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.
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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.
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.315 Melanoma, the immune system,
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/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.
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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)