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CLINICAL PRACTICE GUIDELINE CU-012
Version 2
SYSTEMIC THERAPY
FOR UNRESECTABLE STAGE III OR METASTATIC
CUTANEOUS MELANOMA
Effective Date: February 2013
The recommendations contained in this guideline are a consensus of the Alberta Provincial Cutaneous Tumour Team
and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific
literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical
judgment in the context of individual clinical circumstances to direct care.
CLINICAL PRACTICE GUIDELINE CU-012
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BACKGROUND
The Alberta Cancer Foundation published a report in 2009 indicating that in 2015, the expected number of
new cases and deaths from malignant melanoma in Alberta will be 570 and 80, respectively; this
represents an increase in incidence of 12.9% from 2010. 1 Metastatic melanoma accounts for less than
5% of all cases of melanoma, but is associated with a poor rate of survival at 5 years (13%). 2 Common
site of metastases include distant skin, lymph nodes, liver, lungs, bone, and the brain.
Surgery is the preferred option for the management of metastatic melanoma with resectable solitary sites
of disease in selected patients. 3,4 Following complete resection, adjuvant systemic treatment in the
context of clinical trial can be considered. Patients with residual disease should be treated with systemic
therapy for metastatic melanoma.
Most metastatic melanomas are not amenable to surgery; systemic therapy is often the best option.
Optimal selection of systemic agents depends on the mutation status of cancer, volume and tempo of
disease, and presence of symptoms and host performance status. Certain agents may be better suited for
selected subgroups of patients as well. Therefore, this guideline aims to provide recommendations on the
medical management of unresectable metastatic melanoma.
TARGET POPULATION
The recommendations outlined in this guideline apply to adults over the age of 18 years with unresectable
stage III and stage IV cutaneous melanoma, without involvement of the central nervous system (CNS).
Different management strategies may apply to pediatric patients. This guideline does not include
recommendations for the management of uveal, mucosal, or acral melanomas.
For patients with CNS metastases, the priority of treatment should typically focus on the CNS disease. An
CancerControl Alberta guideline on Palliative Radiotherapy describes recommended strategies for the
management and treatment of adult patients with brain metastasis. 5
GUIDELINE QUESTIONS
1.
2.
3.
4.
What types of systemic therapy should be considered for patients with metastatic melanoma?
Should patients be carefully selected; if so by what criteria?
Which agents should be used as first-line therapy and at what dosing regimen?
Which agents should be used as second- or third-line therapy and at what dosing regimen?
DEVELOPMENT
This guideline was reviewed and endorsed by the Alberta Cutaneous Tumour Team. Members of the
Alberta Cutaneous Tumour Team include medical oncologists, surgeons, dermatologists, radiation
oncologists, pathologists, and nurses. Evidence was selected and reviewed by a working group comprised
of members from the Alberta Cutaneous Tumour Team and a Knowledge Management Specialist from
the Guideline Utilization Resource Unit. A detailed description of the methodology followed during the
guideline development process can be found in the Guideline Utilization Resource Unit Handbook.
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SEARCH STRATEGY
The EMBASE and Medline OVID databases were searched using the following initial search terms:
malignant melanoma or advanced melanoma or unresectable melanoma or inoperable melanoma or
stage IV melanoma or metastatic melanoma (50785 citations) AND systemic therapy or chemotherapy or
immunotherapy or hormone therapy or cytotoxic drug (43523 citations), limited to publications between
1990 and 2011 September 26 and duplicates removed: 632 citations. Additional search terms included:
(1) ipilimumab and melanoma, limited to clinical trials: 23 citations; (2) vemurafenib and melanoma, limited
to clinical trials: 3 citations; (3) dacarbazine and melanoma, limited to randomized controlled trials: 138
citations; (4) temozolomide and melanoma, limited to randomized controlled trials: 16 citations; (5) highdose interleukin-2 and melanoma, limited to randomized controlled trials: 20 citations.
Randomized controlled trials, prospective cohort or case series, comparative (treatment) retrospective
studies, and phase II studies published in 2009 or later or to obtain toxicity data, were included. In vitro
and animal studies, phase I studies or studies that did not include at least ten patients with advanced,
unresectable melanoma (i.e., non-melanoma skin cancer, other cancers), studies that did not test the
efficacy of a particular treatment, non-comparative retrospective studies, review articles, and abstracts
published in 2008 or prior were excluded.
