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ABSTRACT: Uveal melanoma (UM) is a rare disease with a distinct molecular profile. About half of the patients with UM eventually develop metastatic disease. The prognosis of these patients remains poor. Treatment options are limited and none of them have been able to show a survival benefit. Ipilimumab was the first agent to show a survival benefit in patients with cutaneous melanoma in a randomized trial; however, there is limited published evidence for its role in the management of advanced UM. Here, we report our experience of ipilimumab in five patients with advanced UM treated at an academic cancer centre in the UK. Two patients had durable stable disease and three developed progressive disease. Of the patients with stable disease, one maintained disease control at 11 months from the commencement of treatment with ∼10% reduction in tumour volume compared with the baseline, and the second patient progressed after 15 months. We also examined the tumour kinetics and response patterns that resembled that of ipilimumab in cutaneous melanoma. Given the lack of randomized trial data, our findings indicate that ipilimumab might be a reasonable treatment option for patients with advanced UM.
Melanoma research 11/2012; · 2.06 Impact Factor
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ABSTRACT: Systemic treatment of renal cell carcinoma has changed dramatically since 2007, with the development and approval of six new agents, which target complex molecular pathways regulating tumour angiogenesis and cell proliferation and survival. These treatments have significantly improved survival times in metastatic renal cell carcinoma, but remain palliative. A number of newer agents are in clinical development, which offer theoretical advantages over existing treatments, and research methodologies are adapting with the aim of defining an individualised approach to therapy which exploits the underlying tumour biology. This review will provide an overview of current and emerging systemic treatments and how they might be integrated with surgical therapy, with a particular focus on advanced, clear cell metastatic renal cell carcinoma.
Seminars in Cancer Biology 06/2012; · 6.47 Impact Factor
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ABSTRACT: Following Phase I and II studies revealing vemurafenib to be a safe potent inhibitor of mutated BRAF in patients with metastatic melanoma, a multicenter randomized Phase III trial was carried out to compare vemurafenib with dacarbazine in treatment-naive patients. The interim analysis results from this trial, BRIM-3, were sufficient for an independent data and safety monitoring board to recommend crossover from dacarbazine to vemurafenib, vemurafenib being associated with a relative risk reduction of 63% in the risk of death and 74% in the risk of death or disease progression compared with dacarbazine (p < 0.001 for both comparisons) with an acceptable toxicity profile. Such striking results have prompted analysis of our approach to the classification and treatment of metastatic melanoma in an age of molecular markers and targeted therapy.
Future Oncology 05/2012; 8(5):499-507. · 3.16 Impact Factor
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Simon Pacey,
Martin Gore,
David Chao,
Udai Banerji, James Larkin,
Sarah Sarker,
Karen Owen,
Yasmin Asad,
Florence Raynaud,
Mike Walton,
Ian Judson,
Paul Workman,
Tim Eisen
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ABSTRACT: A Phase II study to screen for anti-melanoma activity of the heat shock protein 90 (HSP90) inhibitor, 17-AAG (17-allylamino-17-demethoxygeldanamycin) was performed. The primary endpoint was the rate of disease stabilisation in patients with progressive, metastatic melanoma treated with 17-AAG. Secondary endpoints were to determine: the toxicity of 17-AAG, the duration of response(s), median survival and further study the pharmacokinetics and pharmacodynamics of 17-AAG.
Patients with metastatic melanoma (progressive disease documented ≤6 months of entering study) were treated with weekly, intravenous 17-AAG. A Simon one sample two stage minimax design was used. A stable disease rate of ≥25% at 6 months was considered compatible with 17-AAG having activity.
Fourteen patients (8 male: 6 female) were entered, eleven received 17-AAG (performance status 0 or 1). Median age was 60 (range 29-81) years. The majority (93%) received prior chemotherapy and had stage M1c disease (71%). Toxicity was rarely ≥ Grade 2 in severity and commonly included fatigue, headache and gastrointestinal disturbances. One of eleven patients treated with 17-AAG had stable disease for 6 months and median survival for all patients was 173 days. The study was closed prematurely prior to completion of the first stage of recruitment and limited planned pharmacokinetic and pharmacodynamic analyses.
