Immunotherapy in Advanced Melanoma

Deepika Narasimha, MD1, Anthony Jarkowski, III, PharmD2,
and Nikhil I. Khushalani*, MD1,3
Published: Monday, Jun 18, 2012
Dr. Nikhil I. Khushalani Corresponding Author:

Nikhil I. Khushalani, MD

Associate Professor of Oncology, Roswell Park Cancer Institute,
Department of Medicine,
Elm & Carlton Streets,
Buffalo, New York;

nikhil.khushalani@roswellpark.org

  1. Department of Medicine, State University of New York, Buffalo, NY
  2. Department of Pharmacy, Roswell Park Cancer Institute, Buffalo, NY
  3. Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY

Abstract

Metastatic melanoma has historically been one of the most therapeutically challenging malignancies, with poor 5-year survival. Until recently, dacarbazine and high-dose interleukin-2 were the only agents approved by the FDA for metastatic melanoma. The year 2011 witnessed the approval of an anti-CTLA-4 antibody, ipilimumab, and a BRAF-targeted agent, vemurafenib, in advanced melanoma, which has led to a renaissance in melanoma therapeutics. This is an exciting phase for melanoma immunotherapy and holds important implications for clinicians, due to novel paradigms of treatment, assessment of response, and management of immune-related toxicities. This review seeks to summarize the data on approved immunotherapeutic options in metastatic melanoma, with a special focus on ipilimumab.

The incidence of cutaneous melanoma has been steadily rising in the United States, especially in Caucasian women under 40 years of age, in whom an increase of 50% occurred from 1980 until 2004. Approximately 9200 deaths from melanoma are estimated in 2012.1 Thickness of the primary tumor, ulceration, and nodal metastatic status are the most important determinants of prognosis for localized disease, for which surgery remains the mainstay of therapy. A selected subset of oligometastatic stage IV patients also may benefit from surgical resection. Metastatic melanoma has a dismal prognosis, with a median survival of 7 months and a 5-year survival rate of 15%.2,3

Until recently, therapeutic options centered on dacarbazine (DTIC), the only FDA-approved chemotherapeutic agent for metastatic melanoma since 1975.4 An active regimen that was commonly used until recently is carboplatin and paclitaxel, with response rates ranging from 11% to 26%.5-7 In 2011, ipilimumab and vemurafenib gained regulatory approval in the United States for the treatment of advanced melanoma based on positive randomized trials, ushering in a new era in melanoma therapy. This in turn has initiated a cascade of clinical trials that hopefully will build on this improvement and improve the outlook for this disease.

This review will summarize the role of immunotherapy in advanced melanoma, with a focus on the use of ipilimumab in the community practice setting.

Immunotherapy Options in Advanced Melanoma

Melanoma is a highly immunogenic tumor. Clinical observations of a higher incidence in organ transplant recipients, as well as rare spontaneous tumor regressions, have led to investigations into harnessing the immune system in therapy against melanoma. It is well known that melanomas exhibiting a brisk lymphocytic infiltrate have a better prognosis than those lacking this, and that melanomas are often associated with areas of histologic regression that correlate with lymphocytic infiltration.8 Several biologic agents, vaccines, and checkpoint agents have been tested in clinical trials.

Interleukin-2 (IL-2)

IL-2 is a glycoprotein that binds to IL-2 receptors on T-cells and augments lymphocyte mitogenesis and cytotoxicity. It is essential for T-cell immunity and exerts its anticancer activity by acting as a growth factor for T lymphocytes, increasing interferon-gamma production, stimulating antigen-independent natural killer cells, and facilitating movement of lymphocytes to sites of malignancy.9-11 It was first identified in 1976, and received FDA approval in 1998 for the treatment of metastatic melanoma based on its ability to produce durable, complete responses in this disease.12-14

The Cytokine Working Group described its findings for a patient database of 270 patients with metastatic melanoma who were entered into eight clinical trials assessing the efficacy and toxicity of the high-dose IL-2 regimen.13 The overall response rate (ORR) was 16% (95% confidence interval [CI], 12%-21%); there were 17 complete responses (CR; 6%) and 26 partial responses (10%). Of the responders, 28% (including 59% who achieved CR) were progression-free at a median follow-up period of 62 months.


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Online CME Activities
TitleExpiration DateCME Credits
Medical Crossfire®: Evolving Roles for Targeted Melanoma Therapies: Assessing Rapid Progress in the Field and Looking Toward Future CombinationsFeb 28, 20191.5
Community Practice Connections™: New Directions in Advanced Cutaneous Squamous Cell Carcinoma: Emerging Evidence of ImmunotherapyAug 13, 20191.5
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