In addition, the National Guidelines Clearinghouse and individual guideline organizations were searched
for practice guidelines relevant to this topic, published in 2009 or later. A total of two original clinical
practice guidelines were identified from the following organizations: National Comprehensive Cancer
Network (2012) and the European Society for Medical Oncology (2010).
For the 2013 update of the guideline, PubMed was searched for evidence on systemic therapy for
unresectable stage III or metastatic cutaneous melanoma. The search term “melanoma” was used and
results were limited to clinical trials, published through January 2013. Citations were hand-searched for
studies pertaining to systemic therapy, resulting in a total of twelve randomized controlled trials. Following
a review of the evidence by the Alberta Cutaneous Tumour Team, no changes to the recommendations
were made.
RECOMMENDATIONS
For American Joint Committee on Cancer melanoma staging, 2 please refer to the Appendix.
• Patients with unresectable stage III and stage IV cutaneous melanoma should undergo BRAF
biomarker testing by a College of Physicians and Surgeons of Alberta accredited laboratory to
determine whether they are candidates for vemurafenib.
o Molecular validation should be performed using parallel testing with early access program testing
kits; a reasonable number of duplicate test cases (i.e. 40 samples) should be performed.
• First-line systemic therapy:
o BRAF-positive patients
1. Clinical trials.
2. Vemurafenib (960 mg orally, twice per day) in patients with high volume, symptomatic disease,
or who are poor candidates to receive immunotherapy with ipilimumab.
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3. Ipilimumab in patients with low volume, asymptomatic disease.
4. Dacarbazine- or paclitaxel-based systemic chemotherapy.
o
BRAF-negative patients
1. Clinical trials.
2. Ipilimumab.
3. Targeted therapy based on tumour mutational status (based on probability of clinical benefit).
4. Dacarbazine- or paclitaxel-based systemic chemotherapy.
• Second-line systemic therapy
o Patients who are intolerant or who have progressed after first-line therapy may be considered for:
1. Clinical trials.
2. Treatment with a different agent not used from the first-line list.
3. Ipilimumab, if vemurafenib was given as first-line.
DISCUSSION
B-RAF Inhibitors
The BRAF gene is responsible for encoding the B-Raf protein, which plays a role in cell signaling and cell
6,7
growth, and is mutated in about 50% of individuals with cutaneous melanoma. The most common
variants are BRAF V600E, BRAF V600K, and BRAF V600R. Therapy targeted at inhibiting the BRAF
gene may therefore be efficacious in patients with metastatic melanoma. Vemurafenib (PLX4032) is a
BRAF inhibitor that is active against the BRAF V600E mutation. A phase III trial by Chapman, et al.
compared vemurafenib (960 mg orally, twice per day) with dacarbazine (1000 mg/m2, every 3 weeks) in
previously untreated patients (n=675) with metastatic melanoma who tested positive for the BRAF V600E
mutation and demonstrated a hazard ratio for tumor progression of 0.26 (95% CI 0.20-0.33; p<.001) for
vemurafenib , with an estimated median progression-free survival time was 5.3 months versus 1.6 months
for dacarbazine. 8 Vemurafenib produced a 20% increase in overall survival at 6 months (84%, 95% CI
78-89% versus 64%, 95% CI 56-73%; relative risk of death 63%, p<.001); 8 however, the survival
advantage dropped to 12% by 12 months (55% versus 43%). 9 Among previously treated patients with
BRAF V600–mutant metastatic melanoma, vemurafenib has been shown to produce an overall response
rate of 53% (8 complete and 62 partial responses) for a median duration of 6.7 months; median
progression-free survival in this cohort was 6.8 months. 10
Other BRAF inhibitors include sorafenib, GDC-0879, PLX-4720, and dabrafenib. Unfortunately, sorafenib
in combination with either temsirolimus or tipifarnib) has not demonstrated efficacy in the phase II clinical
setting 11 and PLX-4720 has even shown tumour promoting activity. 12 However, GDC-0879 has shown
promise in mice with both cell line- and patient-derived BRAF(V600E) tumours and may therefore have
potential as a future therapeutic agent. 13 Dabrafenib has been the most successful of these agents. The
BREAK-3 open-label trial compared dabrafenib (150 mg 2 times per day) with dacarbazine (1000 mg/m2
IV q 3 wks) in patients with stage IV or unresectable BRAF V600+ melanoma (N=250) and demonstrated
a progression-free survival advantage with dabrafenib (median PFS 5.1 months vs. 2.7 months; HR 0.30;
95% CI 0.18-0.51; p<.001). Treatment compliance was also better with dabrafenib (57% vs. 22%).