Some evidence of 17-AAG activity was observed although early study termination meant study endpoints were not reached. Stable disease rates can be incorporated into trials screening for anti-melanoma activity and further study of HSP90 inhibitors in melanoma should be considered.
Investigational New Drugs 02/2012; 30(1):341-9. · 3.36 Impact Factor
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ABSTRACT: The BRAF inhibitor, vemurafenib, has demonstrated improved progression-free and overall survival compared with chemotherapy in a randomized trial, and represents a new standard of care in patients with advanced melanoma harboring a BRAF-V600 mutation. A BRAF-V600 mutation is identified in approximately half of patients with cutaneous melanoma, and is unequivocally a biomarker predictive of profound clinical benefit for these patients. However, acquired vemurafenib resistance is a major clinical challenge and therapy is not yet curative. A substantial body of translational research has been performed alongside clinical trials of vemurafenib, providing key insights into the molecular basis of response and resistance. This review summarizes the development of vemurafenib for the treatment of BRAF-V600 mutant melanoma and discusses how knowledge of critical signaling pathways will be applied for its optimal clinical use in future.
Cancer Management and Research 01/2012; 4:243-52.
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Frontiers in oncology. 01/2012; 2:155.
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ABSTRACT: Ipilimumab is a fully humanized monoclonal antibody to cytotoxic T-lymphocyte-associated antigen 4. Data from preclinical and clinical studies have shown that ipilimumab can cause tumor regression in patients with metastatic melanoma with response rates of 5.8-22%. Phase III trials have demonstrated a benefit in median overall survival in the first-line setting in combination with dacarbazine versus dacarbazine alone (11.2 vs 9.1 months) and in the second-line setting in combination with gp100 versus gp100 alone (10.1 vs 6.4 months). The main toxicities of ipilimumab are immune related, most commonly skin and gastrointestinal. Bowel perforation and treatment-related deaths have occurred, although prompt use of steroids and other immunosuppressive agents can minimize this risk.
Future Oncology 11/2011; 7(11):1255-64. · 3.16 Impact Factor
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ABSTRACT: INTRODUCTION: The aim of treatment in metastatic renal cell carcinoma is palliation. In the last 5 years, multiple targeted agents have been developed which have resulted in prolongation of patients' lives, but complete responses remain rare. New therapies and approaches are required to further improve the prognosis for patients with this disease. AREAS COVERED: This review discusses the molecular targets in renal cell carcinoma relevant to the development of new treatments and describes the progress of novel therapies. The evidence is compiled from the PubMed database and proceedings of scientific meetings, searched up to December 2010. EXPERT OPINION: A multitude of experimental agents are in clinical development and offer theoretical advantages over those currently in use. It is hoped that these treatments will result in better long-term control of metastatic renal cell carcinoma, with improved side effect profiles, but curative treatment in this disease remains elusive until the mechanisms underlying response and resistance to therapy are elucidated. Progress in the field has been limited by inadequate tissue collection within clinical trials; current and future clinical trial design will incorporate a larger translational component in an attempt to establish predictive biomarkers.
Expert Opinion on Investigational Drugs 07/2011; 20(7):933-45. · 5.27 Impact Factor
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ABSTRACT: Novel targeted agents, such as VEGF receptor-tyrosine kinase inhibitors (VEGFR-TKIs) and mTOR inhibitors, have improved therapy for metastatic renal cell carcinoma. Sequential administration of agents with similar mechanisms of action has shown some efficacy in small retrospective studies; however, prospective Phase II studies have reached differing conclusions, and there is a current lack of prospective randomized data to validate this approach. Sequential administration of agents with different mechanisms of action has shown clinical efficacy in prospective trials, including a randomized Phase III study (RECORD-1) of the mTOR inhibitor everolimus, the only targeted agent recommended for use after VEGFR-TKI failure in metastatic renal cell carcinoma. Ongoing research will further define the relative merits of other sequences in terms of clinical outcome.
Expert Review of Anti-infective Therapy 04/2011; 11(4):639-49. · 2.65 Impact Factor
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Frontiers in oncology. 01/2011; 1:51.
