Metastatic Melanoma Recent Advances and Emerging Therapies In the Systemic Treatment of

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Recent Advances and Emerging Therapies
In the Systemic Treatment of
Metastatic Melanoma
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JEFFREY T. YORIO, MD
Fellow, Hematology and Oncology
KEVIN B. KIM, MD
Associate Professor
Department of Melanoma
Medical Oncology
The University of Texas
MD Anderson Cancer Center
Houston, Texas
M
elanoma, the malignant transformation of melanocytes, most
commonly occurs in the skin but also may arise from the mucosal
surfaces or in the choroid of the eyes. Melanoma is the fifth and
sixth most common cancer in men and women, respectively, in the United
States.1 In 2012, more than 76,000 people will be diagnosed with malignant
melanoma, and more than 9,000 people will die from the disease nationally.1
I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
agent’s ability to induce a durable response. Unfortunately, this response is observed in only a small subset of
patients, and IL-2 is associated with significant toxicities,
such as capillary leak syndrome, that frequently require
intensive monitoring in a dedicated unit or intensive care
facility.7,8 Other agents—including temozolomide (Temodar, Schering-Plough), cisplatin, carboplatin, vinblastine,
paclitaxel, carmustine, and lomustine (CeeNu, BristolMyers Squibb)—are commonly used off-label to treat
melanoma, but none of these agents or their various
combinations have been found to offer a survival advantage over dacarbazine alone.9 Clearly, more active and
d.
Although surgery offers a great cure rate for patients
with early-stage melanoma, those who have either metastatic disease or a high risk for recurrence are given a
much poorer prognosis. In fact, the median overall survival (OS) of patients with stage IV melanoma is only 6
to 9 months.2-4
Dacarbazine remains the only cytotoxic chemotherapy that is FDA-approved for the treatment of metastatic
melanoma. However, dacarbazine has modest clinical
efficacy, with a response rate of only about 10%.2,4-6 The
FDA also has approved high-dose interleukin-2 (IL-2) for
the treatment of advanced melanoma because of the
C L I N I C A L O N C O L O G Y N E W S • J U LY 2 0 1 2
1
less toxic drugs are needed for patients with advanced
melanoma. In this article, we review recent advances and
emerging therapeutic approaches in the systemic treatment of metastatic melanoma.
Newly Approved Drugs
For Late-Stage Melanoma
IPILIMUMAB
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Immunotherapy has been used to treat melanoma
for decades. Cancer cells, such as those that make up
melanoma, have tumor-associated antigens that can be
recognized by T cells. This recognition leads to a host
response that targets the tumor cells.10 The standard
immunotherapy, high-dose IL-2, enhances this response
but elicits a durable clinical response in only a small subset of patients.8,11,12 Accordingly, researchers have actively
sought to identify and develop more effective immunologic agents with better safety profiles.
Ipilimumab (Yervoy, Bristol-Myers Squibb) is a fully
human monoclonal antibody that binds to cytotoxic
T-lymphocyte antigen-4 (CTLA-4), a co-inhibitory receptor molecule found on the surface of activated T cells.
T-cell activation begins when the T-cell receptor binds
to an antigen presented by a major histocompatibility
complex on antigen-presenting cells, such as dendritic cells. Cluster of differentiation 28 (CD28), a co-stimulatory receptor molecule found on T cells, binds to B7
(CD80/CD86) found on antigen-presenting cells, leading to T-cell proliferation and IL-2 production. As T cells
become activated, CTLA-4 is upregulated to the cell
surface, where it competes successfully with CD28 for
B7 to halt further cell proliferation in a self-regulatory
mechanism. Ipilimumab blocks CTLA-4 on the cell surface, thereby preventing CTLA-4 from binding to B7
molecules and allowing CD28 to bind to these molecules instead, leading to further T-cell proliferation and
IL-2 production.13,14 Ultimately, this can help increase the
immune response to cancer cells.
