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Chapter 2:
Therapeutic Options in
Metastatic Melanoma
Core Educational Resource
CONFIDENTIAL – FOR INTERNAL USE ONLY
Content
•
•
•
•
•
Melanoma Treatment Overview
Treatment Options Overview
Chemotherapy for Metastatic Melanoma
Immunotherapy for Metastatic Melanoma
Targeted Therapies
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Melanoma Treatment Overview
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Learning Objectives
By completing this section you should be able to:
• Understand the development of melanoma treatment from a chronologic perspective
• Recall key features associated with each stage of the disease
• Recall the basic treatment guidelines for each stage
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Key Therapeutic Milestones in Melanoma
French physician René
DTIC received US FDA
Laennec described
approval for metastatic
melanoma as a disease1
melanoma3
1804
High dose IFN-α-2b was
approved by the FDA for
adjuvant treatment of patients
having undergone complete
surgical resection and at high
risk of relapse5
1975
1971
Zelboraf received FDA approval for the
treatment of BRAFV600E mutationpositive advanced (unresectable or
metastatic) melanoma in 20119 and
EMA approval for BRAFV600 mutationpositive advanced melanoma in 2012.10
1995
1980s–1990s
2010–2012
1998
2011: Ipilimumab received
High dose IL-2
Due to the limited performance of
approval from the FDA for the
received FDA
single-agent chemotherapy, several
treatment of unresectable or
approval for
clinical trials evaluating multi-drug
metastatic melanoma7 and
metastatic
combinations were initiated, comparing
from the EMA for the
melanoma6
regimens such as
treatment of advanced
cisplatin/vinblastine/DTIC,
melanoma in adults who have
carmustine/cisplatin/DTIC or
received prior therapy8
3
carboplatin/DTIC
compared
with
DTIC.
DTIC = dacarbazine; EMA = European
Medicines Agency;
FDA = US
Food
and
Drug Administration;
IFN = interferon; IL-2 = interleukin-2.
First trial of DTIC, an
inhibitor of DNA
(alkylating agent)2
1. Roguin A, et al. Clin Med Res 2006;4;1:230–5.
2. Burke PJ, et al. Cancer 1971;27:744–750.
3. Mouawad R, et al. Crit Rev Oncol Hematol 2010;74:27–39.
4. Khayat D, et al. Cancer Invest 1994;12:414–420.
5. National Cancer Institute. Available from www.cancer.gov.
6. Bhatia S, et al. Oncology 2009;23:488–96.
7. Yervoy Prescribing Information, March 2011.
8. Yervoy Summary of Product Characteristics, July 2011.
9. Zelboraf Prescribing Information, August 2011.
10. Zelboraf Summary of Product Characteristics, March 2012.
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Current Treatment Options
• Prior to the development of Zelboraf and ipilimumab, single agent DTIC represented
the most common treatment option for advanced or metastatic melanoma, however,
this strategy provided only limited benefit3
• Currently, preferred systemic therapy options for this patient population include
Zelboraf, ipilimumab and enrolment on to clinical trials11
3. Mouawad R, et al. Crit Rev Oncol Hematol 2010;74:27–39.
11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™.
Melanoma V.1.2011. Available from www.nccn.org (last accessed November 1, 2012).
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Clinical Stages for Melanoma
Treatment of melanoma depends on the stage of the disease.11–13 The NCCN provide diagnostic and treatment
guidelines for all cancer types; the NCCN guidelines stage melanoma based on clinical and pathologic
characteristics as set-out by the AJCC11
Stage 011
Stage I11
Stage II11
• In situ tumor
• No regional lymph node metastases
• No distant metastases
Stage IA
• ≤1.0 mm thick; no ulceration;
mitosis <1/mm2
• No regional lymph node metastases
• No distant metastases
Stage IIA
• 1.01–2.0 mm thick; with ulceration
• No regional lymph node metastases
• No distant metastases
or
• 2.01–4.0 mm thick; no ulceration
• No regional lymph node metastases
• No distant metastases
Stage IB
• ≤1.0 mm thick; with ulceration or mitosis ≥1/mm2
• No regional lymph node metastases
• No distant metastases
or
• 1.01–2.0 mm thick; no ulceration
Stage IIB
• 2.01–4.0 mm thick; with ulceration
• No regional lymph node metastases
• No distant metastases
or
• >4.0 mm thick; no ulceration
• No regional lymph node metastases
• No distant metastases
Stage IIC
• >4.0 mm thick; with
ulceration
• No regional lymph
node metastases
• No distant metastases
AJCC = American Joint Committee on Cancer; NCCN = National Comprehensive Cancer Network.
11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V.2.2013. Available from www.nccn.org
(last accessed December 18, 2012).
12. Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii91.
13. Garbe C, et al. Eur J Cancer 2010;46:270–83.
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Clinical Stages for Melanoma
Treatment of melanoma depends on the stage of the disease.11–13 The NCCN provide diagnostic and treatment
guidelines for all cancer types; the NCCN guidelines stage melanoma based on clinical and pathologic
characteristics as set-out by the AJCC11
Stage IIIA
• Any tumor thickness; no
ulceration
• Micrometastases* of 1–3
regional lymph nodes
• No distant metastases
Stage III11
Stage IV11
Stage IIIB
• Any tumor thickness; with
ulceration
• Micrometastases of 1–3 regional
lymph nodes
• No distant metastases
or
• Any tumor thickness; no ulceration
• Macrometastases† of 1–3 regional
lymph nodes or in transit
metastases of 2–3 regional lymph
nodes/satellite(s) without
metastatic nodes
• No distant metastases
Stage IIIC
• Any tumor thickness; with
ulceration
• Macrometastases of 1–3 regional
lymph nodes or in transit
metastases of 2–3 regional lymph
nodes/satellite(s) without
metastatic nodes
• No distant metastases
or
• Any tumor thickness; with/without
ulceration
• ≥4 metastatic nodes or in transit
metastases regional lymph
nodes/satellite(s) with metastatic
nodes
• Any tumor thickness
• Any regional lymph node metastases
• Distant metastases
*Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for metastases. It should be used after complete excision
of the primary melanoma with clinical assessment for regional and distant metastases.
†Pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after partial or complete
lymph node dissection. Pathologic Stage 0 or Stage IA patients do not require pathologic evaluation of lymph nodes.
11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V.2.2013. Available from www.nccn.org
(last accessed December 18, 2012); 12. Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii91; 13. Garbe C, et al. Eur J Cancer 2010;46:270–83.
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Current Treatment Guidelines
for Melanoma
The NCCN, ESMO and European consensus-based interdisciplinary guidelines11–13 provide recommendations for
treatment of melanoma at each stage of the disease based on the AJCC classification system
Localized
(stage I/II)11–13
• Current NCCN, ESMO and European guidelines recommend local excision of the primary tumor
with or without adjuvant treatment, depending on the degree of invasion of the primary tumor
Many treatment options exist for stage III disease and are based on size, location and number of
lesions but there is no consensus on best approach.11 Approaches recommended in the NCCN,
ESMO and European consensus guidelines include:
Locally advanced
(stage III)11–13
• Clinical trials for in-transit or sentinel node positive tumors11,12
• Excision with clear margins for resectable regional recurrence 11,13
• Lymph node dissection11,12
• Non-surgical options such as intralesional injections with bacillus Calmette-Guerin or IFN-α, laser
ablation, topical imiquimod and radiation therapy may be used for unresectable asymptomatic
regional recurrence11
• Isolated limb perfusion with melphalan and/or tumor necrosis factor-α for unresectable in-transit
metastases or inoperable primary tumors of the limbs without additional metastases11,12
• Systemic therapy with Zelboraf or ipilimumab for unresectable disease11,12
ESMO = European Society for Medical Oncology.
