2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

COMBINATIONS FOR MELANOMA
agents that, when combined, have increased antitumor
activity with decreased toxicities.
Despite the wealth of supportive preliminary evidence,
14,16-18 studies combining a BRAF inhibitor with a
PI3K or AKT inhibitor to treat or prevent MAPKindependent
resistance are not in the clinic. However, there
are several experiences combining MEK inhibitors with
PI3K inhibitors that may provide the benefit of blocking
both pathways. But this potential benefit has to be weighed
against the expected increase in toxicities because neither
agent would be directly blocking a mutated oncogene in this
setting.
Combination of Immunotherapies and
Targeted Therapies
Combinations of immunotherapy agents and oncogene
driver inhibitors have the potential to merge the benefits of
both types of agents for patients with advanced melanoma.
Targeted oncogene pathway inhibitors induce high rates of
tumor responses that tend to last months, whereas immunemodulating
agents tend to have infrequent but highly durable
tumor responses. The promise of combining them is to
maintain the high rate of targeted therapy responses and
make them more frequently durable with immunotherapies.
23,24
Key to the development of this type of combination is
demonstrating that both approaches are not negatively
interacting, although they can have synergistic effects by
potentiating each other. In vitro studies have shown that
Author’s Disclosures of Potential Conflicts of Interest
Author
Employment or
Leadership
Positions
Consultant or
Advisory Role
Antoni Ribas Amgen; Bristol-
Myers Squibb;
Celgene;
Genentech;
Merck;
Millennium;
Roche
1. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with
ipilimumab in patients with metastatic melanoma. New Engl J Med. 2010;
363:711-723.
2. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine
for previously untreated metastatic melanoma. New Engl J Med. 2011;364:
2517-2526.
3. Chapman PB, Hauschild A, Robert C, et al. Improved survival with
vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med.
2011;364:2507-2716.
4. Tarhini AA, Kirkwood JM. Tremelimumab and interferon combination
in melanoma. Semin Oncol. In press.
5. Maker AV, Phan GQ, Attia P, et al. Tumor regression and autoimmunity
in patients treated with cytotoxic T lymphocyte-associated antigen
4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol. 2005;12:
1005-1016.
6. Ribas A, Comin-Anduix B, Chmielowski B, et al. Dendritic cell vaccination
combined with CTLA4 blockade in patients with metastatic melanoma.
Clin Cancer Res. 2009;15:6267-6276.
7. Uno T, Takeda K, Kojima Y, et al. Eradication of established tumors in
mice by a combination antibody-based therapy. Nat Med. 2006;12:693-698.
8. Takeda K, Kojima Y, Uno T, et al. Combination therapy of established
tumors by antibodies targeting immune activating and suppressing molecules.
J Immunol. 2010;184:5493-5501.
BRAF inhibitors are not detrimental to human or murine
lymphocyte function. 25,26 Furthermore, given the evidence
that BRAF inhibitors can induce a paradoxical activation of
the MAPK pathway in cells that have strong RAS/GTP
activity, 27-29 which would be expected to also occur in
activated lymphocytes, it is certainly possible that at certain
doses and concentrations BRAF inhibitors may actually
potentiate the function of lymphocytes. Besides this potential
beneficial effect of BRAF inhibitors directly in immune
cells, these agents may benefit in combination by increasing
expression or cross-presentation of tumor antigens to the
immune system, or by releasing signals that lead to an
adverse tumor environment limiting immune cell function.
Conclusion
Advances in the treatment of metastatic melanoma are
based on an improved understanding of the immunobiology
and oncogenic signaling in this disease. Single-agent therapies
with ipilimumab and vemurafenib have demonstrated
improvement in patient survival in randomized clinical
trials. 1-3 However, the majority of patients still require
additional treatment options. Understanding the mechanisms
of action and resistance to the new single-agent
therapies allows an opportunity to rationally design combination
therapies that may provide additional benefits to
patients. Such combinations are being developed preclinically
and in the clinic, and are poised to change the current
treatment approaches for patients with metastatic melanoma.
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REFERENCES
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Remuneration
9. Poulikakos PI, Persaud Y, Janakiraman M, et al. RAF inhibitor resistance
is mediated by dimerization of aberrantly spliced BRAF(V600E).
Nature. 2011;480:387-390.
10. Shi H, Moriceau G, Kong X, et al. Melanoma V600E BRAF amplification
drives acquired resistance to vemurafenib. Nat Commun. In press.
11. Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to
B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468:
973-977.
12. Wagle N, Emery C, Berger MF, et al. Dissecting therapeutic resistance
to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol.
2011;29:3085-3096.
13. Johannessen CM, Boehm JS, Kim SY, et al. COT drives resistance to
RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468:
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14. Shi H, Kong X, Ribas A, et al. Combinatorial treatments that overcome
PDGFR{beta}-driven resistance of melanoma cells to V600EB-RAF inhibition.
Cancer Res. 2011;71:5067-5074.
15. Villanueva J, Vultur A, Lee JT, et al. Acquired resistance to BRAF
inhibitors mediated by a RAF kinase switch in melanoma can be overcome by
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16. Jiang CC, Lai F, Thorne RF, et al. MEK-independent survival of
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