Initial clinical studies revealed that ipilimumab
could be a promising new therapy for metastatic melanoma.15,16 A Phase I/II trial of ipilimumab (≤10 mg/kg
every 3 weeks) in 23 patients with metastatic melanoma demonstrated a disease control rate of 39%, with
at least 2 patients experiencing a durable response of
longer than 21 months.15 These encouraging results led
to several Phase III trials of ipilimumab in patients with
metastatic melanoma (Table 1).17,18
In the first Phase III study of ipilimumab, 676 previously treated patients with unresectable stage III or
IV melanoma were randomly assigned, in a 3:1:1 ratio,
to receive ipilimumab with a glycoprotein 100 (gp100)
peptide vaccine (n=403), ipilimumab alone (n=137), or
the gp100 peptide vaccine alone (n=136).17 Ipilimumab was given at a dose of 3 mg/kg every 3 weeks for
4 doses. The median OS of patients who received ipilimumab alone (10.1 months) was significantly longer
than that of patients who received the gp100 vaccine
alone (6.4 months; hazard ratio [HR], 0.66; P=0.003).
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However, the median OS of patients who received ipilimumab with the gp100 vaccine did not differ significantly from that of patients who received ipilimumab
alone. The risk for disease progression in patients who
received ipilimumab alone was 36% lower than that
for patients who received the gp100 vaccine alone
(P<0.001). The median progression-free survival (PFS)
durations of the 3 groups were similar (2.76 months in
the combination group, 2.86 months in the ipilimumab-alone group, and 2.76 months in the gp100 vaccine-alone group). The results of this trial led to the
FDA’s approval of the drug for the treatment of metastatic melanoma in March 2011.
In the second Phase III study of ipilimumab, 502
treatment-naive patients with metastatic melanoma
were randomized to receive dacarbazine with or without ipilimumab.6 During the induction phase, ipilimumab was given at a dose of 10 mg/kg every 3 weeks for
4 doses. During the maintenance phase, patients who
did not experience severe toxicity during the induction phase were given additional doses of ipilimumab
(10 mg/kg every 12 weeks). The median OS duration
of the patients who received dacarbazine plus ipilimumab (11.2 months) was significantly longer than that
of the patients who received dacarbazine alone (9.1
months; P<0.001). The 3-year OS rates in the dacarbazine plus ipilimumab group and the dacarbazine-only
group were 20.8% and 12.2%, respectively. The risk
for disease progression in the patients who received
dacarbazine plus ipilimumab was 24% lower than
that for the patients who received dacarbazine alone
(P=0.006).
As with other immune-stimulating agents, ipilimumab induces immune-related adverse events (AEs). In the
first Phase III trial, the most common immune-related
AEs among those receiving ipilimumab alone were diarrhea (28%), pruritus (24%), rash (19%), and colitis (8%).17
Grade 3 or 4 diarrhea and colitis was seen in 5% of the
patients. The addition of dacarbazine to ipilimumab in
the second Phase III trial also resulted in notable elevations in serum liver enzyme levels. Of the 247 patients
receiving the combination, elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
were observed in 33% and 27% of the patients, respectively.6 Grade 3 or 4 elevations in ALT and AST were seen
in 21% and 17%, respectively. Endocrine immune-related
AEs such as hypothyroidism, hypopituitarism, and adrenal insufficiency were observed but were uncommon.
Patients who develop grade 2 diarrhea should be
considered for treatment with oral steroids such as
budesonide, whereas patients with grade 3 and 4 diarrhea should discontinue ipilimumab and receive highdose systemic corticosteroids until improvement.18
Infliximab, an anti-tumor necrosis factor-α antibody, has
been used with some success to treat patients who are
unresponsive to high-dose steroids. The use of highdose IV corticosteroids also has been suggested for
grade 3 or 4 elevations in serum liver enzyme levels and
endocrinopathies.
I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
d.
