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Cancer Therapy Vol 7, page 188
Cancer Therapy Vol 7, 188-199, 2009
Treatment options for metastatic melanoma. A
systematic review
Review Article
Joan Manel Gasent Blesa1,*, Enrique Grande Pulido2, Mariano Provencio Pulla3,
Vicente Alberola Candel4
Medical Oncology Service, Hospital Marina Alta de Dénia, Alacant, Spain
Pfizer Medical Oncology Department, Madrid, Spain
3
Medical Oncology Service, Hospital Arnau de Vilanova, València, Spain
4
Medical Oncology Service, Hospital Puerta de Hierro, Madrid, Spain
1
2
__________________________________________________________________________________
*Correspondence: Joan Manel Gasent Blesa MD Ph.D., Hospital de Dènia Marina Salud, Partida de Beniadlà, s/n. Denia. 03700,
Alacant, Spain; Tel: +34 606311233; e-mail: joanmagasent@telefonica.net
Key words: angiogenesis, DTIC, immunotherapy, melanoma, treatment
Abbreviations: Adoptive Cell Transfer, (ACT); cisplatin, DTIC, and carmustine, (CBD); cisplatin, DTIC, carmustine, and tamoxifen,
(CBDT); dacarbacin, (DTIC); Eastern Cooperative Oncology Group, (ECOG); European Organization for Research and Treatment of
Cancer, (EORTC); Food and Drug Administration, (FDA); interferon α, (IFN-α); interleukin-2, (IL-2); temozolomide, (TMZ); totalbody irradiation, (TBI); umor-infiltrating lymphocytes, (TILs)
Received: 12 January 2009; Revised: 9 March 2009
Accepted: 13 March 2009; electronically published: April 2009
Summary
Metastatic melanoma is considered to be one of the most resistant tumors to standard chemotherapy approaches
nowadays. Old anti-cancer treatments like dacarbacin (DTIC) or interleukin-2 (IL-2) continue to be the only
approved treatments by the main worldwide health authorities. Up to now, no combination or new anti-targeted
agent has shown an improvement in overall survival when compared to either of these two drugs alone. In fact,
more than a dozen phase III randomized trials have tried to go beyond these old approaches, without meeting any
success. Despite the fact that the median overall survival of patients diagnosed with metastatic melanoma is lower
than 9 months, melanoma emerges as a challenging disease for testing new drugs and implementing the deeper
knowledge in the molecular biology underlying this tumor. New immunotherapeutic targets have appeared recently
trying to modulate the host immune response against the tumor. Furthermore, in the last three years, new targeted
agents have changed the standard of care of other solid tumor types like renal cancer. We wonder if these new
agents will be incorporated in the standard management of advanced melanoma patients in the coming years.
I. Introduction
term disease control with a good quality of life, and some
of them may even achieve a complete remission, with
potential to cure (Coates and Segelov, 1994).
Dacarbazine (DTIC) induces response rates ranging
from 15% to 25% in single-institution trials with median
response durations of 5 to 6 months, but less than 5% of
these responses are complete in historical series (Balch et
al, 1997).
Long-term follow-up of patients treated with DTIC
alone shows that less than 2% can be expected to survive
for 6 years. In modern designed Phase III trials that used
strict response assessment criteria, the response rates with
DTIC did not exceed 12% (Falkson et al, 1998; Middleton
et al, 2000; Avril et al, 2004). It has been demonstrated
that single doses of DTIC (850-1000 mg/m2) are well
tolerated, and should be the reference standard for
randomized trials comparing new therapies with DTIC
(Eggermont and Kirkwood, 2004).
DTIC remains the only cytotoxic drug approved by
the U.S. Food and Drug Administration (FDA) for the
treatment of metastatic melanoma. Despite its low singleagent activity, it has remained the basis for many
combination chemotherapy regimens.
Metastatic melanoma is highly resistant to
chemotherapy, radiation therapy, hormonal therapy and
current immunotherapeutic approaches. There are several
promising phase II studies suggesting long-term benefits
with immunotherapeutic approaches like IL-2, ipilimumab
or tremelimumab; however, no large-scale phase III
randomized trial has demonstrated any superiority versus
chemotherapy alone as of yet.
In this article we will review the current data
regarding the agents most used either as monotherapy or in
combination, as well as the promising data derived from
the new targeted therapies and new immunotherapeutic
agents under clinical development.
II. Single agent therapy
A. Dacarbazine and Temozolomide
Single-agent chemotherapy produces objective
response rates of less than 20%. However, a small subset
of patients, mainly those with metastases to the lungs,
good performance status and normal blood lactate
dehydrogenase (LDH) enzyme levels, can achieve long-
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Blesa et al: Update on melanoma treatment
A DTIC related agent is temozolomide (TMZ), an
oral formulation prodrug of DTIC with demonstrated
improved brain penetration. Based on this, TMZ may
represent a viable alternative to DTIC, which is ineffective
against CNS metastases (Bafaloukos, 2002).
