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Healthcare Resource Utilization and Associated Costs in Patients with Advanced Melanoma Receiving First-Line Ipilimumab  [PDF]
Ahmad Tarhini, Shelby L. Corman, Sumati Rao, Kim Margolin, Xiang Ji, Sonam Mehta, Marc F. Botteman
Journal of Cancer Therapy (JCT) , 2015, DOI: 10.4236/jct.2015.610091
Abstract: Background: To describe healthcare costs, excluding ipilimumab drug costs, in patients with advanced melanoma receiving ipilimumab in the US community practice setting. Methods: This was a retrospective chart review of unresectable stage III/IV melanoma patients who received first-line ipilimumab monotherapy between 04/2011 and 09/2012. Healthcare resource utilization included inpatient, emergency, specialist and hospice visits, laboratory tests, radiation, surgeries, and nursing home stays. Publicly available US unit costs were applied to each resource type to estimate costs, which were analyzed by time periods: during ipilimumab treatment, post-ipilimumab treatment (post-regimen), and within 90 days prior to death (pre-death). Generalized linear mixed models were used to explore cost predictors during the treatment period, on a per-dose-interval basis, defined as the time between ipilimumab doses. Results: Data were abstracted from 273 patient charts at 34 sites. Excluding ipilimumab drug costs, total monthly costs during the treatment regimen, post-regimen, and pre-death periods were $690, $2151, and $5123, respectively. Total healthcare costs were 27 times higher during dose intervals with a grade 3/4 adverse event compared with intervals without a grade 3/4 adverse event. Eastern Cooperative Oncology Group performance status ≥ 2 (vs 0) was also associated with significantly higher cost per dose interval. Conclusions: In this population, monthly costs exclusive of drug were significantly lower during the treatment period than in subsequent periods. Unfavorable ECOG PS was associated with significant increases in cost per dose interval. Grade 3/4 adverse events were associated with a marked increase in healthcare costs, but occurred in a small proportion of dose intervals.
Health related quality of life outcomes for unresectable stage III or IV melanoma patients receiving ipilimumab treatment
Dennis A Revicki, Alfons J M van den Eertwegh, Paul Lorigan, Celeste Lebbe, Gerald Linette, Christian H Ottensmeier, Shima Safikhani, Marianne Messina, Axel Hoos, Samuel Wagner, Srividya Kotapati
Health and Quality of Life Outcomes , 2012, DOI: 10.1186/1477-7525-10-66
Abstract: The Phase III clinical trial (MDX010-20) was a double-blind, fixed dose study in 676 previously treated advanced unresectable stage III or IV melanoma patients. Patients were randomized 3:1:1 to receive either ipilimumab (3?mg/kg q3w x 4 doses)?+?gp100 (peptide vaccine; 1?mg q3w x 4 doses; ipilimumab plus gp100, n?=?403); gp100 vaccine?+?placebo (gp100 alone, n?=?136); or ipilimumab?+?placebo (ipilimumab alone, n?=?137). The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) assessed HRQL. Baseline to Week 12 changes in EORTC QLQ-C30 function, global health status, and symptom scores were analyzed for ipilimumab with/without gp100 vaccine compared to gp100 alone. Mean change in scores were categorized “no change” (0–5), “a little” (5–10 points), “moderate” (10–20 points), and “very much” (>20).In the ipilimumab plus gp100 and ipilimumab alone groups, mean changes from baseline to Week 12 generally indicated “no change” or “a little” impairment across EORTC QLQ-C30 global health status, function, and symptom subscales. Significant differences in constipation, favoring ipilimumab, were observed (p?<?0.05). For ipilimumab alone arm, subscales with no or a little impairment were physical, emotional, cognitive, social function, global health, nausea, pain, dyspnea, constipation, and diarrhea subscales. For the gp100 alone group, the observed changes were moderate to large for global health, role function, fatigue, and for pain.Ipilimumab with/without gp100 vaccine does not have a significant negative HRQL impact during the treatment induction phase relative to gp100 alone in stage III or IV melanoma patients.Clinicaltrials.gov identification number NCT00094653
Immune Monitoring of the Circulation and the Tumor Microenvironment in Patients with Regionally Advanced Melanoma Receiving Neoadjuvant Ipilimumab  [PDF]
Ahmad A. Tarhini, Howard Edington, Lisa H. Butterfield, Yan Lin, Yongli Shuai, Hussein Tawbi, Cindy Sander, Yan Yin, Matthew Holtzman, Jonas Johnson, Uma N. M. Rao, John M. Kirkwood
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0087705
