Chapter 2: Therapeutic Options in Metastatic Melanoma

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 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 Zelborafreceived FDA approval for the treatment of BRAFV600Emutation-positive advanced (unresectable or metastatic) melanoma in 20119and EMA approval for BRAFV600mutation-positive advanced melanoma in 2012.10 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 unresectableor metastatic melanoma7and from the EMA for the treatment of advanced melanoma in adults who have received prior therapy8 High dose IL-2 received FDA approval for metastatic melanoma6 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 First trial of DTIC, an inhibitor of DNA (alkylating agent)2 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 OncolHematol2010;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. YervoySummary of Product Characteristics, July 2011. 9. Zelboraf Prescribing Information, August 2011. 10. Zelboraf Summary of Product Characteristics, March 2012.

6. Current Treatment Options 3. Mouawad R, et al. Crit Rev OncolHematol2010;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). 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

7. Clinical Stages for Melanoma Treatment of melanoma depends on the stage of the disease.11–13The 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 • In situ tumor • No regional lymph node metastases • No distant metastases • Stage I11 • Stage IA • ≤1.0 mm thick; no ulceration; mitosis <1/mm2 • 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 II11 • 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 IIC • >4.0 mm thick; with ulceration • No regional lymph node metastases • No distant metastases • 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 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 Cancer2010;46:270–83.

8. Clinical Stages for Melanoma Treatment of melanoma depends on the stage of the disease.11–13The 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 • 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 • 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 IIIA • Any tumor thickness; no ulceration • Micrometastases* of 1–3 regional lymph nodes • No distant metastases • Stage IV11 • Any tumorthickness • 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 Cancer2010;46:270–83.

9. Current Treatment Guidelinesfor 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 • Locally advanced(stage III)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 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 Cancer2010;46:270–83.

10. Current Treatment Guidelinesfor 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 • Metastatic(Stage IV)11–13 • 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 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 Cancer2010;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% atpresentation* • Wide excision (with/without sentinel node biopsy) • Clinical trial or observation (stage IB/IIA/IIB/IIC) • IFN-α† (stage IIB/IIC) • Surgery or lymphadenectomy or radiotherapy or clinical trial • 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 orradiotherapy or clinical trial • Locally advanced11–13(stage III)10–13% atpresentation* Sentinel node positive = Sentinel lymph node metastases as determined by a sentinel lymph node biopsy;11clinically positive = nodal metastases confirmed by lymphadectomy or when nodal metastasis exhibits gross extracapsularextension;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.1111. 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 Cancer2010;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 furthermetastases) • Unresectabledisease: 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.1111. 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 Cancer2010;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?

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?

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 BRAFV600mutation-positive patients), ipilimumaband 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 (catagory2B)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 Cancer2010;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.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 Cancer2010;46:270–83

22. IFN-α • 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 ClinOncol2004;22:53–61. • 17. Eggermont AM, et al. Lancet2005;366:1189–96. • 18. Kefford RF, Ann Oncol2003;14:358–65. • 19. Kirkwood JM, et al. Clin Cancer Res 2004;10:1670–7. • 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;16for intermediate doses, toxicity was reported as acceptable, with 18% of patients needing to withdraw17

23. IFN-α RFS OS HDI vs. observation: P2=0.006, HR=1.30 HDI vs. observation: P2=0.42, HR=1.07 1.0 1.0 0.8 0.8 0.6 0.6 Proportion alive and relapse-free Proportion alive and relapse-free 0.4 0.4 0.2 0.2 HDI Observation 0.0 0.0 0 0 2 2 4 4 6 6 8 8 10 10 12 12 14 14 16 16 Time (years) Time (years) HR = hazard ratio.19. Kirkwood JM, et al. Clin Cancer Res 2004;10:1670–7. • 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

24. Locally Advanced Melanoma (Stage III) • 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.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 Cancer2010;46:270–83. 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

25. Locally Advanced Melanoma (Stage III) • 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 Cancer2010;46:270–83. 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

26. Treatment of Metastatic Melanoma (Unresectable Stage IIIC and Stage IV) • 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 OncolHematol2010;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. CurrOncol Rep 2009;11:397–404. • 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

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: • Zelborafin 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) melanoma7and by the EMA for the treatment of advanced melanoma in adults who have received prior therapy;8 †Approved for metastatic melanoma in the USA.6IL-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,11however 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.

28. Metastatic Melanoma (Unresectable Stage IIIC and Stage IV) *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. CurrOncol 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. • 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 patients22and 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 BRAFV600E9and BRAFV60010mutation-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

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?

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?

33. 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

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 • 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. • 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

37. Monotherapy for the Treatment of Metastatic Melanoma • *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. MiddletonMR, et al. J ClinOncol2000;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 ClinOncol2004;22:1118–25. • 32. Mornex F, et al. Melanoma Res 2003;13:97–103. • 33. Nelimark RA, et al. Am J ClinOncol1983;6:561–4. • 34. Carmichael J, et al. Eur J Cancer ClinOncol 1982;18:1293–5. Monotherapy is relatively ineffective in treatment of melanoma27

38. Alkylating Agents: DTIC • DTIC is one of the alkylating agents included in cytotoxic agents with modest anti-tumour efficacy • 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,11it is often used in cases where approved targeted compounds or appropriate clinical trials are unavailable11,12 • Approval status • 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.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; OralPresentation 8502; 31. Avril MF, et al. J ClinOncol2004;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 PFS OS HR=0.92, 95% Cl (0.80–1.06) Median (months) = 2.30 (TMZ) vs. 2.17 (DTIC) p=0.27 HR=1.00, 95% Cl (0.86–1.17) Median (months) = 9.13 (TMZ) vs. 9.36 (DTIC) p=1.0 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 0 0 3 6 6 12 9 12 18 15 24 18 30 21 24 36 Months Months DTIC TMZ 26. Temodar [package insert]. Whitehouse Station, NJ: Merck + Co, Inc; 2011. • 28. Middleton MR, et al. J ClinOncol 2000;18:158–66. • 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

40. Nitrosourea Agents • Used off-label in the US and the EU for the treatment of cerebral metastasis of malignant melanoma6,31 • Off-label use • Activity • 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 • Safety • 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.ClinDermatol2009;27:614–25. • 30. Jacquillat C, et al. Cancer 1990;66:1873–8. • 31. AvrilMF, et al. J ClinOncol2004;22:1118–25. 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

41. Platinum Agents • 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.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. • Single-agent platinum-based therapy shows modest activity in patients with metastatic melanoma6 • Mostly prescribed as combination regimens6,11

42. Antimitotic Agents • 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 • Paclitaxel is associated with fatigue, alopecia, myelosuppression, neuropathy, myalgias and hypersensitivity reactions6 • Safety Bhatia S, et al. Oncology 2009;23:488–96. 32. O’Day S, et al. J ClinOncol2009;27:5452–58. • 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

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, lomustinand fotemustine) which are associated with higher rates of alopecia and myelosuppressioncompared 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 21. Sznol M. CurrOncol Rep 2009;11:397–404;22. Hodi SF, et al. N Engl J Med 2010;363:711–23; 40. Schadendorf D, et al. Ann Oncol2012;23(suppl):x104–x108;41. Sapoznik S, et al. ClinDevImmunol 2012; [Epub ahead of print] doi:10.1155/2012/818214; 42. Lebbe C, et al. Presented at ESMO 2012; Poster Presentation 1116PD. • 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