REVIEW

Upcoming strategies for the treatment of metastatic melanoma

Francesco Spagnolo • Paola Queirolo

Received: 4 April 2011 / Accepted: 31 January 2012 / Published online: 17 February 2012

� Springer-Verlag 2012

Abstract Prognosis for advanced and metastatic mela-

noma is poor, with a 5-year survival of 78, 59 and 40% for

patients with stage IIIA, IIIB and IIIC, respectively, and a

1-year survival of 62% for M1a, 53% for M1b and 33% for

M1c. The unsatisfactory results of actual standard therapies

for metastatic melanoma highlight the need for effective

new therapeutic strategies. Several drugs, including BRAF,

KIT and MEK inhibitors, are currently being evaluated

after promising data from Phase I and Phase II studies;

Vemurafenib, a BRAF-inhibitor agent, has been approved

by the Food and Drug Administration (FDA) for the

treatment of patients with unresectable or metastatic mel-

anoma with the BRAF V600E mutation after a significant

impact on both progression-free and overall survival was

demonstrated compared with dacarbazine in a Phase III

trial. Ipilimumab, an immunotherapeutic drug, has proven

to be capable of inducing long-lasting responses and was

approved for patients with advanced melanoma in first- and

second-line treatment by the FDA and in second-line

treatment by the European Medicines Agency. Further-

more, a significant survival benefit of the combination of

ipilimumab with dacarbazine compared with dacarbazine

alone for first-line treatment was reported. In the near

future, patients with BRAF mutations could have the

chance to benefit from treatment with BRAF inhibitors;

patients harboring BRAF or NRAS mutations could be

treated with MEK inhibitors; finally, the subgroup of

patients with acral, mucosal or chronic sun-damaged mel-

anoma harboring a KIT mutation could benefit from KIT

inhibitors. Ipilimumab could become a standard treatment

for metastatic melanoma, both as a single agent and in

combination; its efficacy has been proven, and researchers

should now address their efforts to understanding the pre-

dictive variables of response to treatment.

Keywords Melanoma � Targeted therapy �Immunotherapy

Introduction

Malignant melanoma, which develops from a neoplastic

transformation of melanocytes, is the most aggressive form

of skin cancer. Its incidence has been increasing faster than

any other cancer in the USA. Overall, melanoma incidence

has increased by 3.1% annually during the last 20 years. In

2007, the incidence rate in the USA was 27.5/100,000 in

whites and 11.1/100,000 in blacks [31]. Despite that sur-

gical treatment of early melanoma leads to 90% cure rates,

unresectable advanced and metastatic melanoma presents

an intrinsic resistance to chemotherapy, aggressive

behavior and tendency to rapidly metastasize. Therefore,

prognosis for advanced and metastatic melanoma is poor,

with a 5-year survival of 78, 59 and 40% for patients with

stage IIIA, IIIB and IIIC, respectively, and a 1-year sur-

vival of 62% for M1a, 53% for M1b and 33% for M1c [5].

Only few effective therapies are currently available for

advanced and metastatic melanoma. High-dose interleukin-

2 and dacarbazine are the only two therapies approved by

the FDA, but they are associated with response rates of

F. Spagnolo (&)

Plastic and Reconstructive Surgery, IRCCS Azienda Ospedaliera

Universitaria San Martino – IST Istituto Nazionale per la Ricerca

sul Cancro, L.go R. Benzi, 10, 16132 Genoa, Italy

e-mail: francesco.spagnolo85@gmail.com

P. Queirolo

Medical Oncology, IRCCS Azienda Ospedaliera Universitaria

San Martino – IST Istituto Nazionale per la Ricerca sul Cancro,

L.go R. Benzi, 10, 16132 Genoa, Italy

123

Arch Dermatol Res (2012) 304:177–184

DOI 10.1007/s00403-012-1223-7

only 10–20% and an even lower percentage of complete

responses [4, 11]. Furthermore, there have been no large

randomized clinical trials, which assessed a clear

improvement in the overall survival. The median survival

among patients treated with dacarbazine is reported to be

less than 8 months [28]. Dacarbazine-based combination

chemotherapy regimens generally confer increased toxicity

without improvement in progression-free survival (PFS) or

overall survival (OS) compared to dacarbazine alone [2].