Single-agent activity of TMZ in metastatic melanoma
has been detected in Phase I/II studies (Newlands et al,
1992). In a randomized trial conducted on 305 patients
with advanced melanoma, TMZ showed equivalence to
DTIC in terms of objective response rate, time to
progression, disease-free survival and overall survival
(Avril et al, 2004). The median survival was 7.7 months
for patients who received TMZ and 6.4 months for
patients who received DTIC. The median progression-free
survival was 1.9 months in the TMZ-treated group and 1.5
months in the DTIC-treated group. Overall, TMZ had a
good tolerance, and appeared to have advantages in terms
of improved quality of life. This trial excluded patients
who had brain metastases. The FDA did not accept the
results of this trial for approving a melanoma indication
for TMZ, because the trial design was intended to
demonstrate the superiority of TMZ over DTIC, not its
equivalence.
It has been suggested that the administration of TMZ
in multiple doses per day or as a prolonged daily
administration may overcome some chemotherapy drugresistance mechanisms. The rationale for the use of these
doses of TMZ is based on an evaluation of recent data on
the drug’s mechanism of action. Five-(3-methyltriazen-1y) imidazole-4-carboximide, which is the active metabolite
of DTIC and the end product of spontaneous metabolism
of TMZ, methylates guanine residues in DNA at the O6
position (Newlands et al, 1992). Increased levels of O6alkylguanine-DNA alkyltransferase (ATase) are associated
with resistance to agents that produce O6 methylation
(DTIC, TMZ, and nitrosoureas). Administration of TMZ
results in decreased ATase activity within 4 hours of an
oral dose that persists in peripheral blood mononuclear
cells for at least 24 hours (Newlands et al, 1992). Daily
administration resulted in the progressive depletion of
ATase activity over the 5 days of treatment. Thus, on each
day of treatment, there is increased sensitivity to the
cytotoxic effects of TMZ resulting from the decrease in
ATase activity induced by the prior day's chemotherapy.
Currently, there is an ongoing trial conducted by the
European Organization for Research and Treatment of
Cancer (EORTC) comparing DTIC with prolonged daily
administration of TMZ. The extended dose of TMZ (75
mg/m2 per day) administered for 6 weeks followed by a 2week rest is well tolerated and may be used in patients
who have a borderline performance status. Other agents
that lower ATase are Lomeguatrib (Patrin, PM), which is
an orally bioavailable, highly potent O6-MeG analog and
poly (ADP-ribose) polymerase inhibitor that is well
tolerated as a singe agent (Plummer et al, 2006; Tawbi et
al, 2006) (Table 1).
B. Nitrosoureas
Nitrosoureas induce objective responses ranging
from 13% to 18% of patients. It is supposed that these
drugs cross the blood-brain barrier. However, when given
at conventional doses, little or no activity was observed
against melanoma brain metastases (Boaziz 1991).
Furthermore,
nitrosoureas
induce
prolonged
myelosuppression. Despite this, they have frequently been
included in multiagent chemotherapy regimens,
presumably because of their ability to penetrate into the
CNS. Fotemustine is probably the most active nitrosourea
in metastatic melanoma. It has been tested in 5 Phase II
trials on 351 patients with response rates of 20 to 25% and
complete response rates of 5 to 8% (Jacquillat et al, 1990;
Calabresi et al, 1991; Kleeberg et al, 1995). Fotemustine
was the first drug to show significant efficacy in brain
metastases. In the first published phase II trial, one
hundred sixty-nine patients with histologic evidence of
disseminated malignant melanoma, including patients with
cerebral metastases, were treated with a regimen based on
100 mg/m2 1 hour IV infusion every week for 3
consecutive weeks, followed by a 4 to 5 week rest period
(induction therapy) of fotemustine. One hundred fiftythree
patients
were
evaluable
for
response.
Table 1. Randomized studies comparing dacarbazine monotherapy with combinaton chemotherapy.
Reference
Cocconi
Falkson
Buzaid
Falkson
Chapman
Year
1992
1991
1993
1998
1999
Response Rate %
n of pat. combinat.
117
28
64
53
150
19
280
21
240
18.5
Three complete responses and 34 partial responses were
observed, leading to an objective response rate of 24.2%
(95% confidence interval: 17.4% to 31.0%). Responses
were also documented on cerebral (25.0%), visceral
(19.2%), or nonvisceral (31.8%) metastatic sites. The
median duration of response was 22 weeks (range, 7 to 80
weeks). The objective response rate in previously
untreated patients was 30.7% (19 of 62 patients). The main
toxicity was hematologic with delayed and reversible
leukopenia and/or thrombopenia (Jacquillat et al, 1990).
PFS
monother combinat
20
14
15
2.6
10.2
20
SURV (mo)
monother
48 VS 29
2.6
8.9
7
48 VS 29
53% of patients (Glover et al, 1987). Some of the
responses were complete, and the median response
duration was 4 months (Glover et al, 2003).
A response rate of 19% was reported in 26
chemotherapy-naïve patients with metastatic melanoma
who received carboplatin. In those patients, there were 5
partial responses, and thrombocytopenia was the doselimiting toxicity (Evans et al, 1987).