2
Table 1. Clinical Data From Positive Phase III Studies of Melanoma
N
Treatment Setting
Primary End
Point Results
Hazard Ratio (95%
CI)
gp100 vaccine
136
Second-line
OS, 6.4 mo
Reference
Ipilimumab
137
OS, 10.1 mo
0.66 (0.51-0.87)
0.003
Ipilimumab + gp100 vaccine
403
OS, 10.0 mo
0.68 (0.55-0.85)
<0.001
OS, 9.1 mo
Reference
OS, 11.2 mo
0.72 (0.59-0.87)
OSa
Reference
Trial and Regimen
P Value
NCT00094653
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NCT00324155
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Dacarbazine + placebo
First-line
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Dacarbazine + ipilimumab
252
<0.001
s
NCT01006980
Dacarbazine
338
Vemurafenib
337
Dacarbazine
Vemurafenib
First-line;
V600E BRAF
mutation
a
OS
0.37 (0.26-0.55)
338
PFS, 1.6 mo
Reference
337
PFS, 5.3 mo
0.26 (0.20-0.33)
PFS, 2.7 mo
Reference
PFS, 5.1 mo
0.30 (0.18-0.51)
PFS, 1.5 mo
Reference
PFS, 4.8 mo
0.45 (0.33-0.63)
<0.001
<0.001
NCT01227889 (BREAK-3)
Dacarbazine
63
Dabrafenib
187
First-line;
V600E BRAF
mutation
<0.0001
NCT01245062 (METRIC)
Chemotherapyb
108
Trametinib
214
≤1 prior systemic
therapy; V600E
BRAF mutation
<0.001
CI, confidence interval; gp100, glycoprotein 100; OS, overall survival; PFS, progression-free survival
a
b
Inadequate number of patients in follow-up to provide reliable estimates of the survival curve
Dacarbazine or paclitaxel
VEMURAFENIB
d.
The Ras/Raf/MEK/extracellular signal-regulated
kinase (ERK) pathway is a key pathway for cell proliferation, particularly in cancer cells (Figure).19 In 2002, Davies
et al reported that nearly 60% of melanomas harbor a
mutation in BRAF, which codes for a serine-threonine
protein kinase involved in the Ras/Raf/MEK/ERK pathway.20 Most BRAF mutations are the result of a single
nucleotide substitution in which valine is replaced by
glutamic acid at codon 600 (V600E) of exon 15, leading
to the constitutive activation of the MEK protein and
ERKs, which are essential to melanoma cell proliferation.
Melanoma cells with the BRAF mutation do not require
Ras activation to proliferate, indicating that the BRAF
mutation is a driving force behind melanoma cell growth.
To inhibit the Raf/MEK/ERK pathway, researchers
investigated sorafenib (Nexavar, Bayer), an inhibitor of
multiple kinases, including BRAF, CRAF, and vascular
endothelial growth factor receptor (VEGFR). However,
2 Phase II trials of sorafenib at a dose of 400 mg twice
daily revealed that the drug elicited little or no response
in patients with metastatic melanoma; additionally, the
presence of the BRAF mutation was not correlated with
response.21,22 Similarly, 2 large randomized Phase III trials
revealed that the addition of sorafenib to front- or second-line carboplatin or paclitaxel yielded no additional
clinical benefit in patients with metastatic melanoma.23,24
Despite the underwhelming results with sorafenib,
researchers used scaffold-based drug design methods to develop increasingly selective inhibitors of the
mutated Raf kinase. One of these new drugs, PLX4032
(later named vemurafenib [Zelboraf, Roche]), was found
to have a high affinity for the mutant BRAF kinase.25 A
first-in-human Phase I trial of oral vemurafenib enrolled
55 patients and found the maximum tolerated dose
(MTD) of the drug to be 960 mg twice a day.26 Thirty-two patients with metastatic melanoma harboring a
BRAF mutation were then enrolled in the dose-extension cohort and received vemurafenib at a dose of 960
mg twice a day. Of these 32 patients, 26 had a partial
or complete response (CR), for an overall response rate
(ORR) of 81% with a confirmed response rate of 56% per
Response Evaluation Criteria in Solid Tumors (RECIST).