Treatment-related grade 3/4 adverse events were uncommon in both groups. 14,15 Combination therapy
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may also be beneficial for patients with unresectable BRAFV600+ melanoma. In the phase II setting, the
combination of dabrafenib with MEK inhibitor trametinib (2 mg per day) produced a median progression
free survival of 9.4 months, as compared with 5.8 months for dabrafenib alone. 16
CTLA-4 Blockers
Ipilimumab is a human monoclonal antibody that blocks the action of cytotoxic T lymphocyte-associated
antigen 4 (CTLA-4). 17 By blocking CTLA-4, ipilimumab promotes an immune response against tumours.
Clinical trials have demonstrated overall survival rates of 13 to 47% at one year and 24 to 33% at two
years in patients treated with ipilimumab (10 mg/kg, every three weeks for four cycles, then every 12
weeks as maintenance) as second line therapy. 18,19 A phase III clinical trial by Robert, et al. (2011),
among previously untreated patients (n=502) with metastatic melanoma, compared ipilimumab (10 mg/kg
every three weeks for four cycles) plus dacarbazine (850 mg/m2 every three weeks through week 22) with
dacarbazine alone; both regimens included an induction phase followed by a maintenance phase. The
overall survival rates at one year and two years were 47.3% and 28.5% for ipilimumab combination
therapy and 36.3% and 17.9% for dacarbazine monotherapy, respectively. 20 Ipilimumab and dacarbazine
combination therapy was also shown to produce better overall survival rates than ipilimumab alone (62%
and 45%, respectively, at one year; 24% and 21%, respectively, at two years; 20% and 9%, respectively,
at three years). 21 Another phase III trial (CA184-024) compared ipilimumab and dacarbazine with
dacarbazine alone in patients with previously untreated stage III-IV melanoma (N=488) and reported
improvements in median overall survival (11.2 months for combination therapy vss 9.2 months for DTIC
alone; HR=0.72; p=.0009) and median progression-free survival (2.8 months for combination therapy vs.
2.6 months for DTIC alone; HR=.76; p=.006). 22,23 In the phase II clinical setting, overall survival among
patients treated with ipilimumab was shown not to be associated with age, stage of disease, or prior
response to systemic therapy. 24
Other Biologic Agents
Imatinib is a tyrosine kinase inhibitor that targets Abl, c-Kit, and platelet-derived growth factor receptor 25
and therefore may be effective in patients with metastatic melanoma who have c-kit mutations. A phase II
clinical trial among patients with metastatic melanoma and c-Kit aberrations showed that the
administration of imatinib mesylate at 800 mg per day, orally (in six-week cycles) resulted in a durable
response rate (i.e., CR and PR) of 16% (4 of 24 patients), with a median overall survival time of 10.7
months; response was associated with mutations affecting recurrent hotspots or with a mutant to wild-type
allelic ratio of more than 1 (40% versus 0%, p=.05). 26 Another phase II clinical trial demonstrated an
overall response rate (i.e., PR) of 23% (10 of 43 patients), with a median overall survival time of 14.0
months; among those with a partial response, 90% had c-Kit mutations in exons 11 or 13. 27 At this time, it
may be considered for c-kit mutation positive patients on a case by case basis.