Alternative chemotherapy agents currently used in the

management of metastatic melanoma include fotemustine,

temozolamide, paclitaxel (often in combination with car-

boplatin) and docetaxel [7].

Temozolamide was compared to dacarbazine in a Phase

III clinical trial yielding an overall response rate (ORR) of

13.5 versus 12.1%. No differences between PFS or OS

were noted; a subsequent retrospective analysis demon-

strated fewer relapses in the CNS in patients treated with

temozolamide [2].

Fotemustine is approved for the treatment of advanced

and metastatic melanoma in several European countries.

Paclitaxel yielded in chemotherapy-naıve patients ORR

ranging from 0 to 16.4% [1, 7, 14]. Second-line trials of

paclitaxel in combination with carboplatin yielded ORR of

11–36% [18].

The unsatisfactory results of actual standard therapies

for metastatic melanoma highlight the need for effective

new therapeutic strategies. Several drugs are currently

under investigation as part of large clinical trials.

Targeted therapy

Several oncogenic mutations have been documented to

drive the malignant phenotype by altering downstream

signaling through the P13K/AKT/mTOR and MAP kinase

pathways to inhibit apoptosis and promote cell cycling

[34].

Known oncogenic mutations in melanoma include

activating mutations in BRAF, c-KIT and NRAS [12, 30].

Targeting BRAF

Early reports indicated that over 50% of melanomas harbor

activating V600E mutations in BRAF [12], an oncogene

known to be critical for the proliferation and survival of

melanoma cells through the activation of the RAF/MEK/

ERK mitogen activated protein kinase pathway [8], making

BRAF a suitable target for melanoma therapy. More recent

series estimate percentages to be less than 50%, with 75%

of the population harboring the BRAF V600E mutation,

19% the BRAF V600K mutation and a variety of mutations

in the remaining individuals [13]. Several BRAF inhibitors,

such as GSK2118436 (GSK), RAF-265 (Novartis) and

XL281 (Exelis), are currently in advanced stages of clinical

trials, and RO5185426 (Plexxicon/Roche—Vemurafenib)

has been approved by the Food and Drug Administration

(FDA) for the treatment of patients with unresectable or

metastatic melanoma with BRAF V600E.

Vemurafenib is a low molecular weight, orally avail-

able, selective inhibitor of the activated form of the BRAF

serine–threonine kinase enzyme. The first-in-human trial of

RO5185426 was a Phase I dose escalation study (PLX06-

02) in patients with solid tumors. Results have been pub-

lished by Flaherty et al. [16]. The study included a dose

escalation phase open to patients with solid tumors and,

once the Phase II dose was selected, an extension phase

open to patients with V600E BRAF mutation-positive

metastatic melanoma. A total of 55 patients were enrolled

in the dose escalation phase, including 50 patients with

metastatic melanoma. The dose of 960 mg b.i.d. orally was

established as the recommended Phase II dose for the

extension cohort. A total of 32 metastatic melanoma

patients harboring the BRAF V600E mutation were

enrolled in the extension cohort; 24 patients achieved PR

and 2 achieved CR, with an ORR of 81%. The estimated

PFS was more than 7 months.

Subsequently, a single-arm, multicenter Phase II study

(BRIM 2) in previously treated patients with metastatic

melanoma harboring the BRAF V600E mutation was

conducted. The primary objective was to evaluate the

efficacy of RO5185426 using the BORR as assessed by an

independent review committee according to RECIST 1.1

criteria. A total of 132 patients were enrolled and treated

with vemurafenib 960 mg b.i.d. orally. Results for all 132

patients enrolled into BRIM 2 study were reported by

Sosman et al. at the 7th International Melanoma Congress

in Sydney (Interdisciplinary Melanoma/Skin Cancer Cen-

tres - Oral Abstracts - Abstract No. 30). With a median

follow-up of 7 months (0.6–11 months), the best overall

response rate (BORR) was 52% by the independent review

committee (IRC) and 55% by investigator assessment. The

median PFS was 6.2 months with a 6-month PFS rate of

51%. Due to lack of sufficient events at the time of data

cutoff, median OS could not be calculated; however, 69%

of patients were alive at 6 months.