Subsequently, a large Phase II study of vemurafenib
was conducted in 132 previously treated patients who
had metastatic melanoma harboring a V600E BRAF
I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
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Cell membrane
receptor
PI3K
Ras
PTEN
A
AKT
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Raf
mTOR
ERK 1/2
IF4E
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MEK 1/2
Cyclin D1
Transcription
factors
p70
MMP-2
Tumor cell survival,
proliferation, invasion
Nucleus
Figure. Commonly activated signal transduction pathways in melanoma.
ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin
4
I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
of patients experienced grade 2 or 3 photosensitivity reactions, but the use of sunblock helped prevent
the blistering typically observed in grade 3 reactions.
Eighteen percent of patients developed either cutaneous squamous cell carcinomas (SqCC) or keratoacanthomas; fortunately, these were all treated by simple
excision with no further complications or evidence of
SqCC in other organs.
These SqCCs could have been the result of the paradoxical activation of the Ras/Raf/MEK/ERK pathway
in premalignant skin lesions that lack a BRAF mutation.28,29 Poulikakos et al demonstrated that the binding of vemurafenib to BRAF, which forms a dimer with
another Raf kinase, actually leads to transactivation of
adenosine triphosphate (ATP)-bound Raf, causing the
downstream activation of MEK and ERK in wild-type
BRAF cells.30 Many vemurafenib-induced SqCCs harbor a mutation in Ras that ultimately becomes activated when vemurafenib binds to wild-type BRAF.28,29
Based on the statistically significant improvement
in both OS and PFS and the acceptable safety profile,
in summer 2011 the FDA approved vemurafenib for the
treatment of metastatic melanoma harboring a V600E
d.
mutation.27 The ORR, which was validated by an independent review committee, was 53%, with a median
PFS duration of 6.8 months, thus confirming the promising results of the Phase I study.
A concurrent, large multicenter randomized Phase
III trial was then conducted to compare the clinical
benefit of vemurafenib with that of dacarbazine in
treatment-naive patients with metastatic melanoma
harboring a V600E BRAF mutation (Table 1).5 Six hundred seventy-five patients were randomized to receive
either vemurafenib or dacarbazine, with the primary
end points being OS and PFS. At the time of the interim analysis, the hazard ratio for death in the vemurafenib group was 0.37 (P<0.001), and the estimated
median PFS duration of patients in the vemurafenib
arm (5.3 months) was significantly longer than that
of patients in the dacarbazine arm (1.6 months; HR,
0.26; P<0.001). The study was stopped at the time of
the interim analysis so that patients in the dacarbazine
arm could receive vemurafenib.
Overall, patients in the Phase III trial tolerated vemurafenib fairly well.5 The most common AEs were arthralgias, fatigue, and cutaneous events. Twelve percent
Table 2. Ongoing Phase III Clinical Trials for Metastatic Melanoma
Trial and Regimen
Primary
End Point
N
V600E BRAF
mutation
PFS
340
First-line
V600E/K BRAF
mutation
OS
694
First-line
C-Kit
(juxtamembrane)
OS
200
First-line
Any
OS
700
Treatment Setting
Mutation Criteria
First-line
NCT01584648
Dabrafenib (GSK2118436) plus
trametinib (GSK1120212) versus dacarbazine
NCT01597908
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Dabrafenib plus trametinib versus
vemurafenib (Zelboraf, Roche)
Co
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NCT01280565
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Masitinib versus dacarbazine
NCT01515189
Ipilimumab (3 mg/kg) versus ipilimumab
(10 mg/kg)
OS, overall survival; PFS, progression-free survival
BRAF mutation. However, despite the high response
rate, a majority of patients will have disease progression within 1 year, and a long-term clinical benefit is
expected only in a small subset of patients. Therefore, more effective therapeutic strategies are urgently needed.
Emerging Targeted Therapies
SELECTIVE RAF INHIBITORS
MEK INHIBITORS
Another approach to treating metastatic melanoma is to inhibit the mitogen-activated protein (MAP)
kinase pathway at the level downstream of BRAF
kinase. This pathway is commonly activated in melanoma and is induced not only by mutated BRAF, but
also by kinase-activating NRAS mutations or other
upstream aberrations, such as receptor kinase phosphorylation. In this signal transduction pathway, the
MAP kinase kinase (MEK) protein is the direct substrate of activated BRAF kinase. Therefore, targeting
the MEK protein can inhibit the MAP kinase pathway.
