2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

THERAPIES FOR PATIENTS WITH METASTATIC MELANOMA
lines, but has not yet been validated in a large population of
human tumor samples. 9 PTEN deletion and inactivating
mutation are the common causes of PI3 kinase pathway
activation, occurring in approximately 20% of all melanomas.
6 These aberrations commonly coexist with BRAF mutation,
and on occasion with NRAS mutation, and are
critical cofactors in melanoma formation in experimental
models. 10,11 Mutations of p16 are well described in familial
melanoma, and mutations or deletion of p16 are commonly
found in sporadic melanoma as well (approximately 40% of
advanced tumors). 6 Loss of p16 function co-occurs with
BRAF mutation as well as BRAF WT tumors in many cases.
In cooperation with BRAF mutation, p16 loss can facilitate
formation of invasive melanomas in mouse models. 12 CDK4,
a key regulator of the cell cycle, is negatively regulated by
p16. Thus, loss of p16 function permits CDK4 to drive
progression through the cell cycle, independent of its usual
upstream regulation. CDK4 itself is amplified or can harbor
activating mutations in some melanomas (approximately
5%) and cyclin D, the binding partner of CDK4, is amplified
in a distinct subset (20%), resulting in the same cell cycle
dysregulation as p16 loss. 6 To intercept the consequences of
p16 loss, cyclin D amplification or CDK4 mutation, or
selective CDK4 inhibitor are thought be relevant.
Based on currently available evidence, targeting BRAF,
CKIT, and the pathways downstream of NRAS is a promising
starting point for melanoma-targeted therapies. At least
for BRAF, cotargeting of constituents of the PI3 kinase
pathway or CDK4 appears to be a plausible strategy for
overcoming resistance to BRAF inhibitors and antagonizing
multiple oncogenic pathways to achieve greater degrees of
tumor control.
Melanoma Tumor Immunology
Studies of immune regulation and the mechanisms of
tumor-induced immune suppression have identified specific
obstacles to effective immunotherapy of melanoma. These
include the physiologic down-modulation of the immune
response through the upregulation of the expression of
KEY POINTS
● Delineation of genetic alterations in melanoma has
provided the opportunity to develop targeted therapy
in the treatment of refractory disease.
● For the approximately 50% of melanoma patients
whose tumors harbor mutated BRAF, BRAF inhibitors
produce unprecedented response rates and a
survival advantage compared with chemotherapy.
● Advances in the understanding of immune-system
function and tolerance have led to the development of
a new generation of targeted immunotherapies.
● Ipilimumab represents the first immunotherapy to
improve survival in phase III trials, with durable
responses observed in a subset of patients.
● Selection of optimal therapy for individual patients
requires consideration of patients and disease characteristics
to devise best first-line and sequential
therapy approaches.
molecules, such as CTLA4 on the surface of activated T cells.
Mechanisms identified for tumor-induced immune suppression
have included stimulation of CD4�, CD25� T–regulatory
cell (Treg) production, which serves to limit immune
activation, inhibition of T-cell receptor signaling, and melanoma
cell expression of PDL1, blocking the cytolytic function
of tumor-infiltrating T lymphocytes (Lisee; Greenwald, Freeman).
These biologic discoveries have been made clinically
relevant through the development of therapeutic agents that
directly or indirectly target these immunomodulatory pathways,
potentially enabling the restoration of effective,
tumor-specific immune destruction. Ipilimumab, an antibody
directed against CTLA4, has shown a significant survival
benefit in two phase III studies of patients with
advanced melanoma, leading to its U.S. Food and Drug
Administration (FDA) approval in 2011. In addition, antibodies
that block the effects of tumor PDL1 expression
(anti-PD1 antibodies) have shown encouraging response
rates and toxicity profiles in phase I trials, prompting
extensive additional investigation. Other efforts have attempted
to selectively deplete Treg cells through lymphodepletion
with nonmyeloablative chemotherapy coupled
with tumor specific adoptive T-cell immunotherapy. Another
strategy has focused on identifying the patients most likely
to respond to immunotherapy, based on melanoma genomic
profile or gene-expression pattern; immune-cell infiltration;
or, checkpoint inhibitor or plasma cytokine expression.
Treatment is restricted to those most likely to benefit or
focuses on identifying ways of manipulating the immune
system to convert tumors to a more immune-responsive
phenotype.
Immunotherapy for Melanoma
IL 2–Based Therapy
High-dose bolus IL2 (HD IL-2) received FDA approval in
1998 for the treatment of patients with metastatic melanoma,
largely based on its ability to produce durable complete
responses in 5% to 10% of patients. In a retrospective
review of 270 patients treated on multiple phase II studies,
the objective response rate was 16%, with a median duration
of 9 months (range from 4 months to over 106 months).
Despite the low objective response rate, 59% of complete
responders remained progression-free at 7 years, and no
patient responding for longer than 30 months had progressed,
suggesting that some patients were “cured.” 2 Treatment,
however, was associated with significant toxicity
limiting its application to a select group of patients treated
in specialized centers.
Efforts to improve on the efficacy of IL-2 in patients with
melanoma have included combinations with chemotherapy,
i.e., biochemotherapy, vaccines, and adoptive-cell therapy.
Although several phase II trials, a small phase III trial, and
two meta-analyses suggested that combinations of IL-2
and cisplatin-based biochemotherapy offered benefit relative
to either chemotherapy or IL-2 alone, several multiinstitutional
phase III trials have failed to confirm this
benefit.
Another approach to improving the activity of HD IL-2
involved the addition of a gp100 peptide vaccine. A recently
reported phase III trial randomly assigned 185 patients with
metastatic melanoma to HD IL-2 given alone every three
weeks or in combination with a gp100 peptide vaccine. 13
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