After BRIM 2, a randomized, open-label, multicenter

Phase III study (BRIM 3) in patients with treatment-naive

metastatic melanoma (unresectable stage III or stage IV)

positive for the BRAF V600 mutations was conducted to

assess the efficacy as OS of RO5185246 compared to

dacarbazine. The main secondary objectives were PFS,

BORR, time to treatment failure and tolerability/safety.

The first data were presented at the ASCO 2011 and the last

updated survival results were presented at the 2011 Euro-

pean Multidisciplinary Cancer Congress (Abstract No: 28):

178 Arch Dermatol Res (2012) 304:177–184

123

675 patients were enrolled at 104 centers worldwide

between January and December 2010. Median follow-up,

at the time of the last update, was 6.21 months for vemu-

rafenib and 4.46 months for dacarbazine. Kaplan–Meier

estimate of median OS was not reached in the vemurafenib

group and was 7.89 months with dacarbazine. Kaplan–

Meier estimate of 6-month survival was 83% for vemu-

rafenib and 63% for dacarbazine. The safety profile in

vemurafenib-treated patients was consistent with that

reported in previous studies, the most common adverse

events being arthralgia, rash, fatigue, alopecia, keratoac-

anthoma or squamous cell carcinoma, photosensitivity,

nausea and diarrhea; 38% of patients required dose modi-

fication because of toxic effects. Vemurafenib produced

improved rates of overall and progression-free survival in

patients with previously untreated melanoma with the

BRAF V600E mutation [10]. Based on this study, on 17

August 2011, the US Food and Drug Administration

approved vemurafenib tablets (ZELBORAF, Hoffmann-

La Roche Inc.) for the treatment of patients with unresec-

table or metastatic melanoma with the BRAF V600E

mutation.

The enrollment for the multicenter expanded access

study of vemurafenib in patients with metastatic melanoma

harboring the BRAF V600 mutation is currently ongoing. It

is estimated that approximately 900 patients will be

recruited into this study in 140 centers all over the world

(30 countries). Patients will receive continuous oral dosing

of vemurafenib at 960 mg b.i.d. until the development of

progressive disease (PD) or unacceptable toxicity. The

primary objectives are to evaluate the safety and tolera-

bility of vemurafenib; the secondary objectives are to

assess the efficacy of vemurafenib as ORRs determined by

the investigator according to RECIST 1.1 criteria.

Most common AEs are nausea, fatigue, arthralgia,

myalgia, headache, pruritus, rash, photosensitivity and

palmar–plantar dysesthesia. Vemurafenib also has been

associated with reports of cutaneous squamous cell carci-

noma (mostly keratoacanthomas or keratoacanthoma-like,

unlikely to metastasize or invade). AEs with vemurafenib

have been predominantly mild in severity, and transient,

even with continuous dosing [10, 15].

GSK2118436 is an orally available drug, which shows

high selective inhibition activity of the activated form of

BRAF, both with the V600E and the V600K mutations

[13]. Its efficacy is about to be assessed in a Phase III,

randomized, open-label study comparing GSK2118436

with DTIC in previously untreated subjects with BRAF

mutation-positive advanced or metastatic melanoma. The

dose of 150 mg BID of GSK2118436 was based on pre-

liminary results from study BRF112680, a Phase I, dose

escalation study that investigated the safety, pharmacoki-

netics and pharmacodynamics of GSK2118436.

RAF265 is a novel, orally dosed, small-molecule BRAF

kinase and vascular endothelial growth factor receptor-2

(VEGFR-2) inhibitor with potent antitumor activity in

mutant BRAF tumor models and is currently undergoing

Phase I clinical trials in melanoma. Inhibiting mutant

BRAF as well as VEGFR-2 provides a dual mechanism of

action:antiproliferative activity by inhibiting the Ras/Raf/

mitogen activated protein kinase (MAPK) pathway and

indirect antitumor activity by inhibiting angiogenesis

through VEGFR-2 [36].