11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V.2.2013. Available from www.nccn.org
(last accessed December 18, 2012).
12. Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii91.
13. Garbe C, et al. Eur J Cancer 2010;46:270–83.
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Current Treatment Guidelines
for Melanoma
The NCCN, ESMO and European consensus-based interdisciplinary guidelines11–13 provide recommendations for treatment of
melanoma at each stage of the disease based on the AJCC classification system
Treatment for stage IV disease depends on whether disease is resectable (limited) or unresectable (disseminated) 11 and in general,
cases are recommended to be discussed at an interdisciplinary tumor board12
In the case of unresectable disease, the following strategies are recommended:
• Systemic therapy11
• Clinical trial11–13
• Observation11
• Palliative resection and/or radiotherapy for symptomatic patients, including those with brain
metastases11–13 or best supportive care11
Metastatic
(Stage IV)11–13
In the case of resectable disease, the following strategies are recommended:
• Resection followed by clinical trial or observation11,13
• Observation or systemic therapy followed by disseminated treatment if patient is found to have
other disease or resection if patient is negative for other disease11,12
Additionally, ESMO guidelines recommend the following:12
• Systemic therapy: Zelboraf is preferred in BRAFV600 mutation-positive tumors and can be used
for patients with brain metastases; ipilimumab is preferred in BRAF wild-type tumors as first-line
(FDA) or second-line (FDA and EMA) treatment
• If clinical trials or the approved targeted therapy are unavailable, cytotoxic drugs such as DTIC,
TMZ, cytokines or combinations can be used
TMZ = temozolomide.
11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V.2.2013. Available from www.nccn.org
(last accessed December 18, 2012).
12. Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii91.
13. Garbe C, et al. Eur J Cancer 2010;46:270–83.
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Current Treatment Overview
Based on the guidelines for melanoma treatment at each stage, the steps for treatment are defined.
Stage
Localized11–13
(stage I/II)
82–85% at
presentation*
Locally
advanced11–13
(stage III)
10–13% at
presentation*
Initial Treatment Intervention
Wide excision (with/without
sentinel node biopsy)
Adjuvant Therapy
Treatment of Recurrence
Clinical trial or observation
(stage IB/IIA/IIB/IIC)
IFN-α† (stage IIB/IIC)
Sentinel node positive: Clinical trial or
lymph node dissection
Clinically positive: Wide excision + lymph
node dissection
In transit: Clinical trial or local therapy
options or regional/systemic therapy )
Surgery or
lymphadenect
omy or
radiotherapy
or clinical trial
Sentinel node positive: Adjuvant
clinical trial, observation or IFN-α
Clinically positive: Adjuvant clinical trial,
observation, IFN-α or radiotherapy to
nodal basin
Surgery or
lymphadenectomy or
radiotherapy or
clinical trial
In transit: Adjuvant clinical trial,
observation or IFN-α
Sentinel node positive = Sentinel lymph node metastases as determined by a sentinel lymph node biopsy;11 clinically positive = nodal metastases confirmed
by lymphadectomy or when nodal metastasis exhibits gross extracapsular extension;11 in transit = Located in the skin between 2 cm from the site of the
primary tumor and the first draining lymph node.13
*Percentage of melanoma patients (US) presenting with indicated stage of disease; †The NCCN melanoma panel does not recommend the use of adjuvant
IFN-α for completely resected stage IV disease.11
11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V.2.2013. Available from www.nccn.org
(last accessed December 18, 2012); 12. Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii91; 13. Garbe C, et al. Eur J Cancer 2010;46:270–83.
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Current Treatment Overview
Based on the guidelines for melanoma treatment at each stage, the steps for treatment are defined.
Stage
Metastatic11–13
(stage IV)
2–5% at
presentation*
Initial Treatment Intervention
Adjuvant Therapy
Treatment of Recurrence
Resectable disease: Surgery or
observation/systemic therapy with
repeat scans + resection (if no further
metastases)
Unresectable disease: Systemic therapy/
clinical trial/palliative resection and/or
radiotherapy/best supportive care,
resection and/or radiotherapy as initial
intervention for patients with brain
metastases
n/a†
Systemic therapy
or clinical trial
*Percentage of melanoma patients (US) presenting with indicated stage of disease; †For resectable disease, patients either enter a clinical trial or undergo
observation.11
11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V.2.2013. Available from www.nccn.org
(last accessed December 18, 2012); 12. Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii91; 13. Garbe C, et al. Eur J Cancer 2010;46:270–83.
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Check Your Understanding
Clinical trials are neither indicated nor recommended by US or EU guidelines. Is this
statement true or false?
• True
• False
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Check Your Understanding
Clinical trials are neither indicated nor recommended by US or EU guidelines. Is this
statement true or false?
• True
• False
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Check Your Understanding
Now you have learned about the treatment guidelines for melanoma, can you match the
stage of the disease with the treatment strategies?
Stage
Treatment Strategy
Localized (stage I/II)
Local excision of the primary tumor with
or without adjuvant treatment, depending
on the degree of invasion of the primary
tumor
Locally advanced (stage III)
•
•
•
•
Metastatic (stage IV)
• Clinical trials
• Excision with clear margins for resectable
regional recurrence
• Lymph node dissection
• Intralesional injections (bacillus CalmetteGuerin or IFN), laser abalation, topical
imiquimod and radiation therapy
• Isolated limb perfusion with melphalan
and/or tumor necrosis factor-alpha
• Systemic therapy with Zelboraf or
ipilimumab for unresectable disease
Systemic therapy
Clinical trial
Observation
Palliative resection and/or radiotherapy or
best supportive care
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Check Your Understanding
Now you have learned about the treatment guidelines for melanoma, can you match the
stage of the disease with the treatment strategies?
Stage
Treatment Strategy
Localized (stage I/II)
Local excision of the primary tumor with
or without adjuvant treatment, depending
on the degree of invasion of the primary
tumor
Locally advanced (stage III)
• Clinical trials
• Excision with clear margins for resectable
regional recurrence
• Lymph node dissection
• Intralesional injections (bacillus CalmetteGuerin or IFN), laser abalation, topical
imiquimod and radiation therapy
• Isolated limb perfusion with melphalan
and/or tumor necrosis factor-alpha
• Systemic therapy with Zelboraf or
ipilimumab for unresectable disease
Metastatic (stage IV)
•
•
•
•
Systemic therapy
Clinical trial
Observation
Palliative resection and/or radiotherapy or
best supportive care
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Summary
• Treatment strategies for melanoma have developed over the years; the first trial of
DTIC was carried out in 1971
• Chemotherapy as monotherapy has shown limited activity in metastatic melanoma
• Prior to the development of Zelboraf and ipilimumab, single agent DTIC represented
the most common treatment option for advanced or metastatic melanoma but
provided only limited benefit
• Preferred treatment options for advanced melanoma or metastatic melanoma include
treatment with Zelboraf (in BRAFV600 mutation-positive patients), ipilimumab and
enrolment on to clinical trials
• Zelboraf and ipilimumab offer new treatment options for metastatic melanoma
• Treatment options are specific to each stage of the disease
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Treatment Options Overview
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Learning Objectives
By completing this section, you should be able to:
• Identify the major treatment strategies for melanoma
• Recall the key advantages and disadvantages and understand the rationale behind
recommended treatment options for the following disease stages:
– Localized disease (stage I/II)
– Locally advanced (stage III)
– Metastatic melanoma (unresectable stage IIIC and stage IV)
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Treatment of Localized Melanoma (Stage I/II)
Localized melanoma can be treated using strategies like wide excision surgery and adjuvant
therapy11–13
Wide excision surgery11–13
• To remove primary tumors
• Mainstay of treatment
• Recommended safety margins of 1 cm for tumors with a thickness of ≤1 mm (stage IA/IB) and 1–2 cm for
thicker tumors measuring 1.01–2.0 mm in thickness (stage IB/IIA) is recommended; for melanomas measuring
>2.0 mm, 2 cm margins are recommended
Lymph node biopsy
A lymph node biopsy determines whether the melanoma has spread to the lymph nodes. Strictly speaking,
although a lymph node biopsy does not constitute an actual treatment, it is an important staging tool and helps to
form future treatment decisions, although the impact of lymph node biopsy on OS is unclear11,12
• Should be considered for patients with stage IA (no ulceration; mitotic rate <1 mm2) that are 0.76–1.0 mm
thick11
• Should be offered to all stage IB and stage II patients11
• Should also be for offered to patients with a tumor thickness of >1 mm and/or ulceration/resectable solitary
in-transit disease (catagory 2B)11–13
• If positive, patients should be treated as stage III patients 11
• Is not recommended for primary melanomas ≤0.75 mm thick
OS = overall survival.