Abstract: We evaluated neoadjuvant ipilimumab in patients with surgically operable regionally advanced melanoma in order to define markers of activity in the blood and tumor as assessed at baseline (before ipilimumab) and early on-treatment. Patients were treated with ipilimumab (10 mg/kg intravenously every 3 weeks ×2 doses) bracketing surgery. Tumor and blood biospecimens were obtained at baseline and at surgery. Flow cytometry and immunohistochemistry for select biomarkers were performed. Thirty five patients were enrolled; IIIB (3; N2b), IIIC (32; N2c, N3), IV (2). Worst toxicities included Grade 3 diarrhea/colitis (5; 14%), hepatitis (2; 6%), rash (1; 3%), elevated lipase (3; 9%). Median follow up was 18 months: among 33 evaluable patients, median progression free survival (PFS) was 11 months, 95% CI (6.2–19.2). There was a significant decrease in circulating myeloid derived suppressor cells (MDSC). Greater decrease in circulating monocyte gate MDSC Lin1?/HLA-DR?/CD33+/CD11b+ was associated with improved PFS (p = 0.03). There was a significant increase in circulating regulatory T cells (Treg; CD4+CD25hi+Foxp3+) that, unexpectedly, was associated with improved PFS (HR = 0.57; p = 0.034). Baseline evidence of fully activated type I CD4+ and CD8+ antigen-specific T cell immunity against cancer-testis (NY-ESO-1) and melanocytic lineage (MART-1, gp100) antigens was detected and was significantly potentiated after ipilimumab. In tumor, there was a significant increase in CD8+ T cells after ipilimumab (p = 0.02). Ipilimumab induced increased tumor infiltration by fully activated (CD69+) CD3+/CD4+ and CD3+/CD8+ T cells with evidence of induction/potentiation of memory T cells (CD45RO+). The change in Treg observed within the tumor showed an inverse relationship with clinical benefit and greater decrease in tumor MDSC subset Lin1?/HLA-DR?/CD33+/CD11b+ was associated with improved PFS at one year. Neoadjuvant evaluation revealed a significant immunomodulating role for ipilimumab on Treg, MDSC and effector T cells in the circulation and tumor microenvironment that warrants further pursuit in the quest for optimizing melanoma immunotherapy.
Characteristics and management of immune-related adverse effects associated with ipilimumab, a new immunotherapy for metastatic melanoma  [cached]
Andrews S,Holden R
Cancer Management and Research , 2012,
Abstract: Stephanie Andrews,1 Rita Holden21H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 2St Luke's Hospital and Health Network Cancer Center, Easton, PA, USAAbstract: When diagnosed in its early stages, melanoma is highly treatable and associated with good long-term outcomes; however, the prognosis is much poorer for patients diagnosed with advanced or metastatic melanoma. For decades, available treatments were effective in only a few patients and associated with significant safety concerns. Ipilimumab is a novel immunotherapy which has proved to be an exciting breakthrough in the treatment of melanoma. It is the first drug approved for the treatment of melanoma by the Food and Drug Administration (FDA) which has shown a survival benefit in a randomized Phase III clinical trial. The objective of this review is to provide information on the administration, treatment responses, and expected outcomes of treatment of metastatic melanoma with the new immunotherapeutic agent, ipilimumab, a drug with a unique mechanism of action that differentiates it from current treatments. Guidelines for the management of immune-related adverse events associated with ipilimumab therapy are also presented. These stress vigilance, prompt intervention, and the use of corticosteroids as appropriate. Various ipilimumab-associated immune-related adverse events, both common (enterocolitis, dermatitis) and less frequent (hepatitis, hypophysitis), are illustrated in case studies. Nurses are uniquely positioned to provide patient and caregiver education on how this new therapy differs from traditional cytotoxic agents, to recognize the signs and symptoms of immune-related adverse events, and to report them immediately, and finally, to be aware of the patterns of response that are commonly observed in patients receiving ipilimumab therapy.Keywords: melanoma, ipilimumab, immunotherapy, case studies
Characteristics and management of immune-related adverse effects associated with ipilimumab, a new immunotherapy for metastatic melanoma
Andrews S, Holden R
Cancer Management and Research , 2012, DOI: http://dx.doi.org/10.2147/CMAR.S31873