Despite encouraging results from clinical trials with

BRAF inhibitors, most patients who initially respond to

treatment relapse, suggesting the development of drug

resistance [38]. Therefore, it is critical to address research

efforts toward developing models of resistance to BRAF

inhibitors, investigating the mechanisms underlying resis-

tance and designing alternative therapeutic strategies to

overcome it. In a recent study published on Cancer Cell by

Villanueva et al. [38] in December 2011, it was reported

that melanomas chronically treated with BRAF inhibitors

acquire cross-resistance to several selective BRAF inhibi-

tors through an RAF kinase switch and IGF-1R and PI3K/

AKT activity enhancement, allowing the tumor to continue

to rely on MAPK for maintenance of the malignant phe-

notype. No secondary mutations in BRAF that could

explain resistance to BRAF inhibitors were detected and no

de novo mutations or changes in copy number in NRAS,

KIT or PTEN were identified. Therefore, it was proposed

by cotargeting MEK and IGF-1R/P13K to overcome

resistance to BRAF inhibitors. Targeting only one pathway

may not be sufficient to eradicate melanoma [24, 33]

combination strategies and targeting different key onco-

genic pathways may be a requirement for successful

therapy.

Targeting MEK

MAPK pathway plays a key role in the biology of mela-

noma. In addition to targeting BRAF, MEK inhibitors are

efficacious in melanoma patients harboring activating

BRAF or NRAS mutations, the assessment of which is

currently under investigation. In normal cells, BRAF is

recruited to the plasma membrane following activation of

growth factor receptors that enable binding of GTP to RAS

proteins. GTP-bound RAS binds directly to BRAF and this

interaction results in activation of BRAF kinase activity.

The best characterized substrate of BRAF is MEK kinase.

Phosphorylation of MEK by BRAF results in increased

MEK catalytic activity. Phospho-MEK in turn phosphory-

lates the extra-cellular signal-regulated kinases, ERK1 and

ERK2, and phospho-ERK translocates to the nucleus where

a variety of ERK substrates reside, including transcription

and translation factors, resulting in inhibition of apoptosis

Arch Dermatol Res (2012) 304:177–184 179

123

and promoting cell proliferation. Therefore, targeting MEK

may be a suitable option in patients with oncogenic

mutations both in BRAF and NRAS, which are mutually

exclusive and occur in 50–60 and 15–20% of cutaneous

melanomas, respectively [8, 12].

MEK inhibitors have been extensively evaluated pre-

clinically; currently, several MEK inhibitors are under

investigation, although none has yet obtained FDA approval.

MEK162 is a selective, orally available inhibitor of

MEK currently under study in a Phase II trial to determine

the tumor response, safety and tolerability of 45 mg twice

daily (bid) oral MEK162 in previously treated or untreated

patients with BRAF or NRAS-mutated advanced stage

cutaneous malignant melanoma. Patients will be assigned

to either the BRAF or NRAS arm depending upon baseline

mutation status.

AZD6244 shares the same binding mode as MEK162

and selectively inhibits MEK1 and MEK2. It is currently

used in Phase II studies, both in monotherapy (MEK

inhibitor AZD6244 in treating patients with stage III or

stage IV melanoma) and in combination with docetaxel

(docetaxel with or without AZD6244 in melanoma) and

dacarbazine (comparison of AZD6244 in combination with

dacarbazine vs. dacarbazine alone in BRAF mutation-

positive melanoma patients).

GSK1120212 is orally bioavailable, potent and specific.

In a recent study [16], a potent inhibition of ERK phos-

phorylation and inhibition of cell growth were observed

among most cancer lines with activating mutations in the

MAPK pathway. A two-arm, open-label, randomized Phase

III study is comparing single agent GSK1120212 to che-

motherapy (either dacarbazine or paclitaxel) in subjects

with stage IIIc or stage IV malignant cutaneous melanoma

harboring a BRAF mutation. Subjects must have received

up to one prior regimen of chemotherapy in the advanced

or metastatic melanoma setting. Approximately, 297 sub-

jects will be enrolled with 2:1 randomization.

Targeting KIT

Beadling et al. [6] screened 189 melanomas for mutations

in KIT exons 11, 13 and 17 and reported KIT mutations in

23% (3 of 13) of acral melanomas, 15.6% (7 of 45) of

mucosal melanomas, 7.7% (1 of 13) of conjunctival mel-

anomas, 1.7% (1 of 58) of cutaneous melanomas and 0% (0

of 60) of choroidal melanomas. Kong et al. [23] analyzed

in a Chinese population 502 melanoma subtypes for

mutations in exons 9, 11, 13, 17 and 18 of KIT gene and

reported lower percentages for acral and mucosal mela-

nomas of 11.9% (23 of 193) and 9.6% (16 of 167),

respectively.