The results of clinical trials of first-generation MEK
inhibitors were disappointing. For example, CI-1040
(Pfizer) and PD0325901 (Pfizer) had poor clinical activity and caused significant AEs, including retinal vein
occlusion, which resulted in the discontinuation of their
d.
The successful development of vemurafenib has
generated great interest in the clinical evaluation of
selective Raf inhibitors in patients with metastatic melanoma harboring a BRAF mutation. One such agent,
dabrafenib (GSK2118436, GlaxoSmithKline) is an orally available, highly potent ATP-competitive inhibitor of BRAF.31 In a Phase I/II study in patients with
advanced solid tumors, dabrafenib was well tolerated, and the MTD was not reached.32 Dabrafenib inhibited the phosphorylation of ERK in a dose-dependent
manner, and based on the pharmacokinetics and pharmacodynamics of the drug and its early clinical activity in the Phase I study, investigators recommended a
dose of 150 mg twice daily for further studies. Of the
16 patients in the study who had metastatic melanoma harboring a V600 BRAF mutation and received at
least 150 mg of dabrafenib twice daily, 10 (63%) had a
partial response. Interestingly, of the 10 patients in the
study who had active brain metastases measuring at
least 3 mm at baseline, 7 also had a clinical response
in the brain lesions.33
Subsequently, a Phase II study of dabrafenib
enrolled 76 patients who had metastatic melanoma
harboring a V600E/K BRAF mutation.34 Of these 76
patients, 45 (59%) had a confirmed response to dabrafenib, and the median PFS duration was 27.4 weeks.
The common AEs associated with dabrafenib were
arthralgia, pyrexia, fatigue, hyperkeratosis, and SqCC
of the skin.
Recently, a Phase III study (NCT01227889) was conducted to compare the PFS associated with dabrafenib
to that associated with dacarbazine in treatment-naive
patients with V600E BRAF-mutated melanoma. The
results demonstrated that patients who received dabrafenib had a significantly longer median PFS over
dacarbazine (6.7 vs. 2.9 months, respectively; HR, 0.35,
95% confidence interval [CI], 0.20-0.61).35 The ORR
also was superior in the dabrafenib arm (50% vs. 6%).
The OS data are not available because the study was
not designed to compare the OS, and the follow-up
thus far is too short for OS evaluation.
Another promising selective Raf inhibitor is LGX818
(Novartis). The results of a Phase I trial of the drug
(NCT01436656) will be available shortly.
I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
5
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development. 36,37 Selumetinib (AZD6244,
AstraZeneca) is an orally available, highly selective, allosteric inhibitor of
MEK1/2. Although in vitro studies revealed that melanoma cell
lines containing a BRAF mutation were particularly sensitive
to selumetinib,38,39 a randomized
Phase II study showed that the
drug had no clinical benefit over
temozolomide in chemotherapy-naive patients with metastatic melanoma.40 The differences in
the median PFS duration (78 vs
80 days) and ORR (5.8% vs 9.4%)
between the patients who received
selumetinib and those who received
temozolomide, respectively, were not statistically significant, and the response rates among
patients with melanoma containing a BRAF mutation
in each group were both the same, at 11%.
Clinical outcomes with the next-generation, hydrogen sulfate (Hyd-sulfate) formulation of selumetinib,
which has better oral bioavailability than does the
original crystalline formulation, are more promising. A
Phase I dose-finding study revealed the MTD of Hydsulfate selumetinib to be 75 mg twice daily.41 In a separate Phase I study of combination regimens containing
Hyd-sulfate selumetinib, patients with metastatic melanoma with a BRAF mutation had a higher clinical
response rate and longer median time to progression
than did those without a BRAF mutation, suggesting
that BRAF mutation is a positive predictive factor for
Hyd-sulfate selumetinib.42 A randomized Phase II study
comparing dacarbazine plus Hyd-sulfate selumetinib
with dacarbazine alone in treatment-naive patients
with BRAF-mutated melanoma (NCT00936221)
recently completed patient accrual, and the results of
this study are highly anticipated.
