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Targeted Therapies Yield Most Promising Results: A New Era in Melanoma Treatment Has Begun

Jennifer Klem, PhD; Stanton R. Mehr; and Mari Pestil Zimmerman
Published: Wednesday, Feb 08, 2012
Cancerous Mole Melanoma is one of the most frequent cancers; more than 2 million Americans are treated for skin cancer annually. However, in its earlier stages, it can be easily cured by removal of the skin lesion.1 “Melanoma is on the surface of the skin, and therefore easily visible to patients, doctors, and other health professionals without the use of x-rays or invasive procedures,” said Lynn M. Schuchter, MD, professor of Medicine, University of Pennsylvania School of Medicine, Philadelphia. “Therefore, early detection is highly feasible. Most melanomas are cured with surgery because the melanoma is detected at an early stage of disease before melanoma cells have the potential to metastasize.” Schuchter explained, “Once melanoma metastasizes to distant sites, it is highly resistant to therapy.” Melanoma caused an estimated 8700 deaths in 2010.1

Chemotherapy for advanced disease has yielded poor 5-year survivals for patients with metastatic disease—16% of those with metastatic melanoma survive 5 years post-diagnosis.2 Dacarbazine has long been the only drug approved by the FDA for treating metastatic melanoma, and it is often ineffective.3 In other words, the prognosis for patients whose melanoma has spread is generally poor, and very few therapies existed before 2011 that could make more than a marginal difference. Only recently have investigational products emerged that, alone or in combination, seem to yield positive responses in some patients.

Taking Advantage of the Body’s Immune Response

Melanoma is one of the few cancers that triggers the body’s immune response naturally.4 The problem is that the response is easily overwhelmed by the malignancy. Ipilimumab, which was approved by the FDA in March 2011, works by spurring the body’s immune system to attack the tumor. The melanoma pipeline comprises several examples of investigational agents that seek to enhance the immune response, including therapeutic vaccines.

Vaccines

OncoVEXGM-CSF. The therapeutic vaccine that is perhaps furthest along the pipeline is OncoVEXGM-CSF, which is customized to the patient by using his/ her own tumor antigens. This viral vaccine invades both healthy cells and melanoma cells, but it does not harm the healthy cells, only replicating within the malignant cells, according to the manufacturer, BioVex, which was acquired by Amgen in March 2011.5 The virus produces granulocyte-macrophage colony-stimulating factor (GM-CSF), which gathers dendritic cells, causing the rupture of the tumor cell. This releases GM-CSF and tumor-cell peptides into the local area. The dendritic cells collect the tumor-cell peptides, allowing the immune system to recognize and attack them.

In 2009, phase II testing of the vaccine in 50 patients with metastatic melanoma revealed overall survival at 2 years of 52%, and an objective response rate of 26% (stable disease rate of 20%).6 Phase III testing is currently under way, and this OPTiM trial is expected to be completed in June 2012 (ClinicalTrials.gov, NCT00769704). The OPTiM trial compares the vaccine with the use of GM-CSF administered subcutaneously in patients with stage III (b-c) and stage IV (M1a-c) disease.

Prophage (vitespen). Not all autologous vaccinebased therapies entering phase III trials have met with success. This vaccine (formerly known as Oncophage), which is developed using gp96 and other peptides from the patient’s own tumor, was found to not improve survival in patients with stage IV melanoma compared with any other choice of therapy. In this phase III trial, only patients with better prognostic characteristics who were injected with vitespen seemed to improve.7

MVax. In the case of MVax, from Avax Technologies, the phase II clinical trial results were encouraging, yet the phase III study was halted in 2010, not for safety reasons or poor outcomes, but because of a lack of capital. It is unclear as to when or if this phase III trial may be continued, or if an interim analysis of the study results will take place as planned.

Most melanomas are cured with surgery...[but] once melanoma metastasizes to distant sites, it is highly resistant to therapy. ”
–Lynn M. Schuchter, MD
Similarly, in 2005, CancerVax Corp halted its phase III trial of the vaccine Canavaxinin for latestage melanoma, not because of safety reasons, but because it had not shown any benefit over placebo.8

Schuchter commented that, “Current approaches to vaccine development are still a major challenge. Unless there is a whole new approach to melanoma vaccines, I am not optimistic about the future of vaccines for patients with melanoma."


View Conference Coverage
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
Advances in™ Melanoma: Exploring BRAF/MEK in Adjuvant and Neoadjuvant SettingsSep 28, 20191.5
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