The Future of Melanoma Treatment

By Michael M. Mohundro, PharmD, and Alexis E. Horace, PharmD | June 06, 2013
According to the National Cancer Institute’s Surveillance Epidemiology and End Results data, melanoma of the skin was estimated to be the cause of death in almost 10,000 people in 2012.1 Unfortunately, melanoma incidence has been on the rise in the United States since 1981, with annual increases of almost 3%; however, in white women under the age of 44 years, the increase has been double that, at 6.1%. The upward trend in this population may be due to the increased popularity of tanning bed use.2

Currently, there are five types of treatments available to patients diagnosed with melanoma. The treatment types are surgery, chemotherapy, radiation, immune therapy, and targeted therapy.3 Melanoma is classified as a chemotherapy-resistant tumor; however, a response rate of 10% to 15% has been noted with certain single agents. Dating back to 1972, the gold standard for treatment of metastatic melanoma has been dacarbazine.4 Drugs currently approved by the FDA for treatment of melanoma include aldesleukin, dabrafenib, dacarbazine, ipilimumab, trametinib, and vemurafenib.5 This article will explore pharmacologic agents currently being investigated for the treatment of melanoma.

Microtubule Inhibitor

Nab-paclitaxel

Solvent-based taxanes have limited utility due to limited efficacy and high rate of toxicity. In addition to adverse effects from the taxane, patients often experience reactions to the solvent. Albumin-bound paclitaxel is a 130-nanometer albumin-bound (nab) particle formulation of paclitaxel which does not require the use of a solvent. Utilization of nab-paclitaxel over traditional paclitaxel has the advantage of being able to deliver a higher dose while decreasing the incidence of serious grade 3 or 4 side effects.6 Further, the nab-paclitaxel formulation does not have the same “allergic” potential as the solvent-based formulation.6,7 Of particular note, the albumin-binding secreted protein, acidic and rich in cysteine (SPARC) may play an important role in the effectiveness of nab-paclitaxel in melanoma. It is often overexpressed in a large number of malignancies, including melanoma, and is considered a poor prognostic indicator.7 While the exact role in melanoma treatment has yet to be fully defined, the efficacy of nab-paclitaxel has been comparable to standard dacarbazine treatment and single-agent paclitaxel, as well as other combination therapies.7 In a recent phase II trial in combination with carboplatin in patients with unresectable stage IV melanoma, the nab-paclitaxel/carboplatin combination had a slight advantage in survival rate over ipilimumab.6 However, the survival benefit was limited to the chemotherapy-naïve subgroup.6 Several more phase II trials evaluating nab-paclitaxel in combination with either bevacizumab or other agents have been completed, and results are pending.6,8 Results of a phase III open-label, multicenter trial investigating nab-paclitaxel versus dacarbazine in treatment-naïve metastatic malignant melanoma demonstrated better median progression-free survival (PFS) and interim overall survival (OS) with nab-paclitaxel (PFS: 4.8 vs 2.5 months [hazard ratio (HR)= 0.792; 95.1% CI, 0.631-0.992; P = .044], OS: 12.8 vs 10.7 months [HR= 0.831; 99.9% CI, 0.578-1.196; P = .094]).9

Plasmid/Lipid Complex Containing MHC I

Velimogene aliplasmid

Velimogene aliplasmid is a new form of immunotherapy for the treatment of metastatic melanoma. MHC class I and II expression is important for detection and lysis of foreign antigens by the immune system. Oftentimes, tumor cells go undetected by class I-restricted T cells by downregulating these processes.10-12 Velimogene aliplasmid consists of a DNA plasmid, which hosts the genetic code for MHC class I proteins, HLA-B7, and B2-microglobulin, which improve expression of the HLA-B7 gene.12 By encoding these three genes together, it provides several immune-stimulating features that increase the potential for tumor cell lysis. Several phase I studies have been conducted in small groups and demonstrated improved T-cell infiltration into tumor lesion, improved HLA-B7 surface expression, and promoted regression.12,13 An unpublished phase III trial in 2001 compared velimogene aliplasmid combined with dacarbazine versus dacarbazine alone in chemotherapy-naïve patients.14 Response rates for dacarbazine were 11.6% and 13.2% for dacarbazine/velimogene aliplasmid. When comparing dacarbazine with dacarbazine/velimogene aliplasmid, survival durations were 9.24 months versus 10.75 months, respectively. Time to progression was 1.6 versus 1.9 months for dacarbazine and the combination. The authors concluded that velimogene aliplasmid did not increase clinical improvements beyond the standard of care. However, velimogene aliplasmid is currently being compared with dacarbazine alone in an ongoing phase III clinical trial investigating the safety/tolerability and OS rates of the two therapies.15

Vaccines

MAGE-A3 ASCI (astuprotimut-r)


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Online CME Activities
TitleExpiration DateCME Credits
Provider and Caregiver Connection™: Addressing Patient Concerns While Managing Skin Cancer and Other Cutaneous MalignanciesDec 23, 20162.0
Combination Therapy for Metastatic MelanomaJan 21, 20171.0
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