Another potent, highly selective, non–ATP-competitive MEK1/2 inhibitor is trametinib (GSK1120212,
GlaxoSmithKline). Although a Phase I study revealed
the MTD of trametinib to be 3 mg per day, 2 mg per
day was chosen as the recommended dose for future
studies on the basis of pharmacokinetic, clinical activity, and safety data.43 The results of a recent Phase II
study of trametinib (2 mg/d) in 97 previously treated
patients with metastatic melanoma harboring a V600
BRAF mutation are encouraging.44 In this study, of the
57 patients who had not been previously treated with
a BRAF inhibitor (of whom 81% had a V600E BRAF
mutation and 75% had M1c disease), 14 (25%) had a
confirmed response, and the median PFS duration
was 4 months (CI, 3.5-5.6 months). However, of the 40
patients who had previously received a BRAF inhibitor,
none had a confirmed clinical response, and the median PFS duration was 1.8 months (CI, 1.8-2.0 months).
The marked differences in clinical response and PFS
between the 2 groups suggest that the mechanisms
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of resistance to BRAF inhibitors also might
confer resistance to MEK inhibitors. The
results of an open-label randomized
Phase III study (NCT01245062)
comparing the PFS associated with trametinib with those
associated with dacarbazine or
paclitaxel in patients with metastatic melanoma harboring
a V600 BRAF mutation was
recently announced (Table 1).
The trametinib arm had a statistically significant improvement
in all 3 clinical parameters (RR,
PFS and OS).45 The median PFS
was 4.8 months for the trametinib
arm compared with 1.4 months for the
chemotherapy arm (HR, 0.44; CI, 0.310.64; P<0.0001). In addition, a HR for OS was
0.54 (CI, 0.32-0.92) with a P value of 0.0136, favoring
the trametinib arm.
Other MEK inhibitors in the early phases of clinical
investigation include AS703026 (EMD/Merck Serono),
E6201 (Eisai), MEK162 (Novartis), and GDC-0973
(Genentech).
The common AEs of MEK inhibitors include skin
rash, diarrhea, nausea, vomiting, peripheral edema,
and fatigue.36,37,40,41,43,44 Visual disturbances, such as
blurry vision or flashing lights, are common but generally mild. Serious ocular toxicity, including central serous retinopathy and retinal vein occlusion, is
uncommon. The decreased left ventricular ejection
fraction associated with the use of MEK inhibitors is
mostly asymptomatic and is reversible upon discontinuation of the drugs.
I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
Despite the high response rates observed with Raf
inhibitors and the promising clinical activity of MEK
inhibitors in patients with advanced melanoma harboring a BRAF mutation, the durations of response to
these drugs are relatively short because of acquired
drug resistance. Recent studies have elucidated a
number of mechanisms of resistance to these drugs,
including acquisition of activating NRAS mutations,46
acquisition of activating MEK mutations,47 upregulation of upstream receptor kinases,48 upregulation of
CRAF kinase,49 induction of splicing variants of BRAF
kinase,50 increased Cot expression,51 and activation of
PI3K/AKT signaling pathways.52,53 Loss of BRAF mutations and the development of secondary mutations
to the drug-binding domain of BRAF kinase have
not been observed at the time of drug resistance,
however.46,48
A recent study found that although vemurafenib
universally inhibited the phosphorylation of tumoral
ERK1/2 protein within 14 days of treatment, the phosphorylated-ERK1/2 was re-upregulated at the time of
d.
6
COMBINATION STRATEGIES
USING TARGETED THERAPIES
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disease progression in a subset of patients.54 This finding suggests that in at least some patients, the reactivation of the MAP kinase pathway is associated with
resistance to the Raf inhibitors and can, at least partially, bypass the inhibition of the BRAF mutations. In
vitro studies have shown that the addition of a MEK
inhibitor can delay the development of drug resistance
to a selective Raf inhibitor.47
On the basis of these encouraging findings, a Phase
I study of dabrafenib plus trametinib (NCT01072175)
was conducted in patients with metastatic melanoma.