The MEK inhibitors, trametinib and selumetinib have been studied in the setting of advanced/unresectable
melanoma. The METRIC study compared trametinib (2 mg per day orally) with standard dacarbazine in
BRAFV600E/K mutant patients (N=322) and was able to demonstrate better median progression-free
survival for trametinib (4.8 months vs. 1.5 months; HR progession/death 0.45, 95% CI 0.33-0.63; p<.001),
as well as better overall survival at 6 months (81% vs. 67% for chemo despite crossover; HR death 0.54,
95% CI 0.32-0.92; p=.01). The most common adverse events were rash, diarrhea, and peripheral edema
for trametinib; events were managed with dose interruption and dose reduction. 28,29 Studies evaluating
selumetinib have not been able to demonstrate efficacy over standard agents. 30
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Phase II data on the VEGF inhibitor, bevacizumab, has shown some benefit in survival, when this agent is
combined with chemotherapy. A double-blind trial of bevacizumab (15 mg per kg IV) and carboplatin/
paclitaxel, compared with carboplatin/paclitaxel alone, in patients with previously untreated metastatic
melanoma (N=214) produced better median overall survival at 13 months (12.3 months vs. 8.6 months;
HR 0.67; p=.0366) but not progression-free survival (5.6 months vs. 4.2 months; HR 0.78; p=.1414). At 17
months, however, the median overall survival difference was no longer significant (12.3 months vs. 9.3
months; HR 0.79; p=.1916). A subgroup analysis among patients with elevated serum LDH (N=84)
revealed better median progression-free and overall survival times in the bevacizumab group (PFS: 4.4
vs. 2.7 months, HR, 0.62; OS: 8.5 vs. 7.5 months, HR, 0.52). 31 Bevacizumab alone did not show any
survival benefit, as compared to what has been reported for standard chemotherapy. 32
Chemotherapy
Prior to the development of novel agents such as ipilimumab and vemurafenib, standard therapy for
metastatic melanoma has been dacarbazine (DTIC) chemotherapy alone or in combination with other
cytotoxic agents and/or interferon-alpha (IFN-α), or high-dose interleukin-2 (IL-2) alone or in combination
with other agents. However, these regimens have produced only minimal gains in overall survival. 33,34 In
phase III clinical trials, combination therapy using DTIC has produced response rates of 16 to 27%, with
median overall survival ranging from 6 to 16 months. 35-50 Phase III data on high-dose IL-2 is similar:
response rates of 5 to 33%, with median overall survival ranging from 9 to 11 months, 51-55 with the
exception of high-dose IL-2 and gp100 peptide vaccination, which was recently shown to result in a
median overall survival time of 18 months (p=.06, versus high-dose IL-2 alone). 51 A meta-analysis
comparing biochemotherapy (i.e., chemotherapy plus IFN-α, with or without IL-2) with chemotherapy
alone, among 2600 patients with metastatic melanoma, revealed a better response rate with
biochemotherapy (27.9% versus 18.6%; p<.001) but no difference in the overall survival rate (17.2%
versus 17.5%). 56
Future Directions
The future of care for patients with melanoma may lie in targeted therapies, especially as more is
understood about the pathogenesis of melanoma. 57 In addition to ipilimumab and imatinib, other
upcoming therapies at various phases of testing include oblimersen and bevacizumab. Oblimersen is a
Bcl-2 antisense oligonucleotide that decreases Bcl-2 protein production, thereby allowing apoptosis. 46 In
a phase III clinical trial, oblimersen in combination with DTIC improved median overall survival by about a
month as compared to DTIC alone (9.0 versus 7.8 months); however, lack of response appears to be
predicted by higher baseline levels of lactate dehydrogenase (LDH), which may allow for better selection
of patients most likely to benefit from oblimersen. 58 Bevacizumab is an antibody against VEGF-A that
blocks VEGF receptors, thereby inhibiting tumor growth. 57 In the phase II clinical setting, combination
therapy consisting of bevacizumab, carboplatin, and paclitaxel demonstrated a response rate (i.e., PR) of
17% (9 patients) with a median overall survival time of 12 months. 59 New agents will continue to emerge
as more becomes known about the genetic aberrations present in patients with melanoma. Strategies
must be in place for the careful selection of patients, prior to making new targeted therapies available.
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GLOSSARY OF ABBREVIATIONS
Acronym
BRAF
CI
CNS
CR / PR
CTLA-4
DTIC
IFN-α
IL-1
LDH
Description
gene that encodes serine/threonine-protein kinase B-Raf
confidence interval
central nervous system
complete response / partial response
cytotoxic T-lymphocyte antigen 4 (CD152)
dacarbazine
interferon-alpha
interleukin-2
lactate dehydrogenase
DISSEMINATION
• Present the guideline at the local and provincial tumour team meetings and weekly rounds.
