Targeted agents for the treatment of metastatic melanoma

OncoTargets and Therapy, Mar 2012

Targeted agents for the treatment of metastatic melanoma Jose G Monzon, Janet DanceyNCIC Clinical Trials Group, Kingston, Ontario, CanadaAbstract: In the last year, the armamentarium of melanoma therapeutics has radically changed. Recent discoveries in melanoma biology and immunology have led to novel therapeutics targeting known oncogenes and immunotherapeutic antibodies. Phase III clinical trials of these agents have reported measurable and meaningful benefits to patients with metastatic disease. In this article, we review recent findings and discuss their significance in melanoma therapy. As our understanding of melanoma biology grows, this initial therapeutic success may be enhanced through the use of molecular markers to select patients, and new targeted immunotherapies in sequential or combination drug regimens.Keywords: metastatic melanoma, ipilimumab, vemurafenib, antitumor

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://www.dovepress.com/getfile.php?fileID=12194

Targeted agents for the treatment of metastatic melanoma

OncoTargets and Therapy Targeted agents for the treatment of metastatic melanoma Jose G Monzon Janet Dancey 0 0 NCIC Clinical Trials Group , Kingston, Ontario , Canada In the last year, the armamentarium of melanoma therapeutics has radically changed. Recent discoveries in melanoma biology and immunology have led to novel therapeutics targeting known oncogenes and immunotherapeutic antibodies. Phase III clinical trials of these agents have reported measurable and meaningful benefits to patients with metastatic disease. In this article, we review recent findings and discuss their significance in melanoma therapy. As our understanding of melanoma biology grows, this initial therapeutic success may be enhanced through the use of molecular markers to select patients, and new targeted immunotherapies in sequential or combination drug regimens. - Epidemiology and treatment of metastatic melanoma Malignant melanoma is an important health care issue. The incidence of melanoma has increased dramatically over the last four decades and melanoma is now one of the most common forms of cancer. In 2011, over 75,000 North Americans will be diagnosed with melanoma and over 9000 will die from it.1,2 Although less common than cancers of the breast, prostate, or colon, it is potentially more lethal. It has a high propensity for hematogenous and lymphatic dissemination to regional and distant sites and is poorly responsive to most systemic therapies. The 5-year survival rate for metastatic melanoma is dismal, ranging from 5% to 10% with a median survival of less than 8 months with treatment.3 Until recently, the therapeutic options for patients with metastatic melanoma were limited. The only approved treatment options were dacarbazine and interleukin 2 (IL-2). Dacarbazine, an alkylating agent, has a response rate of ,10%, with median response durations of 4–8 months.4 Single-agent therapy with IL-2, an immune-modulatory agent, has similar overall response rates of 16%, with ∼5% of patients achieving durable complete responses (CRs) that may result in long-term survival in selected patients.5 Use of IL-2 is limited by its low overall response rate and its potential severe multiorgan toxicities requiring management in specialized cancer centers. With these agents, remissions are infrequent, usually of short duration, and treatment is primarily palliative, as neither agent has been shown definitively to improve survival. Improved treatments with high-risk resected and advanced metastatic disease are urgently needed. In the last year, there have been major treatment advances for metastatic melanoma patients. Two agents, ipilimumab (Yervoy™, Bristol-Myers Squibb, Princeton, NJ) and vemurafenib (Zelboraf, Plexxikon/Roche, Auckland, NZ), have demonstrated improved survival in patients with advanced melanoma when compared with standard treatments. The clinical benefits of these targeted drugs have been realized after decades of research in the molecular pathogenesis of melanoma. This research has identified tumor and immune cellular signaling pathway abnormalities that promote melanoma development and progression. Once regarded as a cancer with a dismal record of negative Phase III treatment trials, melanoma is now a tumor type for the clinical evaluation of paradigm-shifting therapeutic strategies. In this review, we outline key molecular pathways and the agents targeting them. 8 1 0 2 l u J 3 1 n o 3 5 1 . 4 5 2 . .315 Melanoma, the immune system, 5 /yb and immune targeting monoclonal .com antibodies ss There is overwhelming evidence that melanoma is an rvpee l.yno immune-responsive cancer. Spontaneous regression of mela.dow lsue noma is observed and is probably due to immune processes. tt:/spw rspea Tmheelanidoemntaifainctaitgieonn-sopfectuifmicoTr--cineflilsltrinatpinegriplyhmerpalhbolcoyotdesfraonmd /w no h ro cancer patients are evidence that melanoma-specific immune from F recognition and activation occur.6–8 Moreover, melanoma aedd exhibits cellular properties that can be explained by immune lon selection, such as downregulation of major histocompatdow ibility complex class I expression or release of cytokines ryap such as transforming growth factor-beta.9,10 Lastly, dramatic heT clinical responses have been demonstrated with immunenad modulatory treatments, such as IL-2 and adoptive T-cell tsge transfer in selected patients with metastatic melanoma, raT although neither of these treatments have demonstrated con superiority over standard of care in randomized clinical O trials.4,11 However, ipilimumab, a novel monoclonal antibody modulating the immune system, provides the first evidence that an immunotherapy strategy can change the clinical course of metastatic melanoma and result in improvement in patient survival.12,13 Ipilimumab is a modulator of immune system activation. T-cell activation occurs when an antigen is presented by a major histocompatibility complex molecule and a co-stimulatory molecule, B7.1 or B7.2, (...truncated)


This is a preview of a remote PDF: https://www.dovepress.com/getfile.php?fileID=12194

Jose G Monzon, Janet Dancey. Targeted agents for the treatment of metastatic melanoma, OncoTargets and Therapy, 2012, pp. 31-46, DOI: 10.2147/OTT.S21259