In vitro studies have suggested that oxaliplatin can be
more active than cisplatin or carboplatin in the treatment
of melanoma, but oxaliplatin has yet to be tested
extensively in patients with melanoma (Mohammed and
Retsas, 2000). A small Phase II trial in 10 patients who
had received and failed to prior chemotherapy did not
show any objective responses (Lutzky et al, 2006).
C. Platins
Cisplatin as a single-agent therapy has induced a
15% response rate with a median duration of 3 months
(Kirkwood and Argwala, 1993). Doses up to 150 mg/m2 in
combination with amifostine produced tumor responses in
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Cancer Therapy Vol 7, page 190
D. Vinca alkaloids and taxanes
combination regimen than with DTIC (Chapman et al,
1999).
The 3-drug combination CVD (cisplatin, vinblastine,
and DIC) was developed by Legha and colleagues in 1989
at M. D. Anderson Cancer Center and induced responses
in 40% of 50 evaluable patients in a phase II trial.
Complete response rate was achieved in the 4% of the
patients with a median duration of response of 9 months
(Legha et al, 1989). Nevertheless, in a randomized trial
comparing CVD with single-agent DTIC, the CVD arm
produced a 19% response rate compared with 14% for the
DTIC arm, and there were no differences in either
response duration or survival (Buzaid et al, 1993).
A very small phase II trial of carboplatin and
paclitaxel as a first line therapy published in 2002 reported
20% partial response and 47% stable disease (Hodi et al,
2002), while a randomized phase II study of weekly
paclitaxel versus carboplatin and paclitaxel as a second
line therapy in 2003 produced an overall response rate of
less than 10% in both arms (Zimpfer-Rechner et al, 2003).
In this regard, (Rao et al, 2006) recently added a
retrospective review of 31 pretreated patients to the
carboplatin and paclitaxel literature documenting a 26%
ORR. An Eastern Cooperative Oncology Group phase III
trial of carboplatin and paclitaxel with and without
sorafenib is ongoing.
Vinca alkaloids, particularly vindesine and
vinblastine, have been studied, and responses were found
in approximately 14% of patients (Quagligana et al, 1984).
Taxanes have produced responses ranging from 16 to 17%
of patients (Einzig et al, 1991; Aamdal et al, 1994;
Bedikian et al, 1995).
A potentially active new drug is ABI-007 (abraxane),
which is an albumin-bound nanoparticle formulation of
paclitaxel with an improved therapeutic index. It has been
tested in a Phase II trial in 37 previously treated and
chemotherapy-naïve patients with metastatic melanoma
and showed an overall response rate of around 30%. ABI007 will be explored in a randomized Phase III trial (Hersh
et al, 2006).
III. Combination chemotherapy
Single-agent
chemotherapy
regimens
have
demonstrated only modest activity in the treatment of
metastatic melanoma. Many combination regimens have
been tested in clinical trials with a view to improving these
results.
Initially, 2-agent combinations were used. DTIC was
combined with either a nitrosourea, a vinca alkaloid, or a
platinum compound. In the majority of those trials,
response rates ranging from 10 to 20% were observed, and
there was low evidence to suggest superiority to singleagent DTIC (Constanzi et al, 1975, 1997; Vorobiof et al,
1986; Fletcher et al, 1988; Avril et al, 1990).
After those disappointing results, trials with more
aggressive, multiagent regimens were conducted. Phase II
studies of 3- and 4-drug combinations generally produced
response rates that ranged from 30% to 50% in singleinstitution studies.
The 4-drug combination, named the Dartmouth
regimen, based on cisplatin, DTIC, carmustine, and
tamoxifen (CBDT), produced responses in 46% of 141
patients (16 complete responses and 49 partial responses).
The median response duration was 7 months (Del Prete et
al, 1984). The authors suggested that the inclusion of
tamoxifen was essential, with only 10% of response rates
for the 3 cytotoxic drugs in the same doses when
tamoxifen was omitted (Lattanzi et al, 1995).
A randomized Phase III trial conducted by the
National Cancer Institute of Canada that compared CDBT
with cisplatin, DTIC, and carmustine (CBD) produced a
response rate of 30% for the CDBT arm compared with
21% for the CDB arm (P = .187). Six percent of the
patients who received Tamoxifen achieved a complete
response, compared with 3% of the patients who did not
receive Tamoxifen, although this difference was not
statistically significant (P = .33).
In this study, more patients in the tamoxifen group
achieved a partial remission (27% vs 14%). This
difference was of borderline significance (P = .05). Gender
did not seem to be a predictive factor of response. The
response rate and the median survival for women in the
tamoxifen group did not differ statistically compared with
those for women in the chemotherapy-alone group.
