2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

has been intensively studied. These studies have proposed
and validated a number of resistance mechanisms in small
numbers of patient tumor samples including: (1) Mutations
of NRAS, the protein upstream of BRAF in the MAPK
pathway. 33 (2) Activation of downstream signaling proteins
including MEK1 through mutation or activation by overexpression
of MAP kinases 34,35 (3) The expression of alternate
shortened forms of the BRAFV600 mutated molecule that
are capable of binding together and reactivating the pathway
even in the presence of vemurafenib. 36 All three of these
mechanisms appear to reactivate the MAPK pathway, providing
a direction to pursue in order to effectively delay or
overcome these forms of resistance. (4) Alternatively, activation
or overexpression of alternate pathways through
activation of receptor tyrosine kinases, such as IGFR1 or
PDGFRb. Both of these RTK appear to signal at least in part
through the PI3K/Akt/mTOR pathway. 33,37
Ongoing trials are combining BRAF and MEK inhibitors
with the goal of delaying or overcoming resistance as a
result of reactivation of the MAPK pathway. On the other
hand, combinations of BRAF-inhibitor therapy with either
PI3 kinase, PI3 kinase/mTOR, Akt, mTORC1- and mTORC2dual
inhibitors could be effective inhibiting mechanisms of
resistance involving alternate pathways and different receptor
tyrosine kinases.
Although BRAF inhibitors induce rapid disease regression
and symptom benefit in patients with bulky disease, markedly
delay progression, and improve overall survival for the
overall metastatic melanoma population, there is clearly
need for further improvement of these outcomes.
For patients with BRAFV600E/K mutant melanoma,
there is a choice of therapy between new and older immunotherapy
approaches, including high dose IL-2, ipilimumab,
or a clinical trial investigating anti-PD1 compared
with a BRAF inhibitor. It is apparent that patients with
symptomatic, bulky, rapidly growing, and high-serum LDH–
associated melanoma are much more likely to have rapid
clinical improvement when treated with vemurafenib. The
improvement may be relatively short term but can last up to
12 months in some patients. These patients are unlikely to
benefit from immunotherapy, in part, because immunebased
treatments can take a period of time and some
experience progression initially before later improvement.
Furthermore, the percent of patients having an objective
clinical response is much lower with IL-2 (15% to 20%) or
ipilimumab (5% to 10%) than with vemurafenib (� 50%).
The greater dilemma surrounds the patient with BRAFmutant
melanoma who has nonbulky, asymptomatic disease,
and with a normal LDH. These patients have a choice.
If young enough, with excellent organ function and at a
treatment center with extensive experience, IL-2 may be the
first choice. Or, in others who do not fulfill IL-2 criteria,
ipilimumab. However, because of the delay in beneficial
effect, it may require waiting up to 4 to 6 months before one
can be certain that the melanoma is not responsive. Also, in
this subset of patients, the response rate to vemurafenib is
above 60% in the phase II trial, and overall survival is quite
long with a median of 15.9 months. 31 This compares to 10
months on the previously treated trial and 11.2 months on
the treatment-naive trial with ipilimumab. The definite
answer to the question of which drug to use first will only be
answered through trials including combinations of the two
agents.
528
Treatment Options for BRAF WT Melanoma
BRAF WT melanoma is a heterogeneous disease that
includes patients with NRAS mutated melanoma (about
one-third of these BRAF WT patients) as well as very small
subset of patients with CKIT mutant melanoma from mucosal,
acral, and chronic sun-damaged sites. Characterizing
these mutations can be justified currently for the purposes
of directing patients to relevant clinical trials. There is
supporting literature showing that a fraction of patients
with L597 or K642 mutations in CKIT are responsive to
imatinib, some of which the results are quite durable (� 12
months). 38,39 NRAS approaches will be discussed below.
Immunotherapy remains a strong consideration in BRAF
WT patients. Those who are eligible for IL-2 should consider
this treatment at an experienced center. Since it has the
longest follow-up, we are confident of both its response rate
and the frequency of extremely durable disease responses.
Those patients are frequently assessed at 7 to 8 weeks and
again at 11 to 12 weeks and in the case of progression or
even stable disease, this treatment is rarely continued.
Toxicities are acute and rarely, if ever, delayed. For these
reasons, we believe that consideration of ipilimumab should
come after these patients have received IL-2 if the treatment
is appropriate. As stated previously, new trials with anti-
PD1 antibodies are ongoing and demonstrate exciting, early
results with response rates over 20% of which most are
durable lasting over 12 months.
It is critical to continue efforts to define other driver
kinases within the BRAF WT population that could be
targeted with drug therapy. For now, efforts are underway
to investigate approaches to NRAS mutant melanoma,
These include MEK inhibitors (GSK 1120212, TAK733, or
others) alone or in combination with inhibitors of the PI3K/
AKT, mTOR pathway. These trials are still in dose-finding
phases, but soon phase II efforts will be undertaken in
NRAS mutant melanoma.
Finally, chemotherapy still represents an option for patients
without either good standard options, as listed above,
or clinical phase I and II trial options. Because of its limited
long-term benefit, chemotherapy is best considered for patients
who are symptomatic or with rapidly growing disease
with a goal of improving quality of life. Agents, including
dacarbazine, temozolomide, and taxane-based regimens,
have all demonstrated similar antitumor activity with below
20% response rates. Rarely, long-lasting responses are observed.
Conclusion
FLAHERTY, SOSMAN, AND ATKINS
Given the current availability of multiple treatment options,
patients and physicians now often have choices regarding
initial treatment and the sequence of various
treatments. For patients with BFAFV600E mutant melanoma,
options could include HD IL-2, ipilimumab or vemurafenib.
At the moment, there appears to be only limited
information to guide this choice. Although vemurafenib
appears to be equally active in patients whose disease has
progressed following IL 2-based immunotherapy, there is no
data on its activity following resistance to ipilimumab.
Similarly, there is no data on the activity of ipilimumab (or
even the feasibility of stopping vemurafenib and administering
ipilimumab) following disease progression on vemurafenib.
It is conceivable that patients treated initially with