11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V.2.2013. Available from www.nccn.org
(last accessed December 18, 2012); 12. Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii91; 13. Garbe C, et al. Eur J Cancer 2010;46:270–83.
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Treatment of Localized Melanoma (Stage I/II)
Localized melanoma can be treated using strategies like wide excision surgery and adjuvant
therapy11–13
Adjuvant Therapy
Adjuvant therapy is offered to patients without evidence of metastases but at high risk for further tumor spread
and in published trials, has normally been confined to patients with tumors thicker than 1.5 mm (equivalent to
stages II and III using AJCC criteria)13
Adjuvant therapy is recommended in the following scenarios:
• If positive margins remain following excision of early stage melanoma, topical imiquimod may be used for
melanoma in situ or radiotherapy can be considered in selected patients 11,12
• A clinical trial or observation should be offered to node-negative early stage melanoma who are at risk for
recurrence (stage IB and II)11
• A clinical trial, observation or high-dose IFN-α should be offered for patients with node-negative stage IIB or IIC
disease11,12,13
• IFN-α should be offered to patients with high-risk of further spread13
• The appropriateness of adjuvant IFN-α therapy should be made on an individual basis and may be based on
parameters such as disease control, quality of life and financial cost 11,13
11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V.2.2013. Available from www.nccn.org
(last accessed December 18, 2012); 12. Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86-vii91; 13. Garbe C, et al. Eur J Cancer 2010;46:270–83
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IFN-α
• There are several different subtypes of IFN-α; however, IFN-α-2 is approved
in the US and the EU14,15
• IFN-α-2 is approved for the adjuvant treatment of melanoma patients who are
free from disease following surgery but are at a high risk of systemic recurrence14
– IFN may be administered as low, intermediate or high doses
– Whereas low and intermediate doses failed to show survival benefits compared with
observation-only control,16–18 HDI led to significantly improved RFS compared with
observation19
• Serious side-effects are common in patients receiving HDI, with approximately onethird of all patients requiring dose reduction or cessation of treatment18
– Common toxicities include fever, chills, myalgias, fatigue, autoimmune events and psychologic
impairment
• For low doses, toxicity was reported to be modest, with 15% of patients needing to
withdraw from the study;16 for intermediate doses, toxicity was reported as acceptable,
with 18% of patients needing to withdraw17
HDI = high-dose interferon; RFS = relapse-free survival.
14. Intron-A Product Information. Available from www.introna.com
(last accessed December 18, 2011).
15. Intron-A Summary of product characteristics, December 2011.
16. Hancock BW, et al. J Clin Oncol 2004;22:53–61.
17. Eggermont AM, et al. Lancet 2005;366:1189–96.
18. Kefford RF, Ann Oncol 2003;14:358–65.
19. Kirkwood JM, et al. Clin Cancer Res 2004;10:1670–7.
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IFN-α
• At 12.6 years follow-up, RFS was significantly prolonged with in patients with stage IIB
and III melanoma treated with HDI versus observation19
– However, only moderate improvement in OS was achieved19
OS
1.0
HDI vs. observation: P2=0.006, HR=1.30
0.8
0.6
0.4
0.2
0.0
0
2
4
6
8
10
12
14
16
Proportion alive and relapse-free
Proportion alive and relapse-free
RFS
1.0
HDI vs. observation: P2=0.42, HR=1.07
0.8
0.6
0.4
0.2
0.0
0
2
Time (years)
4
6
8
10
12
14
16
Time (years)
HDI
Observation
HR = hazard ratio.
19. Kirkwood JM, et al. Clin Cancer Res 2004;10:1670–7.
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Locally Advanced
Melanoma (Stage III)
Many different treatment options, mostly local/regional, are available to patients with stage III
disease and are based on the size, location and number of tumor deposits but there is no consensus
on the best approach, therefore enrolment on a clinical trial is recommended if available11–13
Surgery11–13
•
•
Surgical excision is recommended for patients with a single or a small number of in-transit
metastases
Isolated limb perfusion for administration of melphalan and/or tumor necrosis factor-α may be used
for patients with non-resectable in-transit metastases or inoperable tumors of the limbs without
additional metastases*
Non-surgical options11
•
*Such
Non-surgical options such as intralesional injections with bacillus Calmette-Guerin or IFN, laser
ablation, topical imiquimod and radiation therapy may be used for unresectable asymptomatic
regional recurrence
treatment requires major surgery and should therefore be restricted to centers of excellence.11,12
11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V.2.2013. Available from www.nccn.org
(last accessed December 18, 2013).
12. Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii91.
13. Garbe C, et al. Eur J Cancer 2010;46:270–83.
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Locally Advanced
Melanoma (Stage III)
Many different treatment options, mostly local/regional, are available to patients with stage III
disease and are based on the size, location and number of tumor deposits but there is no consensus
on the best approach, therefore enrolment on a clinical trial is recommended if available11–13
Lymph node dissection11–13
•
All patients with sentinel or clinically positive lymph nodes should be offered lymph-node dissection
and adjuvant treatment
Adjuvant therapy11–13
• Adjuvant therapy – consist of IFN-α, or enrollment into a clinical trial
• Radiotherapy – considered to nodal basin if stage IIIC melanoma has multiple nodes or macroscopic
extranodal
11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V.2.2013. Available from www.nccn.org
(last accessed December 18, 2013).
12. Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii91.
13. Garbe C, et al. Eur J Cancer 2010;46:270–83.
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Treatment of Metastatic Melanoma (Unresectable
Stage IIIC and Stage IV)
• The treatment options available to metastatic melanoma patients are dependent on whether the tumor is
resectable or unresectable12,13
– Stage III in-transit melanomas (stage IIIC) may be deemed unresectable because of lack of clear margins, difficulty to access by
surgical means or if the tumor widespread precluding multiple excisions11
• Recently approved systemic therapies such as Zelboraf and ipilimumab have improved PFS and OS in this patient
population and are indicated for use as systemic therapy11
Surgery11–13
• Surgery in resectable metastatic melanoma is used for limited solitary visceral metastasis
• Adjuvant therapy can be offered as part of a clinical trial
• IFN-α is not recommended for adjuvant treatment
• For patients with brain metastases, SRS and/or WBRT may be administered as an adjuvant
following resection, depending on the number and location of lesions
PFS = progression-free survival; OS = overall survival; SRS = stereotactic radiosurgery; WBRT = whole brain radiotherapy.
3. Mouawad R, et al. Crit Rev Oncol Hematol 2010;74:27–39.
6. Bhatia S, et al. Oncology 2009;23:488–96.
11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V.2.2013.
Available from www.nccn.org (last accessed December 18, 2012).
