1. Chapter 2: Therapeutic Options in Metastatic Melanoma
Core Educational Resource

2. Content Melanoma Treatment Overview Treatment Options Overview
Chemotherapy for Metastatic Melanoma
Immunotherapy for Metastatic Melanoma
Targeted Therapies

3. Melanoma Treatment Overview

4. 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

5. Key Therapeutic Milestones in Melanoma
1804
1971
1975
1980s–1990s
1995
1998
2010–2012
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
Zelboraf received FDA approval for the treatment of BRAFV600E mutation-positive advanced (unresectable or metastatic) melanoma in and EMA approval for BRAFV600 mutation-positive advanced melanoma in
French physician René Laennec described melanoma as a disease1
DTIC received US FDA approval for metastatic melanoma3
2011: Ipilimumab received approval from the FDA for the treatment of unresectable or metastatic melanoma7 and from the EMA for the treatment of advanced melanoma in adults who have received prior therapy8
First trial of DTIC, an inhibitor of DNA (alkylating agent)2
Due to the limited performance of single-agent chemotherapy, several clinical trials evaluating multi-drug combinations were initiated, comparing regimens such as cisplatin/vinblastine/DTIC, carmustine/cisplatin/DTIC or carboplatin/DTIC compared with DTIC.3
High dose IL-2 received FDA approval for metastatic melanoma6
DTIC = dacarbazine; EMA = European Medicines Agency; FDA = US Food and Drug Administration; IFN = interferon; IL-2 = interleukin-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
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.

6. 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 Available from (last accessed November 1, 2012).

7. 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
In situ tumor
No regional lymph node metastases
No distant metastases
Stage 011
Stage IA
≤1.0 mm thick; no ulceration; mitosis <1/mm2
Stage I11
Stage IIA
1.01–2.0 mm thick; with ulceration or
2.01–4.0 mm thick; no ulceration
Stage II11
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
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 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V Available from (last accessed December 18, 2012) Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii Garbe C, et al. Eur J Cancer 2010;46:270–83.

8. 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 III11
Any tumor thickness
Any regional lymph node metastases
Distant metastases
Stage IV11
Stage IIIA
Any tumor thickness; no ulceration
Micrometastases* of 1–3 regional lymph nodes
No distant metastases
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
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
*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 Available from (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.

9. 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
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
Localized (stage I/II)11–13
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:
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
Locally advanced (stage III)11–13
ESMO = European Society for Medical Oncology National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V Available from (last accessed December 18, 2012) Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii Garbe C, et al. Eur J Cancer 2010;46:270–83.

10. 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
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
Metastatic (Stage IV)11–13
TMZ = temozolomide National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V Available from (last accessed December 18, 2012) Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii Garbe C, et al. Eur J Cancer 2010;46:270–83.

11. Current Treatment Overview
Based on the guidelines for melanoma treatment at each stage, the steps for treatment are defined.
Stage
Initial Treatment Intervention
Adjuvant Therapy
Treatment of Recurrence
Localized11–13 (stage I/II) 82–85% at presentation*
Wide excision (with/without sentinel node biopsy)
Clinical trial or observation (stage IB/IIA/IIB/IIC)
IFN-α† (stage IIB/IIC)
Surgery or lymphadenect omy or radiotherapy or clinical trial
Locally advanced11–13 (stage III) 10–13% at presentation*
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 )
Sentinel node positive: Adjuvant clinical trial, observation or IFN-α
Clinically positive: Adjuvant clinical trial, observation, IFN-α or radiotherapy to nodal basin
In transit: Adjuvant clinical trial, observation or IFN-α
Surgery or lymphadenectomy or radiotherapy or clinical trial
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 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V Available from (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.

12. Current Treatment Overview
Based on the guidelines for melanoma treatment at each stage, the steps for treatment are defined.
Stage
Initial Treatment Intervention
Adjuvant Therapy
Treatment of Recurrence
Metastatic11–13 (stage IV) 2–5% at presentation*
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 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V Available from (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.

13. Check Your Understanding
Clinical trials are neither indicated nor recommended by US or EU guidelines. Is this statement true or false?
True
False

14. Check Your Understanding
Clinical trials are neither indicated nor recommended by US or EU guidelines. Is this statement true or false?
True
False

15. 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)
Systemic therapy
Clinical trial
Observation
Palliative resection and/or radiotherapy or best supportive care
Metastatic (stage IV)
Clinical trials
Excision with clear margins for resectable regional recurrence
Lymph node dissection
Intralesional injections (bacillus Calmette-Guerin 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

16. 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 Calmette-Guerin 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

17. 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

18. Treatment Options Overview

19. 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)

20. 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 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V Available from (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.