In the Caucasian population, acral melanoma, which

originates in the palms, soles and subungual regions,

represents about 5% of all melanomas; mucosal melano-

mas, arising most often on mucosal surfaces in the ano-

rectal, vaginal and nasal sinus regions, account for 1–2%

[27]. On the contrary, in the Chinese and other Oriental

populations, the most common melanoma subtypes are

acral (38.4%) and mucosal (33.3%) [23].

Targeting KIT may be a therapeutic strategy in those

patients with CSD, acral or mucosal melanoma harboring

an activating c-KIT mutation on exons 9, 11 or 13.

Imatinib is a tyrosine kinase inhibitor registered for

metastatic/inoperable gastrointestinal stromal tumors

(GIST). It was tested in an unselected cohort of patients

with advanced melanoma and not found to be effective [22,

37, 39]. However, there are cases reported in the literature

documenting partial and complete responses to treatment to

imatinib in patients with acral and mucosal melanoma [19,

22, 25]. Retrospective analysis of responses in the unse-

lected cohorts of melanoma patients treated with imatinib

and data from case reports showed that the mutations

sensitive to imatinib have most often been in exons 11 and

13 of c-KIT, whereas patients with other mutations did not

respond to it. Three clinical trials are currently investigat-

ing the efficacy of imatinib therapy in advanced c-KIT

mutated or amplified melanoma. Carvajal et al. [9] treated

28 advanced melanoma patients harboring KIT mutations

and/or amplification with imatinib mesylate 400 mg orally

twice daily until disease progression. Two complete

responses lasting 94 (ongoing at the time of data publica-

tion) and 95 weeks, two durable partial responses lasting

53 and 89 (ongoing at the time of data publication) weeks

and two transient partial responses lasting 12 and 18 weeks

among the 25 evaluable patients were observed. The

overall durable response rate was 16%, with a median time

to progression of 12 weeks, and a median overall survival

of 46.3 weeks. Guo et al. [17] enrolled 43 metastatic

melanoma patients harboring KIT mutations and/or

amplification in a Phase II study. Each patient received a

continuous dose of imatinib 400 mg/day unless intolerable

toxicities or disease progression occurred. Fifteen patients

who experienced progression of disease were allowed to

escalate the dose to 800 mg/day. Forty-three patients were

eligible for evaluation, and the median follow-up time was

12.0 months. The median progression-free survival was

3.5 months, and the 6-month PFS rate was 36.6%. The rate

of total disease control was 53.5%; 10 patients (23.3%) and

13 patients (30.2%) achieved partial response and stable

disease, respectively. Eighteen patients (41.9%) demon-

strated regression of tumor mass. Notably, nine of the ten

PRs were observed in patients with mutations in exons 11

or 13. The 1-year overall survival (OS) rate was 51.0%.

The median PFS and OS times for patients who had PR or

SD versus disease progression were 9.0 versus 1.5 months

and 15.0 versus 9.0 months, respectively. Imatinib 400 mg/

180 Arch Dermatol Res (2012) 304:177–184

123

day was well tolerated, and only one of the 15 patients who

received dose escalation to 800 mg/day achieved SD.

Nilotinib is a second-generation inhibitor of the tyrosine

kinase activity of KIT, PDGFR and Bcr-Abl, already

approved in more than 80 countries for use in the treatment

of patients with Philadelphia-positive chronic myeloid

leukemia (CML), which is currently under investigation in

a randomized Phase III study to compare its efficacy versus

dacarbazine in the treatment of patients with metastatic

and/or inoperable melanoma harboring a c-KIT mutation.

Nilotinib is administered orally at a dose of 400 mg twice a

day. A total of 120 patients will be enrolled and random-

ized 1:1 in the nilotinib experimental arm or the dacarba-

zine control arm. Efficacy data from this study will assess

if nilotinib will be a suitable therapeutic option for that

subgroup of patients with CSD, acral or mucosal melanoma

harboring a c-KIT mutation. Safety data of nilotinib come

primarily from CML patients’ AEs that include myelo-

suppression, bilirubin elevation, lipase elevation/pancrea-

titis, fluid retention, cardiac toxicity, QTc prolongation and

sudden death. Nilotinib cardiac toxicity has been a concern

since the early phase II studies in patients with imatinib-

resistant/intolerant disease. In those studies, five sudden

deaths in 876 patients occurred, which may have been

related to ventricular repolarization [3].