12. Dummer R, et al. Ann Oncol 2010;21(suppl 5):194–7.
21. Sznol M. Curr Oncol Rep 2009;11:397–404.
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Treatment of Metastatic Melanoma (Unresectable
Stage IIIC and Stage IV)
First-line therapy11–13
Current NCCN and ESMO guidelines recommend the following treatment strategies for initial
therapy:11,12
• Resection followed by clinical trial/observation or clinical trial/observation then repeat scans for
resectable stage IV disease
• Systemic therapy, clinical trial and/or palliative resection and/or radiotherapy or best supportive
care for unresectable disease for patients without brain metastases
• For patients with brain metastases, resection and/or SRS or WBRT may be considered as initial
treatment, depending on the number and location of lesions; treatment options thereafter are
the same as patients without brain metastases
• For patients with unresectable stage III in-transit disease of the extremities, isolated limb
perfusion with melphalan with/without tumor necrosis factor-α may also be considered
Systemic therapy options include:
• Zelboraf in BRAFV600 mutation-positive patients; ipilimumab;* chemotherapy or immunotherapy
(IL-2† or IFN‡) if new agents or clinical trial are unavailable
• Clinical trial
*Approved by the FDA for the treatment of advanced (unresectable or metastatic) melanoma7 and by the EMA for the treatment of
advanced melanoma in adults who have received prior therapy;8 †Approved for metastatic melanoma in the USA.6 IL-2 is not for patients
with poor performance status or active brain metastases;11 ‡Approved as adjuvant to surgical treatment;13 while not FDA or EMA approved
for metastatic melanoma, IFN-α-2b is one of several preferred systemic regimens for treatment of unresectable stage III and IV melanoma,11
however the NCCN melanoma panel does not recommend the use of adjuvant interferon alpha for completely resected stage IV disease.11
6. Bhatia S, et al. Oncology 2009;23:488–96; 7. Yervoy Prescribing Information, March 2011 ; 8. Yervoy Summary of Product Characteristics,
July 2011; 11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V.2.2013. Available
from www.nccn.org (last accessed December 18, 2013); 12. Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii91; 13. Garbe C, et al.
Eur J Cancer 2010;46:270–83.
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Metastatic Melanoma (Unresectable Stage IIIC and Stage IV)
• Prior to recent developments in the treatment od metastatic melanoma, many agents showed
modest response rates in metastatic melanoma patients6,11
• Response rates to DTIC monotherapy range between 5.3% and 28%20
• IL-2 induces prolonged CR in approximately 5% of a selected group of patients21
• Approved in the US and Europe, ipilimumab demonstrated a BORR of 10.9% and a median OS of
approximately 10 months in previously-treated patients22 and a BORR of 15.2%, a 24% reduction
in risk of disease progression and a median OS of approximately 11 months in treatment-naïve
patients24*
• Zelboraf is an FDA and EMA approved targeted therapy indicated for use in BRAFV600E9 and
BRAFV60010 mutation-positive patients, respectively
– In the February 2012 post-hoc survival update of the Phase 3 trial, Zelboraf demonstrated an overall
response rate of 57% and a median OS of 13.6 months compared with 10.3 months with DTIC (p<0.01) in
treatment-naïve patients23
*Ipilimumab + DTIC compared with patients receiving placebo + DTIC (median OS 9.1 months; 95% CI: 7.8–10.5)
BORR = best overall response rate; CI = confidence interval; CR = complete response.
6. Bhatia S, et al. Oncology 2009;23:488–96; 9. Zelboraf Prescribing Information, August 2011; 10. Zelboraf Summary of Product
Characteristics, March 2012; 11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma
V.2.2013. Available from www.nccn.org (last accessed December 18, 2012);
20. Lui P, et al. Cancer Treat Rev 2007;33:665–80; 21. Sznol M. Curr Oncol Rep 2009;11:397–404; 22. Hodi FS, et al. N Engl J Med
2010;363:711; 23. Chapman P, et al. Presented at the ASCO Annual Meeting 2012; Oral Presentation 8502; 24. Robert C, et al. N Engl J Med
2012;365:2517–26.
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Check Your Understanding
Case study:
A 59-year-old male presents with stage IV resectable metastatic melanoma with no brain
involvement. Based on the knowledge you have gained from the Treatment Options
Overview chapter, which of the four treatment options presented below would be best
suited for this patient?
1. Palliative radiotherapy
2. Resection, followed by clinical trial as second-line therapy
3. Best supportive care
4. Isolated limb perfusion
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Check Your Understanding
Case study:
A 59-year-old male presents with stage IV resectable metastatic melanoma with no brain
involvement. Based on the knowledge you have gained from the Treatment Options
Overview chapter, which of the four treatment options presented below would be best
suited for this patient?
1. Palliative radiotherapy
2. Resection, followed by clinical trial as second-line therapy
3. Best supportive care
4. Isolated limb perfusion
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Check Your Understanding
Now you have reviewed the treatment options for stage IV metastatic melanoma, can you
match the treatment with the intervention stage?
Stage
Treatment
Initial treatment intervention
for resectable disease
Resection and/or SRS or WBRT
Initial treatment intervention
for unresectable
(disseminated) disease (no
brain metastases)
Systemic therapy (Zelboraf if
BRAFV600 mutation positive,
ipilimumab, immunotherapy
or chemotherapy), clinical
trial, palliative resection
and/or radiotherapy or best
supportive care
Initial treatment for brain
metastases
Surgery
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Check Your Understanding
Now you have reviewed the treatment options for stage IV metastatic melanoma, can you
match the treatment with the intervention stage?
Stage
Treatment
Initial treatment intervention
for resectable disease
Surgery
Initial treatment intervention
for unresectable
(disseminated) disease (no
brain metastases)
Systemic therapy (Zelboraf if
BRAFV600 mutation positive,
ipilimumab, immunotherapy
or chemotherapy), clinical
trial, palliative resection
and/or radiotherapy or best
supportive care
Initial treatment for brain
metastases
Resection and/or SRS or WBRT
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Summary
• Stage I/II melanoma:
– Wide excision surgery
– Lymph node biopsy (for high risk patients)
– Adjuvant therapy: clinical trial, observation or IFN-α should be offered to node-negative
stage IIB/C patients
• Stage III melanoma:
–
–
–
–
Surgery
Lymph node dissection (if biopsy positive)
Adjuvant therapy: IFN-α, clinical trial or observation
Radiotherapy for stage IIIC patients in the presence of multiple node involvement
• Unresectable stage IIIC and stage IV:
– For resectable stage IV disease: Clinical trial or observation following resection
– For unresectable disease (no brain metastases): Systemic therapy, clinical trial, resection
and/or radiotherapy or best supportive care
– For unresectable disease (with brain metastases): Resection and/or SRS or WBRT as first line;
second-line options are the same as for patients without brain metastases
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Chemotherapy for Metastatic Melanoma
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Learning objectives
By completing this section, you should be able to:
• Recall approval status, key efficacy and safety data for the following chemotherapy
classes:
– Alkylating agents
– Platinum agents
– Antimitotic agents
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Chemotherapy
• Cytotoxic chemotherapy has been used for the treatment of metastatic melanoma
for over 3 decades6
• Cytotoxic agents with modest antitumor efficacy in metastatic melanoma include:6
–
–
–
–
Alkylating agents (e.g. DTIC, TMZ)
Nitrosoureas (e.g. carmustine, lomustine, fotemustine)
Platinum analogs (e.g. cisplatin, carboplatin)
Antimitotic toxins (e.g. vindesine, vinblastine, paclitaxel)
• These agents have been used alone or in combination
– DTIC; FDA and EMA approved as monotherapy6,25
– TMZ; off-label used as monotherapy or in combination in metastatic melanoma26
– Fotemustine; not FDA approved in metastatic melanoma but available in Europe6
6. Bhatia S, et al. Oncology 2009;23:488–96.
25. European Medicines Agency. Available from www.ema.europa.eu (last accessed December 18, 2012).
26. Temodar [package insert]. Whitehouse Station, NJ: Merck + Co, Inc; 2011.
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Monotherapy for the Treatment
of Metastatic Melanoma
• Monotherapy is relatively ineffective in treatment of melanoma27
Chemotherapies
DTIC*†
TMZ
Fotemustine
Response Rate
5.3–28%20
13.5–24%28,29
15.5–24.2%30,31
Paclitaxel
3.6%32
Vindesine
12–26%33,34
*Approved for metastatic melanoma in Europe.25
†Approved for metastatic melanoma in the US.6
6. Bhatia S, et al. Oncology 2009;23:488–96.
20. Lui P, et al. Cancer Treat Rev 2007;33:665–80.
25. European Medicines Agency. Available from www.ema.europa.eu
(last accessed December 18, 2012).