21. 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 Available from (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

22. 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 one- third 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 (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.

23. Proportion alive and relapse-free
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 2 4 6 8 10 12 14 16
0.0
0.2
0.4
0.6
0.8
1.0
Time (years)
Proportion alive and relapse-free
HDI vs. observation: P2=0.006, HR=1.30
HDI vs. observation: P2=0.42, HR=1.07
HDI Observation
RFS OS
HR = hazard ratio Kirkwood JM, et al. Clin Cancer Res 2004;10:1670–7.

24. 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
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
*Such 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 Available from (last accessed December 18, 2013) Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii Garbe C, et al. Eur J Cancer 2010;46:270–83.

25. 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 Available from (last accessed December 18, 2013) Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii Garbe C, et al. Eur J Cancer 2010;46:270–83.

26. 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 Available from (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.

27. 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 Available from (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.

28. 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 Available from (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.

29. 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?
Palliative radiotherapy
Resection, followed by clinical trial as second-line therapy
Best supportive care
Isolated limb perfusion

30. 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?
Palliative radiotherapy
Resection, followed by clinical trial as second-line therapy
Best supportive care
Isolated limb perfusion

31. 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

32. 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

33. Summary Stage I/II melanoma: Stage III 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

34. Chemotherapy for Metastatic Melanoma

35. 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

36. 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 (last accessed December 18, 2012).
26. Temodar [package insert]. Whitehouse Station, NJ: Merck + Co, Inc; 2011.

37. Monotherapy for the Treatment of Metastatic Melanoma
Monotherapy is relatively ineffective in treatment of melanoma27
Chemotherapies
Response Rate
DTIC*†
5.3–28%20
TMZ
13.5–24%28,29
Fotemustine
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– Lui P, et al. Cancer Treat Rev 2007;33:665– European Medicines Agency. Available from (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.

38. Alkylating Agents: DTIC
DTIC is one of the alkylating agents included in cytotoxic agents with modest anti-tumour efficacy
Approval status
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
Activity
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
Safety
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 Available from (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.

39. 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
HR=0.92, 95% Cl (0.80–1.06)
Median (months) = 2.30 (TMZ) vs (DTIC)
p=0.27 3 6 9 12 15 18 21 24 10 20 30 50 60
Months 40 70 90
100 80 36
HR=1.00, 95% Cl (0.86–1.17)
Median (months) = 9.13 (TMZ) vs (DTIC)
p=1.0
DTIC TMZ
PFS OS
Events
Patients
Number of patients at risk
Treatment
398
430
148 93 50 27 17 11 8
DTIC
401
429
187
109 47 25 9
TMZ
Deaths
Patients
Number of patients at risk
Treatment
325
430
289
125 44 20 5
DTIC
320
429
300
115 49 19 2
TMZ
26. Temodar [package insert]. Whitehouse Station, NJ: Merck + Co, Inc; 2011.
28. Middleton MR, et al. J Clin Oncol 2000;18:158–66.

40. 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
Used off-label in the US and the EU for the treatment of cerebral metastasis of malignant melanoma6,31
Activity
Prolonged OS advantage compared with DTIC, although this was not significant (7.3 vs. 5.6 months; p=0.067)31
Safety
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.

41. Cisplatin Carboplatin
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
Ototoxicity, neurotoxicity, nephrotoxicity38
Thrombocytopenia and leukopenia39
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
In chemotherapy-naïve patients with metastatic melanoma single agent carboplatin led to a response rate of 19%6
6. Bhatia S, et al. Oncology 2009;23:488–96.
11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V Available from (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.

42. Antimitotic Agents Approval status Activity Safety
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
Approval status
Paclitaxel
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
Bhatia S, et al. Oncology 2009;23:488–96.
32. O’Day S, et al. J Clin Oncol 2009;27:5452–58.

43. 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

44. 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

45. 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

46. 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

47. 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

48. Immunotherapy for Metastatic Melanoma

49. 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

50. 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: /2012/818214; 42. Lebbe C, et al. Presented at ESMO 2012; Poster Presentation 1116PD.

51. 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) melanoma7 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.

