editorials
Been There, Not Done That — Melanoma in the Age
of Molecular Therapy
Marc S. Ernstoff, M.D.
In 1976, the detection of estrogen-receptor expression in melanomas ushered in the era of targeted
therapy in melanoma, although we did not use that
term back then.1 In 1992, Cocconi et al. found
that dacarbazine plus tamoxifen provided a higher response rate and longer survival than dacarbazine, but only in women.2 Subsequently, whether
melanoma cells express estrogen receptors was
questioned, and the efficacy of tamoxifen could
not be confirmed. Since then, the drug has not
been used to treat melanoma. However, molecular
analysis of tumors has revealed specific growthpromoting pathways in human cancers that have
become targets for therapy.
BRAF is a member of the Raf kinase family,
which signals from growth factor receptors on the
cell surface to the nucleus.3 The most common
mutation in BRAF (BRAF V600E) is found in 30 to
60% of melanomas.3 BRAF V600E constitutively
activates the MAPK–ERK signal-transduction pathway, which enhances the proliferative and metastatic potential of tumor cells. Sorafenib, the first
BRAF-targeted agent that has been studied in metastatic melanoma, has not shown major clinical
effects in this disease and is now recognized as a
weak BRAF kinase inhibitor.
In a phase 1 study, the use of the selective BRAF
V600E kinase inhibitor vemurafenib (PLX4032) was
associated with a response rate of 69% in patients
with melanoma with tumors that harbored the
BRAF V600E mutation.4 In this issue of the Journal,
Chapman and colleagues report the results of a
phase 3 study, called BRAF Inhibitor in Melanoma 3 (BRIM-3), in which patients with metastatic
melanoma with the BRAF V600E mutation were
randomly assigned to receive vemurafenib or dacarbazine.5 The treatment response was determined by the investigators. During the trial, an
independent data and safety monitoring board
determined that survival end points had been
met, and patients who were treated with dacarbazine were permitted to cross over to receive
vemurafenib. At the time of the reported analysis, the hazard ratio for death in the vemurafenib
group was 0.37 (95% confidence interval [CI],
0.26 to 0.55; P<0.001), and the hazard ratio for
progression-free survival was 0.26 (95% CI, 0.20
to 0.33; P<0.001). Although the adverse-events profile for vemurafenib was generally mild, dose interruption and modification were required in 38%
of patients.
Melanoma, like other cancers, is a collection of
heterogeneous tumors that are differentiated by
means of molecular markers, and each molecularly defined subgroup will probably have a different
treatment algorithm.6 The results of the BRIM-3
study represent a major shift in the way we think
about and treat melanoma.
For this preliminary report in the BRIM-3
study, follow-up was short, and the final estimate
of survival outcomes is still to be determined. Furthermore, the study used investigator-reported
response, not the findings of an independent
response-review board, which could bias the rates
of response and progression-free survival, though
not the rates of overall survival. The latter rates
will be influenced by the decision of the data and
safety monitoring board to allow patients to cross
over to receive vemurafenib. Whether the reportedly low rate of complete response to vemurafenib
(0.9%) is the true rate and whether such a response would remain durable after the discontinuation of vemurafenib is not yet known.
To put the BRIM-3 study into perspective, interleukin-2 and ipilimumab have been approved by
the Food and Drug Administration as immunotherapies for metastatic melanoma. The 2-week
administration of high-dose interleukin-2 produces
an objective response in 16% of a highly selected group of patients and complete remission in
6% of patients, with a median duration of complete response of more than 10 years. Four doses of ipilimumab produce a median survival of
10 months (a 4-month advantage over a vaccine
control group), a median progression-free survival of 11 weeks, and an objective response rate of
7% (with a rate of complete remission of 0.5%).