Similarly, there was no difference between men in the
treatment groups. Progression-free survival and overall
survival did not differ significantly between the 2 arms (P
= .86 and P = .52) (Rusthoven et al, 1996). In another
randomized Phase III trial, the CDBT combination was
compared with single-agent DTIC. 240 patients were
recruited for this trial. The response rate was 10.2% for the
DTIC regimen compared with 18.5% for the CDBT
regimen (P = .09). The median survival was 7 months,
with no significant difference between the 2 treatment
arms. Toxicity was substantially greater for the
IV. Combinations of chemotherapy
with immunomodulatory or hormonal
agents
A. Tamoxifen and Interferon α
Combinations of cytotoxic drugs that have minimal
efficacy with immunomodulatory or hormonal agents have
been investigated. The results of adding tamoxifen to CDB
chemotherapy were discussed above; however, tamoxifen
also has been added to single-agent DTIC in several
studies. Results from a small, randomized trial of DTIC
with or without tamoxifen indicated that combination
therapy may be more effective (Cocconi et al, 1992). A
response rate of 28% and a median survival of 41 weeks
were reported for patients who received DTIC plus
tamoxifen compared with a response rate of only 12% and
a median survival of 23 weeks for patients who received
DTIC alone.
Similar results were reported with the combination of
DTIC plus interferon α (IFN-α). In a small, randomized
trial that compared DTIC with or without IFN-α2b, the
combination therapy produced 12 complete responses and
4 partial responses in 30 patients compared with only 2
complete responses and 4 partial responses among 30
patients who received DTIC (Falkson et al, 1991). The
median response and survival were prolonged significantly
for the DTIC plus IFN-α2b arm in that trial. To further
evaluate the potential benefits of combining DTIC with
either tamoxifen or IFN-α, or both, the Eastern
Cooperative Oncology Group (ECOG) conducted a 4-arm,
2 × 2, design, Phase III trial that failed to confirm the
initial results (ECOG 3690) (Falkson et al, 1998) The
overall response rate in that trial was 18%, and the median
time to treatment failure was 2.6 months. The median
survival was identical (9.1 months) for all 4 arms tested. In
that trial, there was no advantage in terms of response or
survival with the addition of IFN-α2b, tamoxifen, or both
agents to DTIC.
In a recent meta-analysis of 6 published, randomized
trials involving a total of 912 patients who were
randomized to receive either chemotherapy or
biochemotherapy with or without tamoxifen, no
improvements in the rates of overall response, complete
190
Blesa et al: Update on melanoma treatment
response, or survival were demonstrated (Lens et al,
2003).
The combination of TMZ plus thalidomide is one of
the most promising of those reported thus far. Thalidomide
is an antiangiogenic agent with immune modulatory
properties. An ORR of 32% was reported in a phase II
study in 38 patients (Hwu et al, 2003) without brain
metastasis and a 15% ORR in 60 patients in a phase II trial
including patients with brain metastasis (Danson et al,
2003). The overall objective response rate of 32% was
higher than that achieved with TMZ alone. One patient
presented deep vein thrombosis and no thrombotic events
were reported in the second one.
In a more recent trial, 26 patients with brain
metastasis achieved an objective response rate of 11% in
the brain lesions (Hwu et al, 2005). However, the
combination of TMZ plus thalidomide should not be
accepted as a standard therapy until and unless it
demonstrates superiority in Phase III trials or at least until
the high response rate can be confirmed in larger, multiinstitutional Phase II trials using strict response assessment
criteria. In addition, it should be noted that, in a Phase II
study of TMZ, thalidomide, and whole-brain radiation
therapy in patients with brain metastases from melanoma
that was conducted by the Cytokine Working Group in 40
patients, no patient exhibited a systemic response (Atkins
et al, 2005).
second meta-analysis of combined studies that involved
7711 patients with advanced melanoma from 168
published trials, treatment with an IL-2/IFNα/chemotherapy combination resulted in a significantly
improved response rate compared with treatment that used
chemotherapy or IL-2-based biotherapy (Keilholz et al,
2005).
Different prospective, randomized studies in the
United States and Europe evaluated aggressive
biochemotherapeutic regimens that contained IL-2 and
IFN-α.
In a prospective European trial, 138 patients with
metastatic melanoma were randomized to receive IFN and
decreasing doses of IL-2 with or without cisplatin
(Keilholz et al, 1998). The results demonstrated a
significant increase in the response rate (from 18% to
33%) in the group that received biochemotherapy
compared to the group that received biotherapy, and an
increase in progression-free survival from 53 days to 92
days without any statistical differences in terms of
survival.
A second trial by the EORTC involving 363 patients
evaluated cisplatin, DTIC, and IFN-α with or without IL-2
(Keiholz et al, 2005). No statistical improvement in
response rate was shown with the addition of IL-2 (22.8%
vs 20.8%, respectively) and in progression-free survival
(median 3.0 months vs 3.9 months, respectively). The
median survival was 9 months in both arms, and the 2-year
survival rate was 12.9% and 17.6%, respectively (P = .32).
Another study that was conducted by Rosenberg and
his colleagues (Rosenberg et al, 1999) at the National
Cancer Institute-Surgery Branch randomized 102 patients
with stage IV melanoma to receive either chemotherapy
(DTIC, cisplatin, and tamoxifen) or biochemotherapy (IL2, IFN-α, DTIC, cisplatin, and tamoxifen). Although the
response rate in the biochemotherapy arm (44%) was
almost twice that obtained in the chemotherapy arm
(27%), the difference was not statistically significant (P =
.07). Furthermore, there was a survival advantage in the
chemotherapy arm compared with the biochemotherapy
arm (median survival 5.8 months in the biochemotherapy
arm vs. 10.7 months in the chemotherapy arm; P = .05).
