF/MEK inhibitors is a viable treatment option for patients with BRAF-mutant melanoma and brain metastases, but further studies should help to define the optimal treatment approach in this population.

17 Article Molecular signatures of circulating melanoma cells for monitoring early response to immune checkpoint therapy. 2018

Hong, Xin / Sullivan, Ryan J / Kalinich, Mark / Kwan, Tanya Todorova / Giobbie-Hurder, Anita / Pan, Shiwei / LiCausi, Joseph A / Milner, John D / Nieman, Linda T / Wittner, Ben S / Ho, Uyen / Chen, Tianqi / Kapur, Ravi / Lawrence, Donald P / Flaherty, Keith T / Sequist, Lecia V / Ramaswamy, Sridhar / Miyamoto, David T / Lawrence, Michael / Toner, Mehmet / Isselbacher, Kurt J / Maheswaran, Shyamala / Haber, Daniel A. ·Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114. · Division of Hematology-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. · Division of Biostatistics, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215. · Center for Bioengineering in Medicine, Massachusetts General Hospital and Shriners Hospital for Children, Harvard Medical School, Boston, MA 02114. · Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114; kisselbacher@mgh.harvard.edu maheswaran@helix.mgh.harvard.edu dhaber@mgh.harvard.edu. · Howard Hughes Medical Institute, Chevy Chase, MD 20815. ·Proc Natl Acad Sci U S A · Pubmed #29453278.

ABSTRACT: A subset of patients with metastatic melanoma have sustained remissions following treatment with immune checkpoint inhibitors. However, analyses of pretreatment tumor biopsies for markers predictive of response, including PD-1 ligand (PD-L1) expression and mutational burden, are insufficiently precise to guide treatment selection, and clinical radiographic evidence of response on therapy may be delayed, leading to some patients receiving potentially ineffective but toxic therapy. Here, we developed a molecular signature of melanoma circulating tumor cells (CTCs) to quantify early tumor response using blood-based monitoring. A quantitative 19-gene digital RNA signature (CTC score) applied to microfluidically enriched CTCs robustly distinguishes melanoma cells, within a background of blood cells in reconstituted and in patient-derived (

18 Article Immune-Related Tumor Response Dynamics in Melanoma Patients Treated with Pembrolizumab: Identifying Markers for Clinical Outcome and Treatment Decisions. 2017

Nishino, Mizuki / Giobbie-Hurder, Anita / Manos, Michael P / Bailey, Nancy / Buchbinder, Elizabeth I / Ott, Patrick A / Ramaiya, Nikhil H / Hodi, F Stephen. ·Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts. Mizuki_Nishino@dfci.harvard.edu. · Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts. · Department of Medicine, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts. · Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts. ·Clin Cancer Res · Pubmed #28592629.

ABSTRACT:

19 Article Impact of Age on Outcomes with Immunotherapy for Patients with Melanoma. 2017

Betof, Allison S / Nipp, Ryan D / Giobbie-Hurder, Anita / Johnpulle, Romany A N / Rubin, Krista / Rubinstein, Samuel M / Flaherty, Keith T / Lawrence, Donald P / Johnson, Douglas B / Sullivan, Ryan J. ·Massachusetts General Hospital Cancer Center & Harvard Medical School, Boston, Massachusetts, USA. · Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Massachusetts General Hospital Cancer Center & Harvard Medical School, Boston, Massachusetts, USA RSULLIVAN7@mgh.harvard.edu. ·Oncologist · Pubmed #28476944.

ABSTRACT: BACKGROUND: Monoclonal antibodies (mAb) targeting PD-1/PD-L1 have revolutionized melanoma treatment, yet data regarding effectiveness and tolerability across age groups is limited. We sought to determine the impact of age on overall survival (OS), progression-free survival (PFS), and rates of immune-mediated toxicities in patients treated with anti-PD-1/anti-PD-L1 mAb at two academic medical centers. METHODS: We retrospectively collected data on all patients with metastatic melanoma treated with anti-PD-1/PD-L1 mAb between May 2009 and April 2015. We used Kaplan-Meier and Cox regression analyses to assess OS and PFS and identify factors associated with these outcomes. We also compared rates of autoimmune toxicity across age groups. RESULTS: Of 254 patients, 57 (22.4%) were <50 years old, 85 (33.5%) were age 50-64, 65 (25.6%) were age 65-74, and 47 (18.5%) were ≥75 years. Across age groups, no differences existed in median OS (age <50: 22.9 months, age 50-64: 25.3 months, age 65-74: 22.0 months, age ≥75: 24.3 months) or PFS (age <50: 4.1 months, age 50-64: 6.5 months, age 65-74: 5.4 months, age ≥75: 7.9 months). The presence of liver metastases and elevated pre-treatment lactate dehydrogenase (LDH) were associated with reduced OS. Presence of liver metastasis, pretreatment LDH, BRAF mutation, and type of melanoma correlated with PFS. Overall, 110 patients (43.3%) experienced immune-mediated toxicities; 25 (9.8%) had colitis and 26 (10.2%) had endocrine toxicity. Rates of colitis, hepatitis, and pneumonitis did not differ across age groups. CONCLUSION: We demonstrated that patients could safely tolerate anti-PD1/PDL-1 mAb therapy and achieve similar outcomes regardless of their age. IMPLICATIONS FOR PRACTICE: Immunotherapy has revolutionized treatment for patients with metastatic melanoma, yet data are lacking regarding the effectiveness and tolerability of these treatments for older patients. In this study, we demonstrated that patients with melanoma safely tolerate immunotherapy and achieve similar outcomes regardless of their age. Specifically, we utilized data from two academic cancer centers and found no significant difference in overall survival, progression free survival, or immune-related toxicities, other than arthritis, across age groups. As the population ages, studies such as this will become critical to help us understand how best to treat older adults with cancer.