52. Duration of response (months) Probability of continuing response
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
Median OS: 12 months; median PFS: 13.1 months; median duration of response: 8.9 months (responders only, n=43)
High-dose IL-2 is associated with cardiovascular, gastrointestinal, neurological, pulmonary, hepatic, renal, and hematological side effects46
CR; n=17 PR; n=26 CR + PR; n=43 10 20 30 40 50 60 70 80
0.0
0.2
0.4
0.6
0.8
1.0
Duration of response (months)
Probability of continuing response 90
100
110
120
130
High-dose IL-2 therapy
(Adapted from Atkins MB, et al)46
*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.

53. High-dose IFN-α-2b FDA approved Activity Safety
High-dose IFN-α-2b is approved in the adjuvant setting
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 (last accessed December 18, 2012).
15. Intron-A Summary of product characteristics, December 2011.

54. 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 (last accessed December 18, 2012)

55. 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
Ipilimumab 3 mg/kg q3w for four doses + gp100 1 mg q3w for four doses (n=403)
Ipilimumab 3 mg/kg q3w for four doses + placebo (n = 137)
gp100 1 mg q3w for four doses + placebo
(n = 136)
Re-induction with same regimen in eligible patients
Patients with previously treated metastatic melanoma (n=676)
Randomized 3:1:1 and stratified by metastatic stage and previous IL-2 treatment
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.

56. 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
Week 24
Maintenance therapy
Phase 3
Patients with treatment-naïve unresectable stage III/IV melanoma (N=502)
Patients with SD or an objective response and no dose-limiting adverse events: Ipilimumab 10 mg/kg q12w
Ipilimumab 10 mg/kg q3w for four doses + DTIC 850 mg/m2 q3w for
eight doses (n=250)
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.

57. 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.

58. 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

59. 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

60. 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

61. Targeted Therapies

62. 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

63. 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 mutation- positive 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 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. NCT Available from
(last accessed December 18, 2012); 63. Falchook GS, et al. Lancet 2012;379:1893–1901.

64. 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.

65. 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.

66. Novel Therapies Molecule Name Mechanism of Action Cytotoxic agents
Albumin-bound paclitaxel65
Microtubule inhibitor6
DHA-paclitaxel66
Immunotherapy agents
Mage-A3 ASCI (astuprotimut-r)67
MAGE-A3 vaccine68
OncoVEX GM-CSF69
Oncolytic HSV-170
BMS
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 (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 (last accessed December 2012); 67. MAGE-A3 Phase III clinical trial. Available from (last accessed December 18,
2012); 68. MAGE-A3 in NSCLC. Available from (last accessed December 18, 2012); 69. OncoVEXGM-CSF efficacy and safety study. Available from
(last accessed December 2012). 70. OncoVEX Phase II results. Available from (last accessed December 2012); 71. Allovectin-7 versus
chemotherapy. Available from (last accessed December 18, 2012); 72. Allovectin-7 Phase III press release. Available from
73. Tropalin SL, et al. N Engl J Med 2012;366:2443–54; 74. Tasigna prescribing information. Available from (last accessed December 18, 2012);
75. Genasense Phase III update. Available from (last accessed December 18, 2012).

67. 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
NRAS
CRAF
MEK
BRAF
PTEN
PI3K
AKT
mTOR
CDK2
CDK4
CyclinD
p16
GDC-0941
XL147
VQD002
MK2206
GSK
Temsirolimus
Everolimus
AP23573
OSI-027
PD032991
CYC202
BMS
GSK
RAF-265
XL281
GSK
GDC-0973
AZD-6244
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.

68. Check Your Understanding
Which of the following is not a targeted therapy?
Vemurafenib
Ipilimumab
Dabrafenib (GSK )
Tasigna (nilotinib)

69. Check Your Understanding
Which of the following is not a targeted therapy?
Vemurafenib
Ipilimumab
Dabrafenib (GSK )
Tasigna (nilotinib)

70. 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%

71. 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%

72. Reference List
Roguin A, et al. Rene Theophile Hyacinthe Laënnec ( ): The Man Behind the Stethoscope. Clin Med Research 2006;4;1:230–5. PMID:
Burke PJ et al. Imidazole carboxamide therapy in advanced malignant melanoma. Cancer 1971;27:744–50. PMID:
Mouawad R, et al. Treatment for metastatic malignant melanoma: old drugs and new strategies. Crit Rev Oncol Hematol 2010;74:27–39. PMID:
Khayat D, et al. Fotemustine in the treatment of brain primary tumors and metastases. Cancer Invest 1994;12:414–20. PMID:
National Cancer Institute. Available from (last accessed on February 18, 2012).
Bhatia S, et al. Treatment of metastatic melanoma: an overview. Oncology 2009;23:488–96. PMID:
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