28. Middleton MR, et al. J Clin Oncol 2000;18:158–66.
29. Bleehen NM, et al. J Clin Oncol 1995;13:910–3.
30. Jacquillat C, et al. Cancer 1990;66:1873–8.
31. Avril MF, et al. J Clin Oncol 2004;22:1118–25.
32. Mornex F, et al. Melanoma Res 2003;13:97–103.
33. Nelimark RA, et al. Am J Clin Oncol 1983;6:561–4.
34. Carmichael J, et al. Eur J Cancer Clin Oncol 1982;18:1293–5.
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Alkylating Agents: DTIC
• DTIC is one of the alkylating agents included in cytotoxic agents with modest antitumour efficacy
•
Approval status
Activity
Safety
•
DTIC has been approved by the FDA and EMA for the treatment of
metastatic melanoma
Although DTIC is not the systemic regimen preferred by the NCCN for
the treatment of metastatic melanoma,11 it is often used in cases
where approved targeted compounds or appropriate clinical trials are
unavailable11,12
• Median OS: 5.6–11 months6
• Median PFS: 2.1 months6
• Response rates: ORR 6–15.3%; CR 0–4.1%; PR 5–11.2%6,23,31,35,36
• Common adverse events include myelosuppression, nausea, vomiting,
and fatigue6,37
ORR = objective response rate; PR = partial response.
6. Bhatia S, et al. Oncology 2009;23:488–96; 11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™.
Melanoma V.2.2013. Available from www.nccn.org (last accessed December 18, 2012);
12. Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii91; 23. Chapman P, et al. Presented at the ASCO Annual Meeting 2012;
Oral Presentation 8502; 31. Avril MF, et al. J Clin Oncol 2004;22:1118–25; 35. Hauschild A, et al. Lancet 2012;380:358–65; 36. Flaherty KT, et al.
N Engl J Med 2012;367:107–14.
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Alkylating Agents: TMZ
• TMZ, an oral analog of DTIC, was approved by the FDA in 1999 for adult patients with newly
diagnosed glioblastoma multiforme26
– Although not indicated for use in melanoma, a randomized Phase 3 trial in patients with histologically
confirmed, surgically incurable or unresectable advanced metastatic melanoma, showed OS was equivalent
to DTIC, and PFS was longer for TMZ compared with DTIC28
PFS
100
90
80
70
60
50
40
30
20
10
0
HR=0.92, 95% Cl (0.80–1.06)
Median (months) = 2.30 (TMZ) vs. 2.17 (DTIC)
p=0.27
0
3
6
9
12
15
18
21
OS
100
90
80
70
60
50
40
30
20
10
0
24
HR=1.00, 95% Cl (0.86–1.17)
Median (months) = 9.13 (TMZ) vs. 9.36 (DTIC)
p=1.0
0
6
12
Months
Events Patients
18
24
30
36
Months
Number of patients at risk
Treatment
Deaths Patients
Number of patients at risk
Treatment
398
430
148
93
50
27
17
11
8
DTIC
325
430
289
125
44
20
5
DTIC
401
429
187
109
47
25
17
11
9
TMZ
320
429
300
115
49
19
2
TMZ
DTIC
TMZ
26. Temodar [package insert]. Whitehouse Station, NJ: Merck + Co, Inc; 2011.
28. Middleton MR, et al. J Clin Oncol 2000;18:158–66.
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Nitrosourea Agents
• Nitrosoureas such as carmustine, lomustine, and fotemustine have single-agent activity
comparable with DTIC but they cause more alopecia and myelosuppression compared
with other classes of chemotherapies6
Off-label use
Activity
Safety
• Used off-label in the US and the EU for the treatment of cerebral
metastasis of malignant melanoma6,31
• Prolonged OS advantage compared with DTIC, although this was not
significant (7.3 vs. 5.6 months; p=0.067)31
• Grade 3/4 thrombocytopenia 40–43%26,27
• Leukopenia 46% and neutropenia 51%30,31
• Hematologic toxicity levels increased during induction treatment31
6. Bhatia S, et al. Oncology 2009;23:488–96.
26. Temodar [package insert]. Whitehouse Station, NJ: Merck + Co, Inc; 2011.
27. Jilaveanu LB, et al. Clin Dermatol 2009;27:614–25.
30. Jacquillat C, et al. Cancer 1990;66:1873–8.
31. Avril MF, et al. J Clin Oncol 2004;22:1118–25.
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Platinum Agents
• Single-agent platinum-based therapy shows modest activity in patients with
metastatic melanoma6
– Mostly prescribed as combination regimens6,11
Approval status
Activity
Safety
Cisplatin
Carboplatin
Not approved for use in melanoma
• Single-agent cisplatin yields a
response rate of <10%6
• In combination with amifostine
the response rate was 53% but
this was not durable6
Ototoxicity, neurotoxicity,
nephrotoxicity38
• In chemotherapy-naïve patients
with metastatic melanoma
single agent carboplatin led to a
response rate of 19%6
Thrombocytopenia
and leukopenia39
6. Bhatia S, et al. Oncology 2009;23:488–96.
11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V.2.2013.
Available from www.nccn.org (last accessed December 18, 2012).
38. Paraplatin [package insert]. Princeton, NJ: Bristol-Myers Squibb Co; 2007.
39. Platinol-AQ [package insert]. Princeton, NJ: Bristol-Myers Squibb Co; 1999.
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Antimitotic Agents
• Antimitotic agents have modest activity in patients with metastatic melanoma
and are not FDA or EMA approved6
– Vinca alkaloids (inhibitors of microtubular assembly): vindesine and vinblastine
– Taxanes (inhibitors of microtubule disassembly): paclitaxel
Paclitaxel
Approval status
• Not approved by the FDA or EMA for use in melanoma
• However, the NCCN considers it as an active regimen for systemic therapy
of advanced metastatic melanoma if an appropriate targeted therapy of
clinical trial is unavailable
Activity
• In a Phase 2 study, it led to a median OS of 7.8 months in stage IV
metastatic melanoma32
Safety
• Paclitaxel is associated with fatigue, alopecia, myelosuppression,
neuropathy, myalgias and hypersensitivity reactions6
6. Bhatia S, et al. Oncology 2009;23:488–96.
32. O’Day S, et al. J Clin Oncol 2009;27:5452–58.
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Check Your Understanding
Complete the following sentence:
DTIC is ________.
•
•
•
•
Not approved in the US or EU
Proven to produce high OS and PFS rates
An alkylating agent
Administered orally
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Check Your Understanding
Complete the following sentence:
DTIC is ________.
