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T
reatment
of
advanced
melanoma
– A
changing
landscape
R
ev
A
ssoc
M
ed
B
ras
2017; 63(9):814-823
819
harboring non-BRAF mutations has been limited, these
results serve as a proof of concept for future molecularly-
driven treatment strategies.
U
sing
the
immune
system
to
fight melanoma
– T
he
growing
field
of
immunotherapy
Using the immune system to fight cancer has evolved
from a “future perspective” to one of the most practice-
changing breakthroughs in oncology in recent years, yield-
ing the possibility of long-term clinical benefit and pro-
longed survival. Indeed, the development of monoclonal
antibodies targeting co-receptors involved in escape
mechanisms has shown exceptional results for the treat-
ment of advanced melanoma.
The immune system can be divided into innate and
adaptive immunity. The innate immune system is the
initial defense against foreign antigens, which includes
dendritic cells (DC), macrophages, neutrophils, basophils,
eosinophils, natural killer cells (NK) and mast cells. These
cells, once activated, release stimulatory cytokines that
recruit additional elements of the immune response. The
adaptive immune system is an antigen-specific response,
dependent mainly on the antigen presenting cells (APCs),
which process antigens and present them via mixed his-
tocompatibility complex (MHC) class I and II molecules,
to T cells through the T-cell receptor (TCR). Activated T
cells, then differentiate into distinct functional pheno-
types (exemplified per Th1, Th2 and Tregs), release cyto-
kines and recruit effector cells, producing the T-cell-
mediated response.
29
Recently, ligands and co-receptors expressed on T
cells, APC and tumor cells have been identified as poten-
tial targets for immunotherapy, due to their critical role
as immune suppressors at the tumor microenvironment.
These ligands and receptors, because of their function as
regulators of the T cell activation and tolerance, have been
termed “immune checkpoints” (Figure 2). Monoclonal
antibodies directed against CTLA-4 and PD-1 and its li-
gand (PD-L1) illustrate successful approaches for the
treatment of advanced melanoma.
30
In the priming phase or early phase of immune activa-
tion, the CTLA-4 receptor is induced on T lymphocytes as
negative regulator of T cell response, competing with CD28
for binding to B7 molecule on the antigen presenting cells.
30
Ipilimumab, a monoclonal antibody that targets CTL4,
was the first checkpoint inhibitor approved for clinical use
in metastatic melanoma patients in 2011, based on sur-
vival gains in both first and second-line settings and re-
sponse rates of 10-15%.
31
In the largest combined analysis
of 1,861 patients treated with ipilimumab in phase 2 and
3 trials, a plateau seen in the survival curve confirmed the
possibility of sustained benefits, with 21% of those patients
surviving beyond three years.
32
Of note, a recently-present-
ed randomized trial comparing ipilimumab at 3 mg/kg
versus 10 mg/kg demonstrated an improvement in overall
survival in the group of patients treated with higher doses
(mOS 15.7 m vs. 11.5 m; HR 0.84; 95CI 0.70-0.99; p=0.04),
accompanied by an increase in the rates of grade 3-5 treat-
ment-related toxicities (34.3% vs. 18.5%).
33
Despite this initial success with CTLA-4 blockade,
even more compelling results were seen with anti-PD1
agents pembrolizumab and nivolumab. The PD-1 recep-
tor is expressed by activated T cells and binds to its ligands
PD-L1 and PD-L2, resulting in abrogation of T cell-me-
diated responses and preventing the recognition and
killing by cytotoxic cells.
30
In phase 1 trials, ORR around 30% and median OS
of 23 months and 16.8 months were seen with pembro-
lizumab and nivolumab, respectively.
34,35
These agents
were initially approved for patients following progression
on ipilimumab (and a BRAF inhibitor, in patients with
melanoma harboring a BRAF mutation) based on the
results of trials that demonstrated both favorable effi-
cacy in comparison to cytotoxic chemotherapy. In the
KEYNOTE 002 randomized phase 2 trial, 540 patients
with ipilimumab-refractory disease were randomly as-
signed to pembrolizumab (2 mg/kg every three weeks),
pembrolizumab (10 mg/kg every three weeks) or chemo-
therapy. The six-month progression-free rate, the pri-
mary endpoint of the study, was 34, 38, and 16%, respec-
tively (pembrolizumab 2 mg/kg versus chemotherapy;
HR 0.57; 95CI 0.45-0.73; p<0.0001; and pembrolizumab
10 mg/kg versus chemotherapy HR 0.50, 95CI 0.39-0.64;
p<0.0001), with objective responses occurring in 21-26%
of the cases.
36
Similarly, in the phase 3 CheckMate 037
study, 405 previously treated patients received either
nivolumab or investigator’s choice of chemotherapy. Ob-
jective responses were reported in 31.7% in the nivolumab
group vs. 10.6% in the chemotherapy group, and less
toxic effects were seen with nivolumab (rate of grade 3-4
adverse events: 9% vs. 32%).
37
In the first-line setting, both pembrolizumab and
nivolumab showed superiority in terms of efficacy and tol-
erability when compared to ipilimumab, and were rapid-
ly incorporated into clinical practice for treatment-naïve
patients. In the phase III KEYNOTE-006 trial, 834 pa-
tients received either pembrolizumab 10 mg/kg every
two weeks, pembrolizumab 10 mg/kg every three weeks
until disease progression or ipilimumab 3 mg/kg every
three weeks for four doses. The trial demonstrated sig-