Abstract: racteristics and management of immune-related adverse effects associated with ipilimumab, a new immunotherapy for metastatic melanoma Review (2509) Total Article Views Authors: Andrews S, Holden R Video abstract presented by Stephanie Andrews Views: 330 Published Date September 2012 Volume 2012:4 Pages 299 - 307 DOI: http://dx.doi.org/10.2147/CMAR.S31873 Received: 17 March 2012 Accepted: 14 May 2012 Published: 12 September 2012 Stephanie Andrews,1 Rita Holden2 1H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 2St Luke's Hospital and Health Network Cancer Center, Easton, PA, USA Abstract: When diagnosed in its early stages, melanoma is highly treatable and associated with good long-term outcomes; however, the prognosis is much poorer for patients diagnosed with advanced or metastatic melanoma. For decades, available treatments were effective in only a few patients and associated with significant safety concerns. Ipilimumab is a novel immunotherapy which has proved to be an exciting breakthrough in the treatment of melanoma. It is the first drug approved for the treatment of melanoma by the Food and Drug Administration (FDA) which has shown a survival benefit in a randomized Phase III clinical trial. The objective of this review is to provide information on the administration, treatment responses, and expected outcomes of treatment of metastatic melanoma with the new immunotherapeutic agent, ipilimumab, a drug with a unique mechanism of action that differentiates it from current treatments. Guidelines for the management of immune-related adverse events associated with ipilimumab therapy are also presented. These stress vigilance, prompt intervention, and the use of corticosteroids as appropriate. Various ipilimumab-associated immune-related adverse events, both common (enterocolitis, dermatitis) and less frequent (hepatitis, hypophysitis), are illustrated in case studies. Nurses are uniquely positioned to provide patient and caregiver education on how this new therapy differs from traditional cytotoxic agents, to recognize the signs and symptoms of immune-related adverse events, and to report them immediately, and finally, to be aware of the patterns of response that are commonly observed in patients receiving ipilimumab therapy.
Ipilimumab Pharmacotherapy in Patients with Metastatic Melanoma
Joanne M. Jeter, Lee D. Cranmer and Evan M. Hersh
Clinical Medicine Insights: Oncology , 2012, DOI: 10.4137/CMO.S7245
Abstract: Immune augmentation with ipilimumab, an anti-CTLA-4 monoclonal antibody, has joined the ranks of approved immunologic agents for the treatment of metastatic melanoma. Phase III studies of ipilimumab in metastatic melanoma have demonstrated an overall survival advantage as compared to other approved and investigational therapies. However, the adverse effects associated with this medication are unique and often require management with steroids or other immunosuppressants. In addition, the time to response differs with ipilimumab as compared to traditional chemotherapy, and alternative means of assessment of response have been proposed. In this review, we will summarize the basic science of this treatment, its preclinical evaluation, and the clinical trials leading to its approval. We will also discuss the details regarding its use, assessment of response to this drug and other immune-related therapies, and further directions for investigation.
Profile of ipilimumab and its role in the treatment of metastatic melanoma
Patel SP, Woodman SE
Drug Design, Development and Therapy , 2011, DOI: http://dx.doi.org/10.2147/DDDT.S10945
Abstract: ofile of ipilimumab and its role in the treatment of metastatic melanoma Review (5169) Total Article Views Authors: Patel SP, Woodman SE Published Date December 2011 Volume 2011:5 Pages 489 - 495 DOI: http://dx.doi.org/10.2147/DDDT.S10945 Sapna P Patel, Scott E Woodman Melanoma Medical Oncology Department, University of Texas, MD Anderson Cancer Center, Houston, TX, USA Abstract: Melanoma is an immunogenic cancer. However, the ability of the immune system to eradicate melanoma tumors is affected by intrinsic negative regulatory mechanisms. Multiple immune-modulatory therapies are currently being developed to optimize the immune response to melanoma tumors. Two recent Phase III studies using the monoclonal antibody ipilimumab, which targets the cytotoxic T-lymphocyte antigen (CTLA-4), a negative regulator of T-cell activation, have demonstrated improvement in overall survival of metastatic melanoma patients. This review highlights the clinical trial data that supports the efficacy of ipilimumab, the immune-related response criteria used to evaluate clinical response, and side-effect profile associated with ipilimumab treatment.