•
•
•
•
Not approved in the US or EU
Proven to produce high OS and PFS rates
An alkylating agent
Administered orally
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Check Your Understanding
Regarding cytotoxic agents, which of these statements is false?
• DTIC monotherapy is associated with the most durable OS rates out of all
chemotherapy agents indicated for use in metastatic melanoma
• The nitrosurea class of agents such as fotemustine are associated with high rates of
alopecia and myelosuppression
• Fotemustine is used off-label in the US and in Europe for treatment of cerebral
metastases
• Common toxicities associated with DTIC include nausea, vomiting , fatigue and
myelosuppression
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Check Your Understanding
Regarding cytotoxic agents, which of these statements is false?
• DTIC monotherapy is associated with the most durable OS rates out of all
chemotherapy agents indicated for use in metastatic melanoma
• The nitrosurea class of agents such as fotemustine are associated with high rates of
alopecia and myelosuppression
• Fotemustine is used off-label in the US and in Europe for treatment of cerebral
metastases
• Common toxicities associated with DTIC include nausea, vomiting , fatigue and
myelosuppression
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Summary
• Chemotherapeutic agents have been used in the treatment of metastatic melanoma for
over 30 years
• Chemotherapy as monotherapy is relatively ineffective, with response rates in the
range of 5–28%
• Chemotherapeutic agents are associated with high toxicity; myelosuppression,
alopecia, myalgia, neurotoxicity, nausea, vomiting and fatigue are common side effects
• DTIC is an alkylating agent approved in Europe and the US and was previously
considered as the standard of care in first-line management of metastatic melanoma
• Other alkylating agents include the nitrosurea class of compounds (carmustine,
lomustin and fotemustine) which are associated with higher rates of alopecia and
myelosuppression compared with other classes of chemotherapy
• Platinum-based agents such as cisplatin and carboplatin are not approved for
metastatic melanoma; they show modest activity and are usually prescribed in
combination with other agents
• Anti-mitotic agents such as taxanes and alkaloids are not approved for use in metastatic
melanoma and show modest benefits when used in combination; they are similarly
associated with significant side effects
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Immunotherapy for Metastatic Melanoma
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Learning Objectives
By completing this section, you should be able to:
• Understand the rationale behind modulating the immune system for the treatment of
melanoma
• Recall the different modes of immunotherapy
• Recall approval status, key efficacy and safety data for the following immunotherapies:
– High-dose IL-2
– High-dose IFN-α-2b
– Ipilimumab
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Proof of Concept for Immunotherapy
in Metastatic Melanoma
• Attempting to modulate the immune response has been a popular strategy
in melanoma
– Strategies previously used in immune modulation trials include the use of cytokines (IFN-α, IL-2), vaccines
(gp100), antibodies (ipilimumab, tremelimumab) and adoptive immunotherapy21
• Key advances suggested potential to manipulate and disrupt immune activation checkpoints and
tumor defense mechanisms:21
–
–
–
–
Immune activation by antigen presentation (e.g. vaccines)
New antigen-specific T-cell expansions in vitro and in vivo
Gene transfer to alter lymphocyte specificity and function
Discovery of new predictive biomarkers
• There are currently a number of immunotherapies in the pipeline for melanoma, some of which
are in late-phase development21,40,41
• The use of immunotherapy has been associated with only modest response rates, with high-dose
cytokine therapies leading to prolonged responses in a minority of patients21
• While the response rate with ipilimumab was limited, median OS was significantly improved when
used as monotherapy and in combination with the peptide vaccine gp100 compared with gp100
alone22
– A recent evaluation of Phase 2 ipilimumab trials in patients with metastatic melanoma demonstrates 5-year
survival in up to 18% of pretreated patients42
21. Sznol M. Curr Oncol Rep 2009;11:397–404; 22. Hodi SF, et al. N Engl J Med 2010;363:711–23;
40. Schadendorf D, et al. Ann Oncol 2012;23(suppl):x104–x108; 41. Sapoznik S, et al. Clin Dev Immunol 2012; [Epub ahead of print]
doi:10.1155/2012/818214; 42. Lebbe C, et al. Presented at ESMO 2012; Poster Presentation 1116PD.
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Immunotherapy as Monotherapy for the Treatment
of Metastatic Melanoma
Immunotherapies
Response Rate
Interferon-α-2b*
13–25%43,44
Interleukin-2
16–22%45,46
Ipilimumab†
10.9% (median OS: ≈10 months)22‡
*Not FDA or EMA approved in metastatic melanoma.
†Approved by the FDA for the treatment of advanced (unresectable or metastatic) melanoma 7 and by the EMA for the treatment of
advanced melanoma in adults who have received prior therapy.8
‡Previously treated patients.
7. Yervoy Prescribing Information, March 2011.
8. Yervoy Summary of Product Characteristics, July 2011.
22. Hodi SF, et al. N Engl J Med 2010;363:711–23.
43. Miller RL, et al. Cancer Res 1989;49:1871–6.
44. Robison WA, et al. Immunobiology 1986;172:275–82.
45. Legha SS, et al. Cancer 1996;77:89–96.
46. Atkins MB, et al. Clin Oncol 1999;17:2105–16.
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High-dose IL-2
• Until the recent approval of ipilimumab in 2011, high-dose IL-2 was the only approved immunotherapy for use in
patients with metastatic melanoma*6,8,46,47
• IL-2 can induce prolonged CR in a small proportion of patients45–47
Probability of continuing response
– Median OS: 12 months; median PFS: 13.1 months; median duration of response: 8.9 months (responders only, n=43)
High-dose IL-2 therapy
(Adapted from Atkins MB, et al)46
1.0
0.8
0.6
0.4
0.2
0.0
0
10
20
30
40
50
60
70
80 90 100 110 120 130
Duration of response (months)
CR; n=17
PR; n=26
CR + PR; n=43
• High-dose IL-2 is associated with cardiovascular, gastrointestinal, neurological, pulmonary, hepatic, renal, and
hematological side effects46
*Approved for metastatic melanoma in the US.48
6. Bhatia S, et al. Oncology 2009;23:488–96; 8. Yervoy Summary of Product Characteristics, July2011;
45. Legha S, et al. Cancer 1996;77:89–96; 46. Atkins MB, et al. J Clin Oncol 1999;17:2105–16;
47. Atkins MB, et al. Cancer J Sci Am 2000;(Suppl 1):S11–4; 48. Proleukin [package insert]. East Hanover, NJ: Novartis; 2008.
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High-dose IFN-α-2b
High-dose IFN-α-2b is approved in the adjuvant setting
FDA approved
Activity
Safety
• FDA and EMA approved as adjuvant therapy for adult melanoma patients
who are disease-free but at high risk for systemic recurrence14,15
• Modest activity in the metastatic setting6
• ORR 22%, CR <4%
• Responses limited to patients with low-volume disease concentrated in
cutaneous and soft-tissue sites
• Limited value in treating patients with stage IV disease due to cumulative
toxicities6
• Common toxicities include fever, chills, myalgias, fatigue and
neuropsychiatric toxicities6
6. Bhatia S, et al. Oncology 2009;23:488–96.
14. Intron-A Product Information. Available from www.introna.com (last accessed December 18, 2012).
15. Intron-A Summary of product characteristics, December 2011.
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Ipilimumab Phase 3: Trial Design and Results
• In 2011, the FDA and EMA approved ipilimumab for use in metastatic melanoma:
– Ipilimumab (an anti-CTLA-4 antibody) is approved by the FDA for the treatment of advanced
(unresectable or metastatic) melanoma7 and by the EMA for the treatment of advanced
melanoma in adults who have received prior therapy8
• Ipilimumab, an intravenous fully humanized IgG1, monoclonal antibody, activates the
immune response against cancer cells49
– It acts by inhibiting the activity of CTLA-4
• Numerous Phase 2/3 studies have been completed in metastatic melanoma either as
monotherapy or in combination regimens50
• Ipilimumab is associated with potentially serious side effects22
– Largely immune related (60% in ipilimumab treated vs. 32% in gp-100 treated), occurring
mainly in the skin and gastrointestinal tract
– Diarrhea is the most common immune-related adverse effect
– Grade 3/4 side effects observed in 17.4–22.9% of patients
CTLA-4 = cytotoxic T-lymphocyte antigen-4; IgG1 = immunoglobulin G1.