Targeted immunotherapy

In recent years, immunologic science has evolved and new

mechanisms for targeted immunotherapies have been dis-

covered, such as anti-cytotoxic T lymphocyte-associated

protein 4 or anti-programmed cell death-1 antibodies.

Immunotherapeutic agents are characterized by different

clinical features compared to chemotherapy drugs that

require adequate tools for evaluation. The biological events

following administration of immunotherapy to a cancer

patient include firstly immune activation and T-cell pro-

liferation starting early after first administration; secondly,

clinically measurable antitumor effects mediated by acti-

vated immune cells over weeks to months; and lastly,

potential delayed effect several months after first admin-

istration compared with agents not requiring immune

activation. In clinical terms, it means that the traditional

chemotherapy paradigms cannot be applied to immuno-

therapy, which presents different response patterns to

treatment. Therefore, new immune-related response criteria

(irRC) need to be adapted from standard RECIST and

WHO criteria, designed to capture the effects of cytotoxic

agent, to correctly assess the response to immunothera-

peutic agents. The spectrum of clinical patterns of antitu-

mor response for immunotherapeutic drugs extends beyond

that of cytotoxic agents and includes two conventional

patterns (immediate response in baseline lesions and

durable stable disease, possibly with a slow but steady

decline in total tumor burden) and two novel patterns

(response after tumor burden increase and response of

index lesions in the presence of new lesions). The novel

patterns are specifically recognized with immunothera-

peutic agents and probably depend on tumor infiltrating

lymphocytes [21].

The most promising immunotherapeutic drug is ipi-

limumab, which was recently reported to improve survival

in patients with metastatic melanoma [20].

Ipilimumab is a fully human monoclonal antibody

(IgG1) that blocks cytotoxic T lymphocyte-associated

antigen 4 (CTLA-4), an immune checkpoint molecule that

downregulates pathways of T-cell activation, to promote

antitumor immunity [21].

Hodi et al. [20] published the results of the Phase III

study, which finally demonstrated an improved survival in

metastatic melanoma patients treated with ipilimumab. It

was a randomized, double-blind study that enrolled 676

patients, including 82 patients who had metastasis in the

CNS at baseline, in 125 centers in 13 countries. Patients

had all received a previous treatment for metastatic mela-

noma. Patients were randomly assigned in a 3:1:1 ratio to

treatment with solely ipilimumab, ipilimumab plus a gp100

peptide vaccine or gp100 plus placebo. Ipilimumab was

administered at a dose of 3 mg/kg of body weight once

every 3 weeks for four treatments. The median OS in the

ipilimumab alone and ipilimumab plus gp100 groups was

10.0 and 10.1 months, respectively, compared with

6.4 months in the gp100-alone group. The difference was

statistically significant.

The most common adverse events related to the study

drugs were immune-related events, which occurred in 60%

of the patients treated with ipilimumab. The frequency of

grade 3 or 4 immune-related adverse events (irAEs) was

10–15% in the ipilimumab groups. The irAEs mostly

affected the skin and the gastrointestinal tract, the most

common event being diarrhea, which occurred at any grade

in 27–31% of the patients in the ipilimumab groups. Other

common toxicities observed with ipilimumab included grade

3 and 4 irAEs such as dermatitis, uveitis, hepatitis and

hypophysitis. The incidence of irAEs has been correlated

with clinical response. Close clinical and laboratory moni-

toring is required for early detection and timely initiation of

treatment with immunosuppressive therapies. Most irAEs

are manageable and generally reversible with corticoste-

roids. Long-term residual irAEs requiring treatment have

been reported at 2-year follow-up and included primarily

dermatologic effects (rash, vitiligo and pruritus), colitis/

diarrhea and endocrine-related adverse events [20, 29, 35].