Profile of ipilimumab and its role in the treatment of metastatic melanoma  [cached]
Patel SP,Woodman SE
Drug Design, Development and Therapy , 2011,
Abstract: Sapna P Patel, Scott E WoodmanMelanoma Medical Oncology Department, University of Texas, MD Anderson Cancer Center, Houston, TX, USAAbstract: Melanoma is an immunogenic cancer. However, the ability of the immune system to eradicate melanoma tumors is affected by intrinsic negative regulatory mechanisms. Multiple immune-modulatory therapies are currently being developed to optimize the immune response to melanoma tumors. Two recent Phase III studies using the monoclonal antibody ipilimumab, which targets the cytotoxic T-lymphocyte antigen (CTLA-4), a negative regulator of T-cell activation, have demonstrated improvement in overall survival of metastatic melanoma patients. This review highlights the clinical trial data that supports the efficacy of ipilimumab, the immune-related response criteria used to evaluate clinical response, and side-effect profile associated with ipilimumab treatment.Keywords: ipilimumab, melanoma, T-cells, CTLA-4
Ipilimumab: A First-in-Class??T-Cell Potentiator for Metastatic Melanoma  [PDF]
Bartosz Chmielowski
Journal of Skin Cancer , 2013, DOI: 10.1155/2013/423829
Abstract: Ipilimumab, a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody that potentiates antitumor T-cell responses, has demonstrated improved survival in previously treated and treatment-na?ve patients with unresectable stage III/IV melanoma. Survival benefit has also been shown in diverse patient populations, including those with brain metastases. In 2011, ipilimumab (3?mg/kg every 3 weeks for 4 doses) was approved by the Food and Drug Administration for unresectable or metastatic melanoma. Ipilimumab can induce novel response patterns for which immune-related response criteria have been proposed. irAEs are common but are usually low grade; higher grades can be severe and life-threatening. irAEs are usually manageable using established guidelines emphasizing vigilance and prompt intervention. This agent provides an additional therapeutic option in metastatic melanoma, and guidelines for management of adverse events facilitate clinical implementation of this new agent. 1. Introduction The incidence of melanoma has more than tripled in the Caucasian population during the last 20 years, and melanoma currently is the sixth most common cancer in the United States [1]. Recent estimates indicate that approximately 70,230 Americans (40,010 men and 30,220 women) developed invasive cutaneous melanoma in 2011, and 53,360 cases of melanoma in situ will be reported [1]. Although melanoma accounts for only 4% of all skin cancers, it is responsible for approximately 80% of all skin cancer deaths [2] with an estimated 8790 deaths from melanoma in 2011 [3]. For the majority of patients, the diagnosis of melanoma occurs at an early stage; 84% are diagnosed with localized disease. In contrast, for the small percentage of patients with a first diagnosis of unresectable stage III or stage IV or for those who recur with advanced disease, the associated clinical burden is significant and the prognosis is poor. For the 8% of patients diagnosed with stage III disease, 5-year relative survival is 62% [4]. For the 4% of patients diagnosed with unresectable stage III or IV (advanced) disease, historical benchmark data from a recent meta-analysis estimates a 25% 1-year survival [5], falling to approximately only 15% by 5 years [4, 5]. In addition to poor survival, patients diagnosed with advanced melanoma have limited treatment options: dacarbazine remains the only chemotherapy approved for use in the United States [6]. However, dacarbazine is associated with modest response rates (7–12%) and has never been tested in a randomized clinical trial setting for the
The monoclonal antibody to cytotoxic T lymphocyte antigen 4, ipilimumab, in the treatment of melanoma  [cached]
Verschraegen C
Cancer Management and Research , 2012,
Abstract: Claire VerschraegenProfessor of Medicine, Division of Hematology Oncology, University of Vermont, Vermont Cancer Center, VT, USABackground: Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an inhibitory regulator of the T-cell immune response against tumor cells. Ipilimumab is a monoclonal antibody directed against CTLA-4.Objective: This review describes the basic mechanism of ipilimumab and discusses data available to date with regards to its safety and efficacy profile.Methods: Data from clinical trials including abstracts was reviewed using the PubMed Database, as well as the American Society of Clinical Oncology Abstract Database.Conclusion: CTLA-4 inhibition with a monoclonal antibody is usually well tolerated and has efficacy as a therapeutic agent in a variety of cancers. The classical response interpretation has changed because of the delayed mechanism of action. The toxicities are autoimmune events and guidelines for treatment of these effects are discussed. Therapy with ipilimumab leads to durable responses. The first two Phase III randomized studies showed an improvement of survival at 1, 2, and 3 years. Other studies are currently underway to better understand the optimal treatment administration of ipilimumab in melanoma.Keywords: melanoma, CTLA-4, ipilimumab, immune-related adverse events, melanoma, modified immune response criteria
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