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Chapter 2: Therapeutic Options in Metastatic MelanomaCore Educational Resource

F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland, March 2013. No. GL/ZELB/1211/0049g

Content

• Melanoma Treatment Overview

• Treatment Options Overview

• Chemotherapy for Metastatic Melanoma

• Immunotherapy for Metastatic Melanoma

• Targeted Therapies

2

3F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland, March 2013. No. GL/ZELB/1211/0049g

Melanoma Treatment Overview

F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland, March 2013. No. GL/ZELB/1211/0049g 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


Key Therapeutic Milestones in Melanoma

5

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 www.cancer.gov.

6. Bhatia S, et al. Oncology 2009;23:488–96.7. Yervoy Prescribing Information, March 2011.8. Yervoy Summary of Product Characteristics, July 2011.9. Zelboraf Prescribing Information, August 2011.10. Zelboraf Summary of Product Characteristics, March 2012.

1804

1971

1975

1980s–1990s

1995

1998

2010–2012

French physician René Laennec described

melanoma as a disease1

DTIC received US FDA approval for metastatic

melanoma3

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

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

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

Zelboraf received FDA approval for the treatment of BRAFV600E mutation-positive advanced (unresectable or metastatic) melanoma in 20119 and EMA approval

for BRAFV600 mutation-positive advanced melanoma in 2012.10

http://www.cancer.gov/


Current Treatment Options

• Prior to the development of Zelboraf and ipilimumab, single agent DTIC represented the most common treatment option for advanced or metastatic melanoma, however, this strategy provided only limited benefit3

• Currently, preferred systemic therapy options for this patient population include Zelboraf, ipilimumab and enrolment on to clinical trials11

3. Mouawad R, et al. Crit Rev Oncol Hematol 2010;74:27–39.11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™.

Melanoma V.1.2011. Available from www.nccn.org (last accessed November 1, 2012).


Clinical Stages for Melanoma

AJCC = American Joint Committee on Cancer; NCCN = National Comprehensive Cancer Network. 11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V.2.2013. Available from www.nccn.org

(last accessed December 18, 2012).12. Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii91. 13. Garbe C, et al. Eur J Cancer 2010;46:270–83.

• In situ tumor• No regional lymph node metastases• No distant metastases

Stage 011

Stage IA• ≤1.0 mm thick; no ulceration;

mitosis <1/mm2

• No regional lymph node metastases• No distant metastases

Stage I11

Stage IIA• 1.01–2.0 mm thick; with ulceration• No regional lymph node metastases• No distant metastasesor• 2.01–4.0 mm thick; no ulceration• No regional lymph node metastases• No distant metastases

Stage II11

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 IB• ≤1.0 mm thick; with ulceration or mitosis ≥1/mm2• No regional lymph node metastases• No distant metastasesor• 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 metastasesor• >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


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 IIIB• Any tumor thickness; with

ulceration• Micrometastases of 1–3 regional

lymph nodes• No distant metastasesor• 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 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 metastasesor• 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.2.2013. Available from www.nccn.org (last accessed December 18, 2012); 12. Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii91; 13. Garbe C, et al. Eur J Cancer 2010;46:270–83.


Current Treatment Guidelinesfor Melanoma

• 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 metastases 11,12

• Systemic therapy with Zelboraf or ipilimumab for unresectable disease11,12

Locally advanced(stage III)11–13

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

ESMO = European Society for Medical Oncology.

11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V.2.2013. Available from www.nccn.org (last accessed December 18, 2012).

12. Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii91. 13. Garbe C, et al. Eur J Cancer 2010;46:270–83.


Current Treatment Guidelinesfor Melanoma

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

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

TMZ = temozolomide.11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V.2.2013. Available from www.nccn.org

(last accessed December 18, 2012).12. Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii91. 13. Garbe C, et al. Eur J Cancer 2010;46:270–83.


