2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

THERAPIES FOR PATIENTS WITH METASTATIC MELANOMA
bazine alone or than that observed with ipilimumab alone.
The increase in hepatic toxicity may be due to its combination
with dacarbazine, which is also known to be hepatotoxic.
On other hand, the incidence of other immune-related
toxicities (colitis, rash, hypophysitis) was less than that seen
in prior studies with ipilimumab alone, perhaps suggesting
that dacarbazine may have blunted the immune-toxicity
profile,and/or the higher incidence of hepatotoxicity may
have pre-empted or altered the immune toxicity profile.
Whether this blunting of immune toxicity by dacarbazine
might have also blunted the antitumor effect of ipilimumab
is a matter of speculation. However, the overall pattern of
toxicity and efficacy of this trial do not support the addition
of dacarbazine to ipilimumab. The relative value of the use
of ipilimumab at the 10 mg/kg dose used in this study and in
multiple phase II studies versus the already approved 3
mg/kg dose awaits the completion of an ongoing phase III
trial directly comparing the two doses.
Other Immune Regulatory Checkpoints
Monoclonal antibodies targeted against a number of other
regulatory checkpoints are being evaluated in patients with
advanced melanoma based on our current understanding of
the development of cellular immunity. The PD-1 receptor
acts as an inhibitory receptor of T cells, in a manner
analogous to CTLA-4S. 20 In a preliminary report of a phase
I study, a monoclonal antibody directed against the PD-1
receptor (MDX-1106) caused significant regression of metastatic
melanoma lesions in three cases and appears to be
associated with less autoimmunity than reported with ipilimumab.
21 Ongoing studies are exploring various doses of
this antibody as well as a variety of different antibodies
targeting either PD1 or PDL1 patients with melanoma. A
member of the tumor necrosis factor (TNF) family, 4–1BB
(CD137), acts as a costimulatory molecule that causes T-cell
proliferation. A humanized Monoclonal Ab (MAb), BMS-
663513, targeted at CD137 acts as an agonist and can cause
costimulation of CD8� and CD4� cells. In a preliminary
report of the initial phase I study with this agent, three
partial responses were observed among 54 patients with
melanoma. 22 OX-40 is another TNF receptor, which also
acts as a costimulatory factor for T cells. A MAb that targets
this receptor has begun a phase I study. 23
Treatment Selection Options
Considerable effort has focused on identifying patients
who respond to immunotherapy in the hope of restricting
such treatment to those most likely to benefit. IL-2 responsiveness
has been shown to be more likely in patients with
normal serum LDH, or low plasma vascular endothelial
growth (VEGF) and fibronectin levels. 24 In addition, response
appears to be more frequent in patients whose
tumors contain mutations in BRAF or NRAS, or possess an
inflammatory gene-expression signature. 25 More recent
studies have suggested that response to IL-2 is associated
with enhancement of a pre-existing gene expression pattern
within the tumor associated with immune-mediated tissuespecific
destruction under the control of IFNgamma. 26
Benefit from vaccination has also been linked to tumors
expressing an IFN driven chemokine signature. 27 Preliminary
results suggest that both PD1 antibody responsiveness
and IL-2 responsive in patients with renal cell carcinoma
(RCC) may be correlated with tumor cell–surface expression
of PDL1. Furthermore, research suggests that tumor PDL1
expression is not constitutive, but is related to the secretion
of IFNg by of tumor reactive CD8 T cells in the microenvironment.
Thus, effective immunotherapy may require
pre-existence of tumor-specific immunity within the microenvironment
and the use of agents that can either drive
T-cell function (HD IL-2 or vaccines) or block inherent
immunoregulatory signals (ipilimumab, or anti-PD1). Several
current studies are underway to validate these predictive
biomarkers for specific immunotherapies as well as
to determine if combinations of immunotherapy with either
other immunotherapies or molecularly targeted agents
could convert nonimmune responsive tumors into those
capable of responding.
BRAF Inhibitor Therapy for BRAFV600
Mutant Melanoma
As previously described, approximately 50% of patients
with cutaneous melanoma, have tumors that express the
mutated BRAF oncogene. Those patients with melanoma
carrying a V600E/K mutation are responsive to selective
BRAF inhibitors of which vemurafenib is the first to obtain
FDA-approval. 28,29 Other BRAF inhibitors are in the late
stages of development and look equally promising. 30
Through a series of clinical trials performed in rapid succession
from phase I to phase II and III, the BRAF inhibitor,
vemurafenib, was shown to effectively inhibit the MAPK
pathway constitutively activated by the BRAF mutation;
affect clinical tumor regression in most patients with objective
clinical responses in over 50% of patients; and, finally,
improve overall survival compared to dacarbazine chemotherapy.
28,29 The phase I trial established that vemurafenib
inhibited its target and demonstrated clinical efficacy in
most of the 32 patients with a BRAFV600E/K mutation. 28 A
much larger phase II trial enrolled patients with 132
BRAFV600E/K mutated-melanoma who had failed either
standard immunotherapy or chemotherapy and documented
an objective response rate of 53%, of which 6% were complete
responses. 31 The median progression-free survival for
the entire population was 6.8 months. The median overall
survival was a remarkable 15.9 months (95% CI 11.8–18.3).
Finally, a randomized phase III trial allocated 675 patients
to open label vemurafenib at 960 mg twice daily orally or
dacarbazine at 1,000 mg/m 2 every 3 weeks with no crossover
allowed. At the first interim analysis, the HR for death
was 0.37 (95% CI 0.26–0.55; p � 0.0001). But the median
follow-up was short, only 3.75 months. Vemurafenib was
approved in August of 2011.
Although vemurafenib is generally well tolerated, it can
cause frequent skin toxicities dominated by hyperproliferative
skin lesions, including keratoacanthomas, a low-grade
cutaneous squamous cell carcinoma. 32 Approximately 25%
of patients develop such lesions in a median time of only 8
weeks, but they can be easily treated by excision without
interrupting treatment. However, there may be a more
significant issue in the adjuvant setting that could be
representative of the agent’s potential to enhance the
growth of other subclinical malignancies.
With a median progression-free survival of 6 to 8 months,
many responses to BRAF inhibitor therapy are short-lived.
A minority are maintained for more than 12 months, and
these patients are typically those with baseline normal LDH
and nonbulky disease. Resistance to these BRAF inhibitors
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