20 Article A Retrospective Analysis of the Efficacy of Pembrolizumab in Melanoma Patients With Brain Metastasis. 2017

Dagogo-Jack, Ibiayi / Lanfranchi, Michael / Gainor, Justin F / Giobbie-Hurder, Anita / Lawrence, Donald P / Shaw, Alice T / Sullivan, Ryan J. ·*Massachusetts General Hospital Cancer Center †Department of Radiology, Massachusetts General Hospital, Harvard Medical School ‡Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA. ·J Immunother · Pubmed #28221189.

ABSTRACT: A total of 50% of patients with melanoma will develop brain metastasis (BM). Pembrolizumab was approved for treatment of metastatic melanoma on the basis of significant systemic antitumor activity. Because of low enrollment of patients with BM in pembrolizumab trials, efficacy against melanoma BM remains unknown. We reviewed records of 89 consecutive patients with melanoma treated with pembrolizumab at our institution between May 1, 2014 and October 31, 2015 to determine the time to progression. Thirty-six (40%) patients had BM before pembrolizumab. Twenty-six (72%) patients with BM had received prior treatment for BM. With median follow-up of 17.2 months, 54 patients (61%) developed progressive disease on pembrolizumab. Intracranial progression occurred in 19 patients (21%), 3 of whom did not have BM before treatment. Median time to progression at any site was 6 months for those without BM (n=53), 5 months for those with treated BM (n=26), and 1.2 months for patients with untreated BM (n=10). Using a Cox regression model adjusted for baseline factors, there was a statistically significant (Wald χ P=0.003) reduction in the hazard of progression for patients without BM [hazard ratio, 0.19; 90% confidence interval, 0.08-0.42) and patients with treated BM (hazard ratio, 0.27; 90% confidence interval, 0.12-0.64) compared with those with untreated BM. In conclusion, melanoma patients with pretreated BM can have durable systemic responses to pembrolizumab. Large, prospective studies are needed to evaluate the intracranial antitumor activity of pembrolizumab in melanoma patients with untreated BM.

21 Article Single Institution Experience of Ipilimumab 3 mg/kg with Sargramostim (GM-CSF) in Metastatic Melanoma. 2015

Luke, Jason J / Donahue, Hilary / Nishino, Mizuki / Giobbie-Hurder, Anita / Davis, Meredith / Bailey, Nancy / Ott, Patrick A / Hodi, F Stephen. ·Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois. jluke@medicine.bsd.uchicago.edu. · Melanoma Disease Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Radiology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. · Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Melanoma Disease Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. ·Cancer Immunol Res · Pubmed #25943535.

ABSTRACT: Ipilimumab, 10 mg/kg with sargramostim (GM-CSF; GM), improved overall survival (OS) and safety of patients with advanced melanoma over ipilimumab in a randomized phase II trial. The FDA-approved dose of ipilimumab of 3 mg/kg has not been assessed with GM (IPI-GM). Consecutive patients treated with IPI-GM at a single institution were reviewed. Treatment included ipilimumab every 3 weeks × 4 and GM, 250-μg s.c. injection days 1 to 14 of each ipilimumab cycle. Efficacy, clinical characteristics, toxicities, and blinded radiology review of tumor burden were evaluated. Thirty-two patients were identified with 25 (78%) having immune-related response criteria (irRC) measurable disease and 41% with central nervous system metastases. A total of 88.6% of GM doses were administered. Response rate by irRC and disease control rate at 12 weeks were 20% and 44%, respectively (median follow-up 37 weeks). Immune-related adverse events (irAE) were observed in 10 (31.3%) patients, with 3 (9.4%) grade 3 events. Patients with grade 3 irAEs had prior autoimmunity, advanced age, and poor performance status. The median OS from first dose of ipilimumab was 41 weeks. Ipi-GM treatment is feasible and in this poor-risk advanced melanoma population, efficacy appeared similar but safety appeared improved relative to historical ipilimumab alone.