One of the reasons for this survival finding may be due to
the administration of high-dose IL-2 as salvage therapy to
a significant proportion of the patients who failed to
respond to chemotherapy alone.
A large-scale Phase III trial that enrolled 482 patients
and compared CVD chemotherapy with CVD plus
intravenous IL-2 and subcutaneous IFN-αwas the ECOG
E3695. Important aspects of the E3695 protocol were that
it was large enough to distinguish clinically meaningful
differences in survival and durable responses, and that it
involved a population with a relatively large percentage of
patients who had prior IFN exposure in the adjuvant
setting. There were no statistically significant differences
between the chemotherapy and biochemotherapy arms in
response rate, progression-free survival, or overall
survival. It should be noted that there were many
inevaluable patients, many patients were not treated
according to the protocol, and more patients were
randomized to the biochemotherapy arm (Atkins et al,
2003). Nonetheless, the conclusion from this and all
randomized biochemotherapy trials performed to date was
that biochemotherapy should not be used routinely outside
of a clinical trial.
The study conducted by Eton and colleagues in 2002
comparing CVD vs. CVD plus intravenous IL-2 and
subcutaneous IFN-αin 183 evaluable patients was the only
one that showed a statistically significant advantage of
biochemotherapy over chemotherapy alone in terms of
response rate (48% vs. 25%, respectively), complete
B. Biochemotherapy
In the last decade, several trials have evaluated the
role of combination chemotherapy with other agents, such
as IFN-α and IL-2. Many investigators have combined IL2 with both IFN-α and chemotherapy in an attempt to
improve both the response rate and the percentage of
durable complete remissions. A large body of data exists
signifying that such biochemotherapy combinations can
produce response rates ranging from 40% to 60%, with a
complete response rate of approximately 10% (Flaherty et
al, 1993; Atkins et al, 1994; Legha et al, 1998). Durable
remissions exceeding 5 years were achieved by
approximately 5% to 10% of patients. Recurrences beyond
the 2-year time point were uncommon, thus suggesting
that those patients who exhibited durable responses may
have achieved a cure (Legha et al, 1998; O´Day et al,
1999). However, many of the most active
biochemotherapy regimens are associated with moderate
to severe toxicity, which has limited their broader use and
acceptance.
Many trials have been performed in an attempt to
identify biochemotherapy regimens that may be
administered in an outpatient setting, with less toxicity,
and using lower doses of intravenous or subcutaneous IL-2
(Keilholzet al, 1998). Unfortunately, biochemotherapy
regimens that involved low-dose, subcutaneous IL-2
administration appeared to produce lower response rates
than were observed generally with regimens involving
intravenous IL-2 (Keilholz et al, 1998).
Two meta-analyses of patients with metastatic
melanoma who were included in studies with various
combinations
of
chemotherapy,
biotherapy,
or
biochemotherapy demonstrated an improvement in
response rates, but not in survival, with the use of
biochemotherapy. In a report by Keilholz and colleagues
(Keilholz et al, 1997) patients with metastatic melanoma
who were treated with IL-2/IFN-α/chemotherapy, IL2/IFN- without chemotherapy, and IL-2/chemotherapy
without IFN-αregimens, had response rates of 45%, 21%,
and 15%, respectively. However, in this trial, survival did
not differ significantly between the groups (10.5 months),
with 20% and 10% survival rates at 2 years and 5 years,
respectively, that did not differ among the groups. In a
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Cancer Therapy Vol 7, page 192
response rate (7% vs. 2%, respectively), and median time
to recurrence (4.9 months vs. 2.4 months). A modest but
statistically significant increase in median overall survival
(11.9 months vs. 9.2 months, respectively) was also
observed (Eton et al, 2002).
More recently the E3695 (Atkins et al, 2008)
published its phase II trial comparing chemotherapy with
CVD versus CVD concurrent with interleukin-2 and INF
α-2b (BCT every 21 days, for a maximum of 4, in four
hundred fifteen enrolled patients, with 395 patients
assessable. The response rate was 19.5% for BCT and
13.8% for CVD, non significant. Median progression-free
survival was significantly longer for BCT than for CVD
(4.8 vs. 2.9 months (P = .015), although this did not
translate into an advantage in either median overall
survival (9.0 vs. 8.7 months) or the percentage of patients
alive at 1 year (41% vs. 36.9%). The side effects were also
more relevant in the biochemotherapy group (Table 2).
Table 2. Randomized studies comparing chemotherapy with bio chemotherapy.
Reference
Kieholz
Rosenberg
Dorval
Eton
Ridolfi
Atkins
Ecog
Year
1997
1999
1999
2002
2002
2003
2008
Response Rate %
n of pat. combinat.