• Post the guideline on the Alberta Health Services website.
• Send an electronic notification of the guideline to all members of CancerControl Alberta.
MAINTENANCE
A formal review of the guideline will be conducted at the Annual Provincial Meeting in 2015. If critical new
evidence is brought forward before that time, however, the guideline working group members will revise
and update the document accordingly.
CONFLICT OF INTEREST
Participation of members of the Alberta Cutaneous Tumour Team in the development of this guideline has
been voluntary and the authors have not been remunerated for their contributions. There was no direct
industry involvement in the development or dissemination of this guideline. CancerControl Alberta
recognizes that although industry support of research, education and other areas is necessary in order to
advance patient care, such support may lead to potential conflicts of interest. Some members of the
Alberta Cutaneous Tumour Team are involved in research funded by industry or have other such potential
conflicts of interest. However the developers of this guideline are satisfied it was developed in an
unbiased manner.
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CLINICAL PRACTICE GUIDELINE CU-012
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APPENDIX
AJCC (7th Edition) Anatomic Stage Groupings for Cutaneous Melanoma
Clinical Staging a
0
IA
IB
2
Pathologic Staging b
T
N
M
Tis
T1a
T1b
T2a
T2b
T3a
T3b
T4a
T4b
Any T
N0
N0
N0
M0
M0
M0
T
0
IA
IB
N
M
5-year Survival
(%)
100%
95%
90%
Tis
N0
M0
T1a
N0
M0
T1b
N0
M0
T2a
IIA
N0
M0
IIA
T2b
N0
M0
78%
T3a
IIB
N0
M0
IIB
T3b
N0
M0
65%
T4a
IIC
N0
M0
IIC
T4b
N0
M0
45%
III
N > N0
M0
IIIA
T1-4a
N1a
M0
66%
T1-4a
N2a
T1-4b
N1a
50%
IIIB
T1-4b
N2a
T1-4a
N1b
T1-4a
N2b
T1-4a
N2c
T1-4b
N1b
27%
IIIC
T1-4b
N2b
T1-4b
N2c
Any T
N3
IV
Any T
Any N
M1
IV
Any T
Any N
M1
13%
a
Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for
metastases. By convention, it should be used after complete excision of the primary melanoma with
clinical assessment for regional and distant metastases.
b
Pathologic staging includes microstaging of the primary melanoma and pathologic information about the
regional lymph nodes after partial (i.e., sentinel node biopsy) or complete lymphadenectomy. Pathologic
stage 0 or IA patients are the exception; they do not require pathologic evaluation of their lymph nodes.
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CLINICAL PRACTICE GUIDELINE CU-012
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AJCC (7th Edition) TNM Staging Categories for Cutaneous Melanoma 2
T
Tis
T1
Thickness (mm)
NA
≤ 1.00
T2
1.01-2.00
T3
2.01-4.00
T4
> 4.00
N
N0
N1
Number of Metastatic Nodes
0
1
N2
2-3
Ulceration Status/Mitoses
NA
a: without ulceration and mitosis < 1/mm2
b: with ulceration or mitoses ≥ 1/mm2
a: without ulceration
b: with ulceration
a: without ulceration
b: with ulceration
a: without ulceration
b: with ulceration
Nodal Metastatic Burden
NA
a: micrometastasisa
b: macrometastaisb
a
a: micrometastasis
b
b: macrometastais
c: in transit metastases/satellites without metastatic
nodes
N3
4+ metastatic nodes, or matted
nodes, or in transit metastases/
satellites with metastatic nodes
M
Site
Serum LDH (lactate dehydrogenase)
M0
No distant metastases
not applicable
M1a
Distant skin, subcutaneous or nodal metastases
Normal
M1b
Lung metastases
Normal
M1c
All other visceral metastases
Normal
Any distant metastases
Elevated
a
Micrometastases are diagnosed after sentinel lymph node biopsy.
b
Macrometastases are defined as clinically detectable nodal metastases confirmed pathologically.
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