22 Article Systemic high-dose corticosteroid treatment does not improve the outcome of ipilimumab-related hypophysitis: a retrospective cohort study. 2015

Min, Le / Hodi, Frank Stephen / Giobbie-Hurder, Anita / Ott, Patrick A / Luke, Jason J / Donahue, Hilary / Davis, Meredith / Carroll, Rona S / Kaiser, Ursula B. ·Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts. lmin1@partners.org. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Melanoma and Developmental Therapeutics Clinics, University of Chicago, Chicago, Illinois. · Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts. ·Clin Cancer Res · Pubmed #25538262.

ABSTRACT: PURPOSE: To examine the onset and outcome of ipilimumab-related hypophysitis and the response to treatment with systemic high-dose corticosteroids (HDS). EXPERIMENTAL DESIGN: Twenty-five patients who developed ipilimumab-related hypophysitis were analyzed for the incidence, time to onset, time to resolution, frequency of resolution, and the effect of systemic HDS on clinical outcome. To calculate the incidence, the total number (187) of patients with metastatic melanoma treated with ipilimumab at Dana-Farber Cancer Institute (DFCI; Boston, MA) was retrieved from the DFCI oncology database. Comparisons between corticosteroid treatment groups were performed using the Fisher exact test. The distributions of overall survival were based on the method of Kaplan-Meier. RESULTS: The overall incidence of ipilimumab-related hypophysitis was 13%, with a higher rate in males (16.1%) than females (8.7%). The median time to onset of hypophysitis after initiation of ipilimumab treatment was 9 weeks (range, 5-36 weeks). Resolution of pituitary enlargement, secondary adrenal insufficiency, secondary hypothyroidism, male secondary hypogonadism, and hyponatremia occurred in 73%, 0%, 64%, 45%, and 92% of patients, respectively. Systemic HDS treatment did not improve the outcome of hypophysitis as measured by resolution frequency and time to resolution. One-year overall survival in the cohort of patients was 83%, and while it was slightly higher in patients who did not receive HDS, there was no statistically significant difference between treatment arms. CONCLUSION: Systemic HDS therapy in patients with ipilimumab-related hypophysitis may not be indicated. Instead, supportive treatment of hypophysitis-related hormone deficiencies with the corresponding hormone replacement should be given.

23 Article Immunity to the vacuolar ATPase complex accessory unit ATP6S1 in patients with malignant melanoma. 2015

Zhou, Jun / Gupta, Meghna / Wu, Xinqi / Yoon, Charles / Giobbie-Hurder, Anita / Hodi, F Stephen. ·Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Center for Immuno-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts. · Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Center for Immuno-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Center for Immuno-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. stephen_hodi@dfci.harvard.edu. ·Cancer Immunol Res · Pubmed #25387894.

ABSTRACT: The augmentation of high-titer antibodies to ATP6S1 is associated with favorable clinical outcomes in patients who received vaccination with autologous, irradiated tumor cells engineered to secrete GM-CSF and allogeneic bone marrow transplantation. Cellular immune responses to ATP6S1 are unknown. To define its role as an immune target, examination of cellular responses to ATP6S1 and immunity related to current therapies such as checkpoint blockade is needed. We used an overlapping peptide library representing the full-length ATP6S1 protein to screen for cellular responses from the peripheral blood of patients with stage III and IV melanoma. Reactive peptide pools were used to determine the individual peptide activity and epitopes. Recombinant ATP6S1 protein was used in an ELISA to assess potential correlation with humoral immune responses and changes in immunity related to CTLA-4 blockade with ipilimumab in these patients. We observed a broad array of CD4(+) and CD8(+) cellular responses against ATP6S1, including the identification of several MHC class I and II ATP6S1 epitopes. The generation of specific CD4(+) and cytotoxic T cells revealed potent functional capability elicited by ipilimumab treatment in patients with metastatic melanoma, which revealed potent functional capability, including cytokine production, proliferation responsiveness to melanoma cell lines, and tumor-cell killing. Furthermore, the augmented humoral immune responses to ATP6S1 as a function of ipilimumab treatment were associated with beneficial clinical outcomes. These results support the continued development of ATP6S1 as a biomarker and therapeutic target.