138
33
102
44
101
24
183
48
176
25.3
482
16.6
395
19.5
PFS
SURV (mo)
monother combinat monother
18
92
53
9
27
10.7 VS 15.8
16
9.1
6.6
10.9 VS 10.4
25
4.9
2.4
11.9 VS 9.2
20.2
4
3
11 VS 9.5
11.9
5
3.1
8.4 VS 9.1
13.8
4.9
2.9
9 VS 9.1
C. Granulocyte-macrophage colonystimulating factor
mutant BRAF in vitro. In addition, the spectrum of kinases
inhibited by sorafenib includes CRAF, vascular
endothelial growth factor receptor 2, platelet-derived
growth factor receptor , flt-3, and c-kit (Wilhelm et al,
2004). Preclinical studies demonstrated a significant
retardation in the growth of human melanoma tumor
xenografts with sorafenib (Karasarides et al, 2004). In a
Phase I study, the maximum tolerated dose of sorafenib as
a single agent was established at 400 mg twice daily, and
the most common toxicities were gastrointestinal (mainly
diarrhea), dermatologic (skin rash, hand-foot syndrome),
and fatigue (Strumberg et al, 2005). In a Phase II trial
involving 20 patients with refractory metastatic melanoma,
sorafenib showed modest activity, with 1 partial response
and 3 patients who achieved stable disease (Ahmad et al,
2004). In another Phase II, randomized, discontinuation
trial, no objective responses were reported, and 19% of
patients achieved stable disease (Eisen et al, 2006).
However, in a Phase I/II study that combined carboplatin
and paclitaxel with escalating doses of sorafenib in 35
patients, a promising response rate of 31% was observed,
and another 54% of patients experienced stable disease
that lasted more than 3 months (Flaherty et al, 2004). This
study was recently updated to include 105 patients, and the
current response rate is 27%. It is noteworthy that
responses to sorafenib have not been correlated to date
with BRAF mutation status (Amaravadi et al, 2006).
Responses were observed in previously treated patients
and in at least 1 patient with a noncutaneous primary
melanoma. Two Phase III trials have been launched to
assess the efficacy of carboplatin and paclitaxel plus
sorafenib versus placebo in chemotherapy-naïve patients
(E2603) and in previously treated patients. Relatively little
is known about the inherent activity of carboplatin and
paclitaxel as systemic therapy for patients with stage IV
melanoma, particularly at the doses employed in the Phase
II trial and, now, in the Phase III trial. In a report on
previously treated patients, no responses were observed
among 19 patients who received the 2-drug combination
(Cocconi et al, 1992), whereas a second trial in
chemotherapy-naïve patients resulted in 3 partial
responders and 7 patients with stable disease among 15
evaluable patients (Rao et al, 2006). Thus, it is likely that
A phase I study to investigate the feasibility and
safety of immunoembolization with granulocytemacrophage
colony-stimulating
factor
(GM-CSF;
sargramostim) for malignant liver tumors, predominantly
hepatic metastases from patients with primary uveal
melanoma, was published by the group of Sato (Sato et al,
2008). This group treated a total of thirty-nine patients
with surgically unresectable malignant liver tumors,
including 34 patients with primary uveal melanoma.
Hepatic artery embolization accompanied an infusion of
dose-escalated GM-CSF given every 4 weeks.
The maximum tolerated dose was not reached up to
the dose level of 2,000 µg, and there were no treatmentrelated deaths.
Thirty-one assessable patients with uveal melanoma
were included. Of these patients, two complete responses
were observed, eight partial responses, and 10 stable
diseases in their hepatic metastases. The median overall
survival of intent-to-treat patients who had metastatic
uveal melanoma was 14.4 months. The multivariate
analyses indicated that female sex, high doses of GM-CSF
(>/= 1,500 µg), and regression of hepatic metastases were
correlated to longer overall survival. Moreover, high doses
of GM-CSF were associated with prolonged progressionfree survival in extrahepatic sites.
β
V. Combinations of chemotherapy
with targeted therapies
The intrinsic resistance of melanoma to conventional
chemotherapy has led investigators to evaluate new
approaches such as protein kinase inhibitors (e.g.
sorafenib), agents that act on cytotoxic T-lymphocyte
antigen 4 (CTLA-4) or on apoptotic mechanisms (e.g.
oblimersen sodium; previously referred to as G3139), and
antiangiogenic agents (e.g. bevacizumab, axitinib, MEDI522, PI-88).
A. Sorafenib plus chemotherapy
Sorafenib targets the adenosine triphosphate-binding
site of the BRAF kinase and inhibits both wild-type and
192
Blesa et al: Update on melanoma treatment
the combination of carboplatin and paclitaxel, by itself,
has inherent activity in metastatic melanoma. The results
of the Phase III trials will define the real impact of adding
sorafenib to this regimen in patients with metastatic
melanoma. A randomized Phase II trial of 2 schedules of
TMZ plus sorafenib is also underway, and the preliminary
results have been considered encouraging (Amaravadi et
al, 2006).
promising activity, a prospective randomized phase III
trial in naïve advanced melanoma patients was recently
reported. A total of 655 patients were randomized to
receive either tremelimumab or chemotherapy (DTIC or
TMZ as single agent). Unfortunately, tremelimumab failed
to demonstrate a better overall survival versus
chemotherapy (11.7 vs. 10.7 months; p = .73). No
differences in either response rate or progression-free
survival were observed. The duration of responses was
clearly longer for those patients treated with
Tremelimumab (Ribas et al, 2005, 2008).