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Journal of Clinical Oncology 10/2010; 28(28):e539-40. · 18.37 Impact Factor
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ABSTRACT: Axitinib (Pfizer Inc., UK) is an oral small-molecule receptor tyrosine kinase inhibitor that targets angiogenesis. Axitinib has greater affinity and is a more selective inhibitor of VEGF receptor 1, -2 and -3, PDGFR and c-KIT than both sunitinib and sorafenib. It has encouraging efficacy and safety data in Phase II trials for metastatic renal cell carcinoma and advanced thyroid cancer patients. It is now being investigated in two Phase III trials in metastatic renal cell carcinoma and in Phase II trials in a range of tumor types. These trials will determine whether axitinib is an effective and safe antiangiogenic therapy.
Expert Review of Anti-infective Therapy 10/2010; 10(10):1545-57. · 2.65 Impact Factor
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ABSTRACT: Sunitinib is an orally available, multitargeted tyrosine kinase inhibitor licensed for the treatment of metastatic renal cell carcinoma. This article is an in-depth review of the mechanism of action of sunitinib, rationale for dose and schedule, toxicity and clinical efficacy. Other targeted therapies and treatment combinations for renal cell carcinoma are discussed. The use of sunitinib for other indications, biomarkers of response and future directions are explored.
Future Oncology 09/2010; 6(9):1377-85. · 3.16 Impact Factor
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The Lancet 08/2010; 376(9741):574-5. · 38.28 Impact Factor
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ABSTRACT: Each year in the UK there are 8100 new cases of malignant melanoma, and 1800 deaths, largely as a result of metastatic disease. The median survival of people with metastatic melanoma is 6 to 9 months after diagnosis, with 10% of people alive at 5 years. Chemotherapy is given with palliative rather than curative intent for metastatic disease. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of chemotherapy for metastatic melanoma? What are the effects of immunotherapy for metastatic melanoma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 24 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding interferon alfa (with or without interleukin-2) to chemotherapy; dacarbazine; single-agent or combination chemotherapy; supportive palliative care alone or with chemotherapy; and temozolomide.
Clinical evidence 01/2010; 2010.
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Nature Reviews Urology 12/2009; 6(12):636-8. · 4.41 Impact Factor
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ABSTRACT: Everolimus (RAD001) is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), an intracellular serine/threonine kinase that regulates protein synthesis and cell growth, proliferation and survival. Dysfunction of mTOR has been implicated in a number of human illnesses including cancer and everolimus is used for a variety of therapeutic indications and is under evaluation in clinical trials for the treatment of cancer. Two phase I studies evaluating the dosing, toxicity, pharmacokinetics, pharmacodynamics and potential biomarkers of everolimus in advanced cancer have been reported. Daily doses of 10 mg and weekly doses of 50 mg of everolimus appear to inhibit relevant therapeutic targets in both tumour tissue and in skin but maximum-tolerated doses of everolimus were not determined formally in these studies. A phase III study of everolimus at 10 mg daily in the treatment of patients with advanced renal cell carcinoma who had failed prior treatment with sorafenib or sunitinib has also been reported. In this study everolimus was generally well tolerated, causing rash, stomatitis and fatigue in approximately a third of patients which generally were not severe. Hyperglycaemia, hypertriglyceridaemia and hypercholesterolaemia were reported in approximately two-thirds of patients but again were easy to manage and mainly of mild or moderate severity. Severe infections and non-infectious pneumonitis were reported in less than 5% of study participants but generally responded to standard therapies. Further work is necessary to define mechanisms of activity and toxicity of everolimus in the treatment of advanced renal cell carcinoma.
Medical Oncology 02/2009; · 2.14 Impact Factor
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ABSTRACT: Each year in the UK there are 8100 new cases of malignant melanoma, and 1800 deaths, largely as a result of metastatic disease. The median survival of people with metastatic melanoma is 6-9 months after diagnosis, with 10% of people alive at 5 years. Chemotherapy is given with palliative rather than curative intent for metastatic disease. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of chemotherapy for metastatic melanoma? What are the effects of immunotherapy for metastatic melanoma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 23 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding interferon alfa (with or without interleukin-2) to chemotherapy; dacarbazine; single-agent or combination chemotherapy; supportive palliative care alone or with chemotherapy; and temozolomide.
Clinical evidence 02/2008; 2008.