7. Yervoy Prescribing Information, July 2011
8. Yervoy Summary of Product Characteristics, July 2011.
22. Hodi SF, et al. N Engl J Med 2010;363:711–23.
49. Weber JS, et al. J Clin Oncol 2008;26(36);5950–6.
50. Ipilimumab in metastatic melanoma. Available from www.clinicaltrials.gov (last accessed December 18, 2012)
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Ipilimumab Phase 3 Pivotal Clinical Trials:
Trial Design and Results
Ipilimumab showed long-term survival benefit in both previously-treated and in treatment naïve
patients with metastatic melanoma22,24
Randomized 3:1:1 and stratified by metastatic
stage and previous IL-2 treatment
Ipilimumab 3 mg/kg q3w for four doses
+ gp100 1 mg q3w for four doses
(n=403)
Patients with previously
treated metastatic melanoma
(n=676)
Ipilimumab 3 mg/kg q3w for four doses
+ placebo
(n = 137)
Re-induction with same
regimen in eligible patients
gp100 1 mg q3w for four doses
+ placebo
(n = 136)
• In previously-treated patients:
– Median OS was approximately 10 months with ipilimumab + vaccine and ipilimumab alone versus 6.4 months with vaccine
alone
– Risk of death was reduced by 32% and 34% with ipilimumab + vaccine versus vaccine alone, and ipilimumab alone versus
vaccine alone, respectively
– Survival rates for ipilimumab alone were 45.6% and 23.5% at 1-year and 2-year time points, respectively
– Ipilimumab + placebo was associated with a 10.9% BORR
q3w = every 3 weeks.
22. Hodi SF, et al. N Engl J Med 2010;363:711–23.
24. Robert C, et al. N Engl Med 2012;365:2517–26.
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Ipilimumab Phase 3 Pivotal Clinical Trials:
Trial Design and Results
Ipilimumab showed long-term survival benefit in both previously-treated and in treatment naïve
patients with metastatic melanoma22,24
Induction therapy
Phase 3
Patients with
treatment-naïve
unresectable
stage III/IV
melanoma (N=502)
Week 24
Maintenance therapy
Ipilimumab 10 mg/kg q3w for
four doses + DTIC 850 mg/m2 q3w for
eight doses (n=250)
Patients with SD or an
objective response and no
dose-limiting adverse events:
Ipilimumab 10 mg/kg q12w
Placebo q3w for four doses + DTIC
850 mg/m2 q3w for eight doses
(n=252)
Placebo q12w
• In treatment-naïve patients:24
– Ipilimumab in combination with DTIC led to a higher median OS (11.2 months) compared with DTIC alone (9.1 months)
– Risk of death was reduced by 28%
– Combination led to a 24% reduction in risk of progression
SD = stable disease; q12w = every 12 weeks.
22. Hodi SF, et al. N Engl J Med 2010;363:711–23.
24. Robert C, et al. N Engl Med 2012;365:2517–26.
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Treatment Combinations for Metastatic Melanoma
• Combination regimens are also relatively ineffective and poorly tolerated3
Select Therapy Combinations
Stage IV Median OS
DTIC + IFN-α + TAMOXIFEN
9.5 months51
TMZ + IFN-α
9.7 months52
DTIC + IFN-α
11–13 months53
Vindesine + IFN-α
33 months54
Carmustine + hydroxyurea + DTIC
4–16 months55
Bleomycin + vincristine + lomustine + DTIC (BOLD)
6–8 months56,57
Cisplatin + vindesine + DTIC (CVD)
9–12 months6
DTIC + carmustine + cisplatin + tamoxifen (Dartmouth)
6.9–7.7 months58,59
Carboplatin + paclitaxel
7.8 months60
3. Mouawad R, et al. Crit Rev Oncol Hematol 2010;74:27–39.
6. Bhatia S, et al. Oncology 2009;23:488–96.
51. Falkson CI, et al. J Clin Oncol 1998;16:1743–51.
52. Kaufmann R, et al. J Clin Oncol 2005;23:9001–7.
53. Bajetta E, et al. J Clin Oncol 1994;12:806–11.
54. Smith KA, et al. Eur J Cancer 1992;28:438–41.
55. Carter RD, et al. Cancer Treat Rep 1976;60:601–9.
56. Seigler HF, et al. Cancer 1980;46:2346–8.
57. York RM, et al. Cancer 1988;61:2183–6.6.
58. Chapman PB, et al. J Clin Oncol 1999;17:2745–51.
59. Creagan ET, et al. J Clin Oncol 1999;17:1884–90.
60. Rao RD, et al. Cancer 2006;106:375–82.
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Check Your Understanding
Which of the following statements is false?
• Phase 3 trials of ipilimumab showed that median OS was approximately 10 months
with ipilimumab alone
• Ipilimumab is generally considered to be easily managed, with less than 5% of patients
reporting grade 3/4 adverse events
• High dose IFN-α-2b has limited utility in treating stage IV patients due to cumulative
toxicities
• In a small subset of patients, IL-2 may induce a durable CR
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Check Your Understanding
Which of the following statements is false?
• Phase 3 trials of ipilimumab showed that median OS was approximately 10 months
with ipilimumab alone
• Ipilimumab is generally considered to be easily managed, with less than 5% of patients
reporting grade 3/4 adverse events
• High dose IFN-α-2b has limited utility in treating stage IV patients due to cumulative
toxicities
• In a small subset of patients, IL-2 may induce a durable CR
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Summary
• The immunogenicity of melanoma has made immunomodulation a popular strategy;
historically, immunotherapy has been associated with limited efficacy and high toxicity
• High-dose IL-2 can induce durable response in a small proportion of patients
• High-dose IFN-α-2b is approved for treatment of melanoma in the adjuvant setting but
has limited utility in metastatic melanoma due to cumulative toxicities
• Ipilimumab has shown survival benefit in pre-treated and treatment-naïve metastatic
melanoma patients, with a median OS of approximately 10 months
• Ipilimumab is associated with potentially serious immune-related adverse events
however these are generally considered to be manageable
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Targeted Therapies
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Learning Objectives
By completing this section, you should be able to:
• Understand how targeted therapies have changed the current treatment paradigm by
making use of our understanding of the molecular basis of the disease
• Recall key efficacy and safety results from the BRIM2 and BRIM3 trials
• Discuss the emerging targets for potential therapeutic treatments of melanoma
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Paradigm Shift in Melanoma Treatment
The discovery that the BRAF gene is mutated in many cancers led to substantial efforts to design molecules that
specifically target mutant forms of the BRAF protein. The majority of mutations result in an amino acid
substitution at position 600 in the protein and substantially increase BRAF kinase activity, leading to enhanced
cancer cell growth.61 Zelboraf is the first targeted therapy to be approved for the treatment of BRAFV600 mutationpositive metastatic melanoma and the first therapy to provide a survival benefit of more than 1 year in BRAFV600
mutation-positive metastatic melanoma patients10,23
Zelboraf key efficacy data from the Phase 3 BRIM3 trial:23*
• Median follow-up was 12.5 months with Zelboraf
• Median OS was 13.6 months for Zelboraf compared with
9.7 months for DTIC
• Median PFS was 6.9 months compared with 1.6 months
with DTIC
• ORR of 57% with Zelboraf compared with 8.6% with DTIC
Zelboraf showed a consistent safety profile and adverse drug reactions caused by Zelboraf were generally
manageable.23 Further targeted therapies are currently being investigated, including dabrafenib and trametinib for
patients with BRAFV600 mutations and nilotinib for patients with c-KIT mutations.35,36,62,63
*February 2012 post-hoc survival update.