An active search for both tumor and host biomarkers
that could predict for response to these anti-CTLA4 agents
is needed and the future role of these drugs is not yet
established.
B. Imatinib mesylate
Twenty-six patients were enrolled in a multicenter
phase II trial of another oral kinase inhibitor, imatinib
(Wyman et al, 2006). No objective clinical responses were
noted among the 25 evaluable patients. The median time
to progression was 54 days and the median overall
survival was 200 days. No patient was free of disease
progression at 6 months. The immunostaining of the
tumors described three tumors with moderate and 5 tumors
with weak staining for c-kit.
D. Anti-BCL2 antisense oligonucleotide
Oblimersen sodium, an anti-BCL2 antisense
oligonucleotide, was originally tested in a Phase I/II trial
in combination with DTIC that was followed by a
randomized Phase III trial in 771 patients. The primary
endpoint of the trial was overall survival, which was not
statistically significantly different between the 2 arms (9.1
months for the combination arm vs. 7.9 months for DTIC
alone arm), although overall and complete response rates
were significantly better for the combination arm (overall
response 11.7% vs. 6.8%, respectively; P = .019) and
progression-free survival was also improved with the
combination (74 days vs. 49 days; P = .0003). In an
updated analysis, for the subgroup of patients with LDH
values ≤2 times the institutional upper limit of normality,
there was a statistically significant survival benefit for
combination therapy (10.2 months vs. 8.7 months; P = .02)
(Bedikian et al, 2006). These data support the idea that
oblimersen has at least modest activity when combined
with DTIC, justifying further studies of this compound and
similar strategies to overcome drug resistance in
melanoma (Eggermont, 2006).
C. Anti-CTLA-4 antibodies and
chemotherapy
Two human anti-CTLA-4 monoclonal antibodies
have been tested in clinical trials: ipilimumab (formerly
MDX-010) and tremelimumab (formerly CP-675,206).
Responses have been observed with both antibodies
administered as single-agent therapy in patients with
metastatic melanoma (Tchekmedyian et al, 2002; Ribas et
al, 2005), providing a rationale for combinations with
chemotherapy. In a Phase II study, the activity of
ipilimumab alone or in combination with DTIC was
assessed. There were 2 partial responses in the antibody
alone arm and 1 complete response and 4 partial responses
in the antibody plus DTIC arm, suggesting more activity
for the combination (Hersh et al, 2004). In the long term
follow-up of this study, 1 additional complete response
was observed in the combination arm, and durable clinical
responses were noted (Fischkoff et al, 2005). These results
are intriguing, but it remains unclear whether the activity
of the combination is simply additive or truly synergistic,
and further study is probably warranted in preclinical
models.
Auto-immune hypophysitis was recently reported to
occur in 5% of patients treated with anti-CTLA-4
antibodies (Blansfield et al, 2005). Symptoms included
extreme fatigue, headaches, memory loss, and loss of
libido. In most cases diagnosis could be confirmed by
enlargement of the pituitary on MRI. Patients treated
emergently with high dose steroids appeared to have better
recovery of pituitary function, although all patients
continued to require some hormone replacement at the
time of publication. The authors recommend that baseline
hormone levels and MRI measurement of the pituitary be
obtained prior to treatment, and that complaints of
headache, fatigue, and visual changes be carefully
evaluated. While auto immune side effects are dangerous,
they are associated with clinical response, thereby
suggesting that the immune system is effectively activated
by anti-CTLA-4.
Tremelimumab is a fully human IgG2 monoclonal
antibody directed against the CTLA-4 receptor of the T
cells. Tremelimumab owns an extremely long half life of
22 days that allows its intravenous administration every 3
months. In a phase I/II study conducted in 119 patients
with pretreated advanced melanoma, tremelimumab
showed an objective response rate of 7% but with a
median overall survival of 11.5 months in those patients
treated with the every three months dosing. The key
element of this trial was the amazing duration of response,
ranging from 11 to more than 36 months. Based on this
VI. MEDI-522
MEDI-522 is a humanized monoclonal antibody
directed against the αVb3 is essential for endothelial cell
proliferation, maturation, and survival; and, when it is
blocked, proliferating endothelial cells undergo apoptosis
and regress. In addition, αV 3 is highly expressed in
melanomas and is associated with tumor growth (Mitjans
et al, 2000). In preclinical studies using αVb3 antagonists,
inhibition of melanoma tumor growth independent of its
antiangiogenic effects was reported (Jaissle et al, 2008). In
the Phase II trial, 57 patients received MEDI-522 alone,
and 55 patients received MEDI-522 plus DTIC. MEDI522 with or without DTIC was well tolerated and was
active in patients with metastatic melanoma. The median
survival was 12.6 months for the group that received
MEDI-522 with DTIC and 9.4 months for the group that
received MEDI-522 without DTIC (Hersey et al, 2005).