24 Article Clinical utility of a blood-based BRAF(V600E) mutation assay in melanoma. 2014

Panka, David J / Buchbinder, Elizabeth / Giobbie-Hurder, Anita / Schalck, Aislyn P / Montaser-Kouhsari, Laleh / Sepehr, Alireza / Lawrence, Donald P / McDermott, David F / Cohen, Rachel / Carlson, Alexander / Wargo, Jennifer A / Merritt, Ryan / Seery, Virginia J / Hodi, F Stephen / Gunturi, Anasuya / Fredrick, Dennie / Atkins, Michael B / Iafrate, A John / Flaherty, Keith T / Mier, James W / Sullivan, Ryan J. ·Beth Israel Deaconess Medical Center, Boston, Massachusetts. dpanka@bidmc.harvard.edu. · Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Dana-Farber Cancer Institute, Boston, Massachusetts. · Massachusetts General Hospital, Boston, Massachusetts. · MD Anderson Cancer Center, Houston, Texas. · Georgetown-Lombardi Comprehensive Cancer Center, Washington, District of Columbia. ·Mol Cancer Ther · Pubmed #25319388.

ABSTRACT: BRAF inhibitors (BRAFi) have led to clinical benefit in patients with melanoma. The development of a blood-based assay to detect and quantify BRAF levels in these patients has diagnostic, prognostic, and predictive capabilities that could guide treatment decisions. Blood BRAF(V600E) detection and quantification were performed on samples from 128 patients with stage II (19), III (67), and IV (42) melanoma. Tissue BRAF analysis was performed in all patients with stage IV disease and in selected patients with stage II and III disease. Clinical outcomes were correlated to initial BRAF levels as well as BRAF level dynamics. Serial analysis was performed on 17 stage IV melanoma patients treated with BRAFi and compared with tumor measurements by RECIST. The assay was highly sensitive (96%) and specific (95%) in the stage IV setting, using a blood level of 4.8 pg as "positive." BRAF levels typically decreased following BRAFi. A subset of these patients (5) had an increase in BRAF(V600E) values 42 to 112 days before clinical or radiographic disease progression (PD). From 86 patients with resected, stage II or III melanoma, 39 had evidence of disease relapse (45.3%). Furthermore, BRAF mutation in the blood after surgical resection in these patients was not associated with a difference in relapse risk, although tissue BRAF status was only available for a subset of patients. In summary, we have developed a highly sensitive and specific, blood-based assay to detect BRAF(V600) mutation in patients with melanoma.

25 Article Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience. 2013

Luke, Jason J / Callahan, Margaret K / Postow, Michael A / Romano, Emanuela / Ramaiya, Nikhil / Bluth, Mark / Giobbie-Hurder, Anita / Lawrence, Donald P / Ibrahim, Nageatte / Ott, Patrick A / Flaherty, Keith T / Sullivan, Ryan J / Harding, James J / D'Angelo, Sandra / Dickson, Mark / Schwartz, Gary K / Chapman, Paul B / Wolchok, Jedd D / Hodi, F Stephen / Carvajal, Richard D. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. ·Cancer · Pubmed #23913718.

ABSTRACT: BACKGROUND: Uveal melanoma exhibits a high incidence of metastases; and, to date, there is no systemic therapy that clearly improves outcomes. The anticytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab is a standard of care for metastatic melanoma; however, the clinical activity of CTLA-4 inhibition in patients with metastatic uveal melanoma is poorly defined. METHODS: To assess ipilimumab in this setting, the authors performed a multicenter, retrospective analysis of 4 hospitals in the United States and Europe. Clinical characteristics, toxicities, and radiographic disease burden, as determined by central, blinded radiology review, were evaluated. RESULTS: Thirty-nine patients with uveal melanoma were identified, including 34 patients who received 3 mg/kg ipilimumab and 5 who received 10 mg/kg ipilimumab. Immune-related response criteria and modified World Health Organization criteria were used to assess the response rate (RR) and the combined response plus stable disease (SD) rate after 12 weeks, after 23 weeks, and overall (median follow-up, 50.4 weeks [12.6 months]). At week 12, the RR was 2.6%, and the response plus SD rate was 46.%; at week 23, the RR was 2.6%, and the response plus SD rate was 28.2%. There was 1 complete response and 1 late partial response (at 100 weeks after initial SD) for an immune-related RR of 5.1%. Immune-related adverse events were observed in 28 patients (71.8%) and included 7 (17.9%) grade 3 and 4 events. Immune-related adverse events were more frequent in patients who received 10 mg/kg ipilimumab than in those who received 3 mg/kg ipilimumab. The median overall survival from the first dose of ipilimumab was 9.6 months (95% confidence interval, 6.3-13.4 months; range, 1.6-41.6 months). Performance status, lactate dehydrogenase level, and an absolute lymphocyte count ≥ 1000 cells/μL at week 7 were associated significantly with survival. CONCLUSIONS: In this multicenter, retrospective analysis of 4 hospitals in the United States and Europe of patients with uveal melanoma, durable responses to ipilimumab and manageable toxicity were observed.

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