The clinical data generated from the study’s interim
analysis are promising.55,56 Given at the recommended
doses for a Phase II study, the combination of dabrafenib (150 mg twice daily) and trametinib (1-2 mg
per day) was well tolerated, with mild AEs, the most
common of which were pyrexia, chills, nausea, diarrhea, and fatigue.55 Skin toxicity, including the development of cutaneous SqCC, occurred much less
commonly than was anticipated based on the safety
data of dabrafenib treatment alone, suggesting that
treatment with the selective Raf inhibitor paradoxically activated MAP kinase in the normal skin, and the
concurrent treatment with MEK eliminated this paradoxical MAP kinase activation. Of the 65 patients who
had metastatic melanoma containing a V600E/K/D
BRAF mutation and who had never received a BRAF
inhibitor, 43 (66%) had objective responses, including
5 (8%) CRs.55 Of the 26 patients who previously had
been treated with a selective Raf inhibitor, 5 (19%) had
partial responses.56 The updated results of the Phase II
study showed that median PFS was 10.8 months
among 24 BRAF inhibitor-naive patients who received
150 mg of dabrafenib twice daily and 2 mg of trametinib once daily.57
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melanoma harboring KIT mutations.65-68 Additionally,
the interim analysis of a Phase II study of imatinib in
patients with advanced acral lentiginous melanoma,
mucosal melanoma, or melanoma in chronic sun-damaged skin revealed that 5 of 10 patients with melanoma
harboring a KIT mutation had a clinical response to the
drug.69 However, none of 10 patients with KIT amplification without a mutation had a response.
In another Phase II study of imatinib in 43 patients
with metastatic melanoma harboring a KIT mutation or
amplification, 10 (23%) patients had an overall clinical
response, and 9 of the 10 responders had a KIT mutation in exon 11 or 13.70 In a separate Phase II study of
imatinib in a similar population, 4 (16%) of 25 patients
had a durable clinical response, including 2 patients
who had CRs.71 The response rate among patients
who had mutations affecting recurrent hotspots of
the KIT gene or a higher KIT mutant-to-wild-type
allele ratio (>1) was 40%, whereas the response rate
among patients who did not have these features was
0% (P=0.05), suggesting that the presence of a functionally relevant KIT mutation is required for imatinib
or other KIT inhibitors to have clinical benefit.
KIT INHIBITORS
ANTI-PD1 ANTIBODY
Like CTLA-4, programmed death 1 (PD-1) is a member of the CD28 family. PD-1 is expressed in activated T cells, memory T cells, and regulatory T cells and
is involved in T-cell regulation. Upon binding to its
ligands, PD-L1 and PD-L2 (which are highly expressed
in tumor cells and the antigen-presenting cells found
in tumors), PD1 suppresses T-cell effector function.
Tumoral PD-L1 expression has been associated with
negative prognosis in cancer patients.72,73
MDX-1106 (Bristol-Myers Squibb), a fully human
immunoglobulin G4 monoclonal antibody against
PD-1, can interrupt the binding of PD-1 with its ligands,
thereby reactivating T-cell function.74 In a Phase I
dose-escalating study evaluating a single dose of the
drug (with 2 additional doses every 4 weeks allowed
in patients in whom continued clinical benefit was
observed), MDX-1106 was well tolerated with only one
serious AE (colitis).75 Of the 39 patients in the study, 3
patients, including one with metastatic melanoma, had
a clinical response to MDX-1106.
Another Phase I study evaluated the safety profile
of a biweekly dosing schedule of MDX-1106 in patients
with refractory metastatic non-small cell lung cancer, renal cell carcinoma, melanoma, or prostate cancer.76 The MTD of the drug was not reached up to a
dose of 10 mg/kg every 2 weeks. Common AEs included fatigue, nausea, diarrhea, xerostomia, and pruritus,
but grade 3 or 4 AEs were uncommon. In the preliminary response evaluation, 6 (38%) of 16 patients had
objective responses; among these patients, 3 patients
with metastatic melanoma had a partial response. The
clinical investigation of MDX-1106 is ongoing.
d.