β
A. Bevacizumab
Bevacizumab is a potent antibody against the
vascular endothelial growth factor (VEGF). Recently, high
effectiveness of bevacizumab in combination with
paclitaxel was reported in a single metastatic melanoma
case of a 68-year-old man with a vitreous melanoma
metastasis of the left eye, treated with a revitrectomy
combined with intravitreal bevacizumab application
because of iris neovascularization and progressive
epiretinal tumor plaques. The melanoma-associated
neovascularization completely disappeared four days after
the treatment, but it recurred after 6 weeks. Although
193
Cancer Therapy Vol 7, page 194
repetitive administration of local bevacizumab produced
the same antiangiogenetic effect, progression of the
epiretinal tumor plaques could not be stopped with the
local bevacizumab treatment (Jaissle et al, 2008).
factor which may function as an oncogene, and genes of
the WNT signaling pathway including b-catenin. Of
particular clinical relevance is the RAS-RAF-MEK-ERK
signaling pathway. This pathway is constitutively
activated in human tumors with somatic missense
mutations in B-RAF reported in 66% of melanomas
(Davies et al, 2002). A further 15% of melanomas have
mutated N-Ras proteins. Intriguingly, these mutations
appear to be mutually exclusive, suggesting that activation
at one stage of the pathway is sufficient, with B-RAF
mutations predicting in vitro sensitivity to MEK inhibitors.
A better understanding of specific genetic lesions in
melanoma should lead to improved targeted therapies. In
this regard, a recent analysis of 126 melanomas published
by Curtin and colleagues in 2005, categorized tumors into
four groups based on clinical profiling, and found that
these groups could be distinguished based on genetic
profiling with 70% accuracy. Acral and mucosal
abnormality
had
more
frequent
chromosomal
abnormalities in this study, while BRAF mutations were
found most commonly in melanomas developing on skin
without sun damage. KIT, a tyrosine kinase receptor
which inhibits the MAP kinase pathway, was recently
found to be selectively activated on mucosal, acral, and
sun-associated melanomas, but not in those melanomas
growing on skin without sun damage (Curtin et al, 2006).
B. Axitinib
Axitinib is a new and potent oral multitargeted
tyrosine kinase inhibitor against the vascular endothelial
growth factor receptor-1 (VEGFR-1), VEGFR-2, VEGFR3, and PDGFR. Fruehauf et al. conducted a small phase II
trial in 32 previously treated advanced melanoma patients.
Six of 32 (19%) patients achieved an objective
radiological response according to RECIST criteria in this
highly pretreated subpopulation. One complete response
was also confirmed. The median duration of response was
7.9 months (95% CI: 2.3-NA). The median progressionfree survival for the whole sample was 2.3 months.
Axitinib was well tolerated, with fatigue and hypertension
being the most common toxicities found. Further
investigation of this new targeted agent is warranted in
advanced melanoma patients (Fruehauf et al, 2008).
VII. Adoptive cell transfer
Adoptive T cell transfer has previously shown
efficacy in melanoma, with an ORR of 51% reported by
Rosenberg and colleagues in a phase I study of 35 patients
(Rosenberg et al, 2004). In order to circumvent the
requirement that patients have preexisting antitumor T
cells which can be expanded in vitro, Morgan and
colleagues (Morgan et al, 2006) isolated peripheral blood
mononuclear cells (PBMCs) from patients, cultured them
with IL-2 and anti-CD3, and transduced them with a
retroviral vector containing the gene for T cell receptor
(TCR) a and b chains reactive against the melanoma
antigen MART-1. Seventeen patients with refractory
disease received fludarabine and cyclophosphamide as
part of a lymphodepleting regimen, followed by
transduced T cells, followed by IL-2. Transduced TCRs
were shown to persist by PCR of DNA from PBMCs and
two out of 17 patients had complete responses. This is the
first published clinical study of treatment with TCRtransduced T cells, and it is hoped that it will lead to future
therapeutic advances.
The group led by Steven Rosenberg (Dudley et al,
2008) performed two additional sequential trials of
Adoptive Cell Transfer (ACT) with autologous tumorinfiltrating lymphocytes (TILs) in patients with metastatic
melanoma refractory to standard therapies. They used a
host preparative lymphodepletion consisting of
cyclophosphamide and fludarabine with either 2 (25
patients) or 12 Gy (25 patients) of total-body irradiation
(TBI) administered
before
cell transfer. The
nonmyeloablative chemotherapy alone showed a response
rate of 49%. When 2 or 12 Gy of TBI were added, the
response rates were 52% and 72% respectively. Responses
were seen in all visceral sites including the brain. There
was one treatment-related death in the 93 patients.
Objective responses were correlated with the telomere
length of the transferred cells.
IX. Conclusions
When compared with standard chemotherapy based
on DTIC, no other drug has shown benefits in terms of
survival up to now. Adding more chemotherapeutic agents
to DTIC or combining chemotherapy with classical
immunotherapeutic drugs like IL-2 or interferon has failed
to improve survival in this setting. It seems that the current
chemo- and biotherapy armamentarium will not
significantly provide a significant benefit in survival to our
patients.
However, a deeper knowledge not only of the
molecular biology of the tumor but also of the immune
system allows the design of new molecular targeted drugs
directed against the tumor or inducing patient immunity
against the melanoma.
Melanoma remains a challenging disease and
represents a niche to explore new targeted agents and
immunotherapeutic approaches.
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