There are several potential long-term health
consequences of BRAF V600E inhibition, which
can cause paradoxical stimulation of MAP-kinase–
mediated events in wild-type BRAF cells and has
been suggested as a mechanism for susceptibility
to nonmelanoma skin cancers in patients receiving vemurafenib.7 Thus, careful surveillance of pa-
n engl j med 364;26 nejm.org june 30, 2011
2547
The New England Journal of Medicine
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Copyright © 2011 Massachusetts Medical Society. All rights reserved.
editorials
tients for other cancers is warranted. Although
little is known about the use of targeted adjuvant
agents in patients undergoing surgery, it is now
reasonable to consider testing of adjuvant vemurafenib in patients with high-risk stage II or III
melanoma with the BRAF V600E mutation on the
basis of the findings in the BRIM-3 study.
Mechanisms of resistance to BRAF V600E kinase inhibitors include upstream and downstream
events and activation of alternative pathways that
are therapeutic targets.8 Experience with other tumor types has shown that the use of a combination of agents that block multiple pathways has
a substantial effect on both efficacy and toxic
effects. Thus, the choice of the components of
drug combinations must be scientifically based
and tested in clinical studies.
The inhibition of BRAF V600E in mutated
melanoma cells blocked phosphorylated ERK, upregulated melanocyte-differentiation antigens with
resultant improved recognition by antigen-specific
T cells, and did not impair T-cell function, which
set the stage for combining immune therapy with
BRAF V600E targeted therapy.9 MAPK has been
implicated in the control of cell-cycle checkpoints,
and MEK inhibition has been shown to enhance
the effects of chemotherapy in vitro, providing a
platform for combination cytotoxic chemotherapy
and BRAF blockade.10 The benefit of vemurafenib
does not seem to be adversely affected by previous
treatment with other agents.4 Until further information is available, careful consideration of the
use of immune therapy before the initiation of
vemurafenib may be warranted.
The new understanding of molecular pathways
changes the way we classify melanomas and influences therapy. The development of vemurafenib
is an example of the translation of these concepts
2548
into clinical practice. For patients with metastatic
melanoma with the BRAF V600E mutation, the
availability of vemurafenib is a major defining moment that will have an important effect on survival and quality of life. Vemurafenib will be part
of our therapeutic armamentarium for patients
with melanoma and potentially for those with
other cancers harboring BRAF V600E mutations,
as well as a valuable tool for exploring new approaches to melanoma treatment.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
From Dartmouth Medical School and the Norris Cotton Cancer
Center, Dartmouth–Hitchcock Medical Center, Lebanon, NH.
This article (10.1056/NEJMe1105792) was published on June 5,
2011, at NEJM.org.
1. Fisher RI, Neifeld JP, Lippman ME. Oestrogen receptors in
human malignant melanoma. Lancet 1976;2:337-9.
2. Cocconi G, Bella M, Calabresi F, et al. Treatment of meta-
static malignant melanoma with dacarbazine plus tamoxifen.
N Engl J Med 1992;327:516-23.
3. Pollock PM, Meltzer PS. A genome-based strategy uncovers
frequent BRAF mutations in melanoma. Cancer Cell 2002;2:5-7.
4. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated,
activated BRAF in metastatic melanoma. N Engl J Med 2010;
363:809-19.
5. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16.
6. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of
genetic alterations in melanoma. N Engl J Med 2005;353:213547.
7. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF
inhibitors transactivate RAF dimers and ERK signalling in cells
with wild-type BRAF. Nature 2010;464:427-30.
8. Solit DB, Rosen N. Resistance to BRAF inhibition in melanomas. N Engl J Med 2011;364:772-4.
9. Boni A, Cogdill AP, Dang P, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res 2010;70:5213-9.
10. Shukla A, Hillegass JM, MacPherson MB, et al. Blocking of
ERK1 and ERK2 sensitizes human mesothelioma cells to doxorubicin. Mol Cancer 2010;9:314.
Copyright © 2011 Massachusetts Medical Society.
n engl j med 364;26 nejm.org june 30, 2011
The New England Journal of Medicine
Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on July 14, 2014. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.