10. Zelboraf Summary of Product Characteristics, March 2012; 23. Chapman P, et al. Presented at the ASCO Annual Meeting 2012; Oral
Presentation 8502; 35. Hauschild A, et al. Lancet 2012;380:358–65 ; 36. Flaherty KT, et al. N Engl J Med 2012;367:107–14;
61. Flaherty KT, et al. Cancer 2010;116:4902–13; 62. A Study of AMNN107 Against DTIC. NCT01028222. Available from www.clinicaltrials.gov
(last accessed December 18, 2012); 63. Falchook GS, et al. Lancet 2012;379:1893–1901.
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Zelboraf (vemurafenib)
Zelboraf is an orally available agent, approved in the US for patients with unresectable or
metastatic melanoma with the BRAFV600E mutation, as detected by an FDA-approved test9
and in the EU for the treatment of adult patients with BRAFV600 mutation-positive
unresectable or metastatic melanoma10
Trial results
• Clinical trial results showed that patients with BRAFV600 mutation-positive metastatic melanoma
experienced considerable tumor regression23,64
– Results from the Phase 2 BRIM-2 trial in previously treated patients showed:64
• Best confirmed ORR assessed by IRC was 53% with median duration of response of 6.7 months
• Median PFS was 6.8 months
• Median OS was 15.9 months
– Results from the Phase 3 BRIM3 trial in treatment-naïve patients showed:*23
• Median OS was 13.6 months for Zelboraf compared with 9.7 months for DTIC†
• Median PFS was 6.9 months for Zelboraf compared with 1.6 months for DTIC†
• 57% of patients experienced PR or CR with Zelboraf compared with 8.6% with DTIC
*February 2012 post-hoc survival update.
IRC = independent review committee.
9. Zelboraf Prescribing Information, August 2011; 10. Zelboraf Summary of Product Characteristics, March 2012; 23. Chapman P, et al.
Presented at the ASCO Annual Meeting 2012; Oral Presentation 8502; 64. Sosman J, et al. N Engl J Med 2012;366:707–14.
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Zelboraf (vemurafenib)
Zelboraf is an orally available agent, approved in the US for patients with unresectable or metastatic
melanoma with the BRAFV600E mutation, as detected by an FDA-approved test9 and in the EU for the
treatment of adult patients with BRAFV600 mutation-positive unresectable or metastatic melanoma10
Side effects
• The most common adverse drug reactions (>30%) reported with Zelboraf include arthralgia,
fatigue, rash, photosensitivity reaction, nausea, alopecia and pruritis10
• cuSCC was very commonly reported (19%) and was most commonly treated by local excision with
no dose modification necessary23*
• With Zelboraf, ADRs can generally be managed through dose modification23
*February 2012 post-hoc survival update.
cuSCC = cutaneous squamous cell carcinoma.
9. Zelboraf Prescribing Information, August 2011.
10. Zelboraf Summary of Product Characteristics, March 2012.
23. Chapman P, et al. Presented at the ASCO Annual Meeting 2012; Oral Presentation 8502.
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Novel Therapies
Molecule Name
Mechanism of Action
Cytotoxic agents
Albumin-bound paclitaxel65
Microtubule inhibitor6
DHA-paclitaxel66
Microtubule inhibitor6
Immunotherapy agents
Mage-A3 ASCI (astuprotimut-r)67
MAGE-A3 vaccine68
OncoVEX GM-CSF69
Oncolytic HSV-170
BMS-93655870
Anti-PD-1 antibody70
Velimugene aliplasmid71
HLA-B772
Targeted agents
Nilotinib62,74
Bcr-Abl/c-KIT/PDGFR inhibitor62,74
Oblimersen75
Bcl-2 antisense75
Dabrafenib35,63
BRAF inhibitor35,63
Tramtenib36
MEK inhibitor36
6. Bhatia S, et al. Oncology 2009;23:488–96; 65. ABI-007 versus DTIC. Available from www.clinicaltrials.gov (last accessed December 2012); 35. Hauschild A, et al.
Lancet 2012;380:358–65; 36. Flaherty KT, et al. N Engl J Med 2012;367:107–14; 63. Falchook GS, et al. Lancet 2012;379:1893–901; 66. DHA-paclitaxel versus DTIC.
Available from www.clinicaltrials.gov (last accessed December 2012); 67. MAGE-A3 Phase III clinical trial. Available from www.clinicaltrials.gov (last accessed December 18,
2012); 68. MAGE-A3 in NSCLC. Available from www.drugs.com (last accessed December 18, 2012); 69. OncoVEXGM-CSF efficacy and safety study. Available from
www.clinicaltrials.gov (last accessed December 2012). 70. OncoVEX Phase II results. Available from www.drugs.com (last accessed December 2012); 71. Allovectin-7 versus
chemotherapy. Available from www.clinicaltrials.gov (last accessed December 18, 2012); 72. Allovectin-7 Phase III press release. Available from www.drugs.com;
73. Tropalin SL, et al. N Engl J Med 2012;366:2443–54; 74. Tasigna prescribing information. Available from www.drugs.com (last accessed December 18, 2012);
75. Genasense Phase III update. Available from www.drugs.com (last accessed December 18, 2012).
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The Emerging Future of Targeted Therapy for Melanoma76
Emerging targeted therapies aim to inhibit mutated proteins that up-regulate signaling
pathways known to promote uncontrolled melanocyte growth and survival
CRAF
MEK
GSK 1120212
GDC-0973
AZD-6244
BMS-387032
CDK2
p16
PI3K
BRAF
PTEN
AKT
GSK 2118436
RAF-265
XL281
CDK4
GDC-0941
XL147
NRAS
PD032991
CYC202
mTOR
VQD002
MK2206
GSK 690693
CyclinD
Temsirolimus
Everolimus
AP23573
OSI-027
CDK = cyclin-dependent kinase; mTOR = mammalian target of rapamycin; PTEN = phosphotase and tensin hemolog.
76. Sosman J, et al. Oral presentation at Melanoma 2010, Sydney, Australia. www.melanoma2010.com.
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Check Your Understanding
Which of the following is not a targeted therapy?
•
•
•
•
Vemurafenib
Ipilimumab
Dabrafenib (GSK2118436)
Tasigna (nilotinib)
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Check Your Understanding
Which of the following is not a targeted therapy?
•
•
•
•
Vemurafenib
Ipilimumab
Dabrafenib (GSK2118436)
Tasigna (nilotinib)
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Check Your Understanding
Now you have reviewed top-line trial results for Zelboraf, can you match the data points
with the correct data parameters for the February 2012 BRIM3 post-hoc survival update?
Parameter
Data
Median OS for Zelboraf
6.9 months
Median PFS for Zelboraf
13.6 months
Response rate (PR or CR)
19%
Grade 3 cuSCC incidence
57%
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Check Your Understanding
Now you have reviewed top-line trial results for Zelboraf, can you match the data points
with the correct data parameters for the February 2012 BRIM3 post-hoc survival update?
Parameter
Data
Median OS for Zelboraf
13.6 months
Median PFS for Zelboraf
6.9 months
Response rate (PR or CR)
57%
Grade 3 cuSCC incidence
19%
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