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Hepner A et al.
814 Rev Assoc Med Bras 2017; 63(9):814-823
INVITED REVIEW
Treatment of advanced melanoma – A changing landscape
Adriana Hepner1, Alessandra Salgues1, Carlos A. dos Anjos1, Marina Sahade1,2, Veridiana P. Camargo1,2 ,
Bernardo Garicochea1, Alexander N. Shoushtari3,4, Michael A. Postow 3,4, Gustavo S. Fernandes1, Rodrigo R. Munhoz1,2 *
1Oncology Center, Hospital Sírio-Libanês, São Paulo, SP, Brazil
2Medical Oncology Service, Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, São Paulo, SP, Brazil
3Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
4Weill Cornell Medical College, New York, NY, USA
Summary
Article received: 12/7/2016
Accepted for publication: 2/5/2017
*Correspondence:
Address: Rua Dona Adma Jafet, 91,
bloco A, 2º andar
São Paulo, SP – Brazil
Postal code: 01308-050
Following decades of relative ostracism, advances in the treatment of melanoma
have brought a new reality for patients, physicians and researchers. While
antibodies targeting molecules involved in the modulation of the interaction
between melanoma and immune cells changed the meaning of the term “cancer
immunotherapy,” a better characterization of the molecular aberrations involved
in melanoma carcinogenesis prompted the development of inhibitors of the
mitogen-activated protein kinase pathway (MAPK) that also led to significant
improvements both in response rates and survival. As a result, new drugs have
been approved for clinical use in the United States and Europe, including the
immune-checkpoint blockers ipilmumab, pembrolizumab and nivolumab, the
oncolytic herpesvirus talimogene laherparepvec, and the targeted-agents
vemurafenib, dabrafenib, cobimetinib and trametinib. In this article, we review
the results of studies that brought new approaches to the bedside and discuss
how these developments are being incorporated into the care of patients in Brazil.
Keywords: melanoma, anti-PD1, anti-CTLA4, BRAF, MEK.
Introduction
Although it represents only 1% of all cutaneous malignan-
cies, melanoma is still a challenge to public health due to
its high metastatic potential and mortality.1 Over the past
decades, the number of cases of melanoma has increased
dramatically, faster than any other type of cancer.2 In the
United States, 76,380 new cases and more than 10,000
deaths related to melanoma are expected in 2016, ac-
counting for the vast majority of skin cancer deaths.1 In
Latin America, data regarding the incidence and prevalence
of this disease are scarce,3 and 5,670 new cases are esti-
mated in Brazil in 2016 according to the Instituto Nacio-
nal do Câncer (Inca).4
While patients with early diagnosis have 5-year sur-
vival rates around 90%, historically, this number decreas-
es to 10% in patients with advanced melanoma, with a
median survival of 6 to 12 months.1,2
Even though surgery and radiotherapy may have a
role in the management of metastatic disease in selected
situations, systemic therapy is the mainstay of treatment
for most patients.5 For over three decades, dacarbazine
was the most commonly used cytotoxic agent, resulting
in objective responses in approximately 10% of the cases
and with an arguable impact on overall survival, with
approximately 20-25% of the patients alive at 12 months.2,5
Other agents, such as vinblastine, cisplatin/carboplatin
and taxanes, either used in combinations or in mono-
therapy, showed only short-lived benefits.5 Non-selective
forms of immunotherapy, including high dose interleu-
kin-2 (IL-2) or biochemotherapy, had their widespread
use hampered by significant toxicity and objective (al-
beit durable and potentially curative) responses limited
to a small proportion of individuals, despite serving as a
proof-of-concept that melanoma cells could be controlled
or eradicated by the immune system.6
In the past decades, however, progress has been made
in the understanding of both melanoma pathogenesis
and the interaction between cancer and immune cells.
The demonstration of aberrant activation of the mitogen-
activated protein kinase pathway (MAPK) paved the way
for the development of so-called targeted therapies, 7 in-
cluding the currently available V-Raf Murine Sarcoma