Ipilimumab was also studied in combination with

dacarbazine in a large Phase III trial; 502 patients with

Arch Dermatol Res (2012) 304:177–184 181

123

previously untreated metastatic melanoma were randomly

assigned, in a 1:1 ratio, to ipilimumab (10 mg/kg) plus

dacarbazine (850 mg/m2 of body-surface area) or dacar-

bazine (850 mg/m2) plus placebo, given at weeks 1, 4, 7

and 10, followed by dacarbazine alone every 3 weeks

through week 22. Patients with stable disease or an

objective response and no dose-limiting toxic effects

received ipilimumab or placebo every 12 weeks thereafter

as maintenance therapy. The primary end point was overall

survival, which was significantly longer in the group

receiving ipilimumab plus dacarbazine than in the group

receiving dacarbazine plus placebo (11.2 vs. 9.1 months),

with higher survival rates in the ipilimumab–dacarbazine

group at 1 year (47.3 vs. 36.3%), 2 years (28.5 vs. 17.9%)

and 3 years (20.8 vs. 12.2%). Grade 3 or 4 adverse events

occurred in 56.3% of patients treated with ipilimumab plus

dacarbazine, as compared to 27.5% treated with dacarba-

zine and placebo [32].

The Italian Network for Tumour Biotherapy (NIBIT)

conducted a Phase II study combining ipilimumab and

fotemustine in patients with metastatic melanoma––the

NIBIT-M1 Trial—to investigate the clinical and immuno-

logic efficacy of ipilimumab in combination with fote-

mustine in metastatic melanoma patients with or without

brain metastasis. From July 2010 to April 2011, 86 patients

were enrolled; 21 patients had evidence (19) or history (2)

of brain metastasis. Data were presented at the 2011

European Multidisciplinary Cancer Congress (Abstract No:

9305). As of April 2011, 28 patients had terminated the

induction phase and 13 had already entered the mainte-

nance phase; 43 patients had completed the induction phase

and 15 had withdrawn due to AE severity or disease pro-

gression. Of the 17 patients for whom tumor assessment at

week 12 was available, 14 achieved disease control (CR,

PR or SD), including brain metastases in 5 out of 6

patients, while 3 had PD.

The combination of ipilimumab with bevacizumab is

currently being investigated in a Phase I trial. The esti-

mated primary completion date is January 2012.

Bristol-Myers Squibb, in collaboration with Roche-

Genentech, will conduct a Phase I/II trial of vemurafenib

and ipilimumab in subjects with V600 BRAF mutation-

positive metastatic melanoma. The end points of Phase I

will be the safety and tolerability of the combination of

these two drugs as determined by the number and grade of

adverse event/serious adverse events. The end point of

Phase II will be overall survival.

Discussion and conclusions

The management of metastatic melanoma patients is cur-

rently changing very fast. A lot of new drugs, including

BRAF, KIT and MEK inhibitors, are being evaluated both

as first- and second-line treatment in Phase III trials after

promising data from Phase I and II studies. Vemurafenib

has been approved by the Food and Drug Administration

(FDA) for the treatment of patients with unresectable or

metastatic melanoma with the BRAF V600E mutation after

a significant impact on both progression-free and overall

survival was demonstrated compared with dacarbazine in a

Phase III trial. Ipilimumab has proven to be capable of

inducing long-lasting responses and was approved for

patients with advanced melanoma in first- and second-line

treatment by the FDA and in second-line treatment by the

EMA.

In the perspective of a large use of targeted treatments, it

has now become of fundamental importance to determine

the molecular status of each melanoma at the time of the

histological diagnosis, in order to optimize and individu-

alize the management of each single patient.

Patients with BRAF mutations will have the chance to

benefit from treatment with BRAF inhibitors; patients

harboring BRAF or NRAS mutations could be treated with

MEK inhibitors; finally, the subgroup of patients with

acral, mucosal or CSD melanoma harboring a KIT muta-

tion could benefit from KIT inhibitors.

The most important issue regarding BRAF inhibitors is

drug resistance. Efforts should be addressed to a better

understanding of the molecular mechanisms of drug

resistance to find solutions to overcome it. Clinical trials

have been currently evaluating combined treatments with

BRAF plus MEK inhibitors, as well as combinations of

BRAF inhibitors and cytotoxic drugs.