Preclinical findings demonstrating the essential role of
stem cell factor and its receptor, KIT tyrosine kinase, in
the proliferation and survival of melanocyte precursors,58,59 and KIT’s frequent expression in melanoma specimens59,60 led investigators to conduct 3 studies evaluating
the use of imatinib (Gleevec, Novartis) in patients with
metastatic melanoma in the early 2000s.61-63 Imatinib had
minimal clinical activity, with only 1 of 63 patients (who
had not been selected on the basis of genomic biomarkers) responding to the drug.
Interest in KIT-targeted therapy in melanoma was
renewed when Curtin et al showed that KIT mutation
and/or amplification is more common in certain subtypes of melanoma than in others.64 In their analysis
of 102 primary melanomas, they used a comparative
genomic hybridization assay and found KIT mutations
and/or increased copy numbers of KIT in 36% of acral
lentiginous melanomas, 39% of mucosal melanomas,
and 28% of melanomas that developed in chronically sun-damaged skin. Following this novel discovery,
a number of case reports have emerged showing that
KIT inhibitors have clinical benefit in patients who have
Emerging Immunotherapies
I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
7
ADOPTIVE T-CELL THERAPY
ll
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In the mid-1980s, Rosenberg et al found that tumorinfiltrating lymphocytes (TILs) isolated from murine
sarcomas and colon adenocarcinomas that had been
transplanted into syngeneic mice could be expanded
with IL-2 in vitro. When infused back into the donor
mice, the TILs could mediate the regression of metastatic tumors.77 They later reported the regression of
metastatic melanoma lesions in 11 of 20 patients who
were treated with the adoptive transfer of TILs and
IL-2 infusion following a single dose of cyclophosphamide.78 Other researchers found that when the adoptive transfer of TILs and IL-2 infusion were preceded
by a 7-day regimen of cyclophosphamide and fludarabine, which depleted the number of endogenous
regulatory cells and lymphocytes competing with the
transferred TILs for growth-promoting homeostatic
cytokines, 6 of 13 patients had a clinical response.79
Notably, this approach resulted in the persistent clonal
repopulation of T cells, which proliferated in vivo and
traveled to tumor sites in these patients.
In an expanded Phase II study conducted by the
same group of investigators, lympho-depleting chemotherapy followed by TIL transfer and high-dose
IL-2 infusion elicited a response rate of 51% among 35
patients with metastatic melanoma.80 When TIL transfer and IL-2 infusion were preceded by myeloablative
chemoradiation (lympho-depleting chemotherapy
plus 2 or 12 Gy of total-body irradiation), clinical activity of the regimen was even better, with response rates
of 52% and 72%, respectively.81 Of 20 patients who
had CRs in these trials of adoptive TIL transfer, only 1
patient’s disease has relapsed. The other patients continue to have CRs 3 to 7 years following the completion of the treatment.81,82
In another study, CD4-positive T-cell clones targeting the DPB1*0401-restricted epitope of a peptide derived from NY-ESO-1 were isolated from the
peripheral blood mononuclear cells of patients with
metastatic melanoma and expanded in vitro, and the
antigen-specific CD4-positive T cells were infused
back into the patient.83 One patient had a complete
resolution of lung and nodal metastases that was
accompanied by the persistent presence of the NYESO-1–specific CD4-positive T cells and lasted for at
least 2 years. This finding suggests that the adoptive
transfer of antigen-specific CD4-positive T cells may
be used to treat advanced melanoma.
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d.
After a long drought in the development of successful therapies, recent advances in targeted therapy and
immunotherapy have set a new standard of treatment
for metastatic melanoma. However, the arrival of ipilimumab and vemurafenib in the clinic has generated more questions and challenges. For example, it is
not clear which of these agents, ipilimumab or vemurafenib, should be offered first in patients with metastatic disease, especially in those with limited or slowly
8
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Conclusion
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