Therefore, the future of patients harboring a BRAF,

NRAS or KIT mutation will probably be associated with

targeted therapies. The management of patients without

these mutations remains more uncertain.

Ipilimumab could become a standard treatment; its

efficacy has been proven, but researchers should now

address their efforts to understanding the predictive vari-

ables of response to treatment. Furthermore, ipilimumab is

now under study in several clinical trials as part of com-

bination treatments with other drugs, such as fotemustine,

dacarbazine and bevacizumab, and will be soon investi-

gated in combination with vemurafenib.

An important issue is the treatment of brain metastasis,

which occurs in a large percentage of patients with meta-

static melanoma. Despite that the spectrum of current

treatments is broad, including surgery for operable lesions,

radiotherapy and chemotherapy using drugs with good

penetration into the CNS, the prognosis of patients with

brain metastasis is poor. The most favorable outcomes have

been reported in patients who are candidates for the most

aggressive forms of surgical and radiation therapy, partic-

ularly using stereotactic radiosurgery. In contrast, systemic

182 Arch Dermatol Res (2012) 304:177–184

123

treatment has shown a very low percentage of responses:

clinical responses to temozolamide, for example, are

observed in a percentage of patients as low as 10%. Ipi-

limumab has shown efficacy in brain metastasis, and it is

currently under investigation in combination with temo-

zolamide in patients with CNS involvement. Furthermore,

recent and ongoing targeted therapy trials allow recruit-

ment of patients with asymptomatic or treated brain

metastasis; data from those studies will show if target

therapy drugs are effective on CNS lesions [26].

The expanded access program CA184-045, a multicen-

ter, open-label study of ipilimumab 3 or 10 mg/kg Q3W for

four doses, included patients with stable and asymptomatic

brain metastases at baseline. Among patients who received

10 mg/kg, overall survival at 1 year was retrospectively

collected via database; of 874 patients treated with ipi-

limumab 10 mg/kg, 165 were identified with brain metas-

tasis. The 1-year overall survival for these patients was

20%. Drug-related adverse events of any grade and grade

3/4 occurred in 41 and 22% of all patients, respectively.

The prospective trial CA184-042 included patients with

active, measurable brain metastasis. At baseline, patients

were either stable without steroid therapy (Arm A) or

required steroids for central nervous system symptoms

(Arm B). Four doses of ipilimumab 10 mg/kg was given

Q3W with potential maintenance dosing Q12W. A total of

51 patients in Arm A and 21 in Arm B were treated with

ipilimumab 10 mg/kg. The 12- and 18-month OS in

patients not requiring steroids was 30% at both time points.

The 12-month OS rate in patients with symptomatic brain

metastases was 10%. Grade 3/4 central nervous system

adverse events occurred in 31% of patients in Arm A and

29% in Arm B. Safety and efficacy of ipilimumab in

patients with melanoma and brain metastases were con-

sistent between the prospective and open-label trials and

ipilimumab also showed similar antitumor activity in the

brain as reported overall for extracranial metastases (data

were presented at the 2011 European Multidisciplinary

Cancer Congress, Abstract No: 9306). An open-label pilot

study is being carried out to evaluate the safety and efficacy

of vemurafenib in patients with metastatic melanoma with

BRAF V600 mutations and non-resectable brain metasta-

sis, pretreated by radiotherapy and/or chemotherapy.

Patients may have symptoms related to their brain metas-

tasis and be on a stable dose of steroids. Twenty patients

have been planned to be included in this study. Preliminary

results were presented at the 2011 ASCO Annual Meeting

(Abstract No: 8548); vemurafenib has been well tolerated

and there were early but strong indications for activity in

brain metastasis.

Until now, the best chance for a metastatic melanoma

patient is to be enrolled in an experimental clinical trial. In

the perspective of future availability of new effective drugs,

such as BRAF inhibitors or ipilimumab, new effective

combinations of drugs and a larger spectrum of therapy

lines, maybe this paradigm will finally be controvert.

Conflict of interest Francesco Spagnolo, M.D. has no financial

interest in any of the products, devices or drugs mentioned in this

article. Paola Queirolo, M.D. received lecture fees from Bristol-Myers

Squibb and Roche and served on advisory boards for Bristol-Myers

Squibb, Roche and Schering-Plough.

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