Current Treatment Overview

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

Stage Adjuvant Therapy Treatment of RecurrenceInitial Treatment Intervention

Sentinel node positive = Sentinel lymph node metastases as determined by a sentinel lymph node biopsy;11 clinically positive = nodal metastases confirmed by lymphadectomy or when nodal metastasis exhibits gross extracapsular extension;11 in transit = Located in the skin between 2 cm from the site of the primary tumor and the first draining lymph node.13

*Percentage of melanoma patients (US) presenting with indicated stage of disease; †The NCCN melanoma panel does not recommend the use of adjuvant IFN-α for completely resected stage IV disease.11


Based on the guidelines for melanoma treatment at each stage, the steps for treatment are defined.


Current Treatment Overview

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

Stage Adjuvant Therapy Treatment of RecurrenceInitial Treatment Intervention

*Percentage of melanoma patients (US) presenting with indicated stage of disease; †For resectable disease, patients either enter a clinical trial or undergo observation.11


Based on the guidelines for melanoma treatment at each stage, the steps for treatment are defined.


Check Your Understanding

Clinical trials are neither indicated nor recommended by US or EU guidelines. Is this statement true or false?

• True

• False



Clinical trials are neither indicated nor recommended by US or EU guidelines. Is this statement true or false?

• True

• False



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 withor without adjuvant treatment, dependingon 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



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 withor without adjuvant treatment, dependingon the degree of invasion of the primarytumor

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


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


Treatment Options Overview


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)


Treatment of Localized Melanoma (Stage I/II)

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 biopsyA 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 unclear 11,12

• 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

Localized melanoma can be treated using strategies like wide excision surgery and adjuvant therapy11–13

OS = overall survival.



Treatment of Localized Melanoma (Stage I/II)

Adjuvant TherapyAdjuvant 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

Localized melanoma can be treated using strategies like wide excision surgery and adjuvant therapy11–13

11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V.2.2013. Available from www.nccn.org (last accessed December 18, 2012); 12. Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86-vii91; 13. Garbe C, et al. Eur J Cancer 2010;46:270–83


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 www.introna.com(last accessed December 18, 2011).

15. Intron-A Summary of product characteristics, December 2011. 16. Hancock BW, et al. J Clin Oncol 2004;22:53–61.

17. Eggermont AM, et al. Lancet 2005;366:1189–96.18. Kefford RF, Ann Oncol 2003;14:358–65. 19. Kirkwood JM, et al. Clin Cancer Res 2004;10:1670–7.


• 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

0 2 4 6 8 10 12 14 160.0

0.2

0.4

0.6

0.8

1.0

Time (years)

Prop

ortio

n al

ive

and

rela

pse-

free

HDI vs. observation: P2=0.006, HR=1.30

0 2 4 6 8 10 12 14 160.0

0.2

0.4

0.6

0.8

1.0

Time (years)Pr

opor

tion

aliv

e an

d re

laps

e-fr

ee

HDI vs. observation: P2=0.42, HR=1.07

HDI Observation

RFS OS

HR = hazard ratio.

19. Kirkwood JM, et al. Clin Cancer Res 2004;10:1670–7.

IFN-α


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


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.


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


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.


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

PFS = progression-free survival; OS = overall survival; SRS = stereotactic radiosurgery; WBRT = whole brain radiotherapy.

3. Mouawad R, et al. Crit Rev Oncol Hematol 2010;74:27–39.6. Bhatia S, et al. Oncology 2009;23:488–96.11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V.2.2013.

Available from www.nccn.org (last accessed December 18, 2012).12. Dummer R, et al. Ann Oncol 2010;21(suppl 5):194–7. 21. Sznol M. Curr Oncol Rep 2009;11:397–404.

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


Treatment of Metastatic Melanoma (Unresectable Stage IIIC and Stage IV)

*Approved by the FDA for the treatment of advanced (unresectable or metastatic) melanoma 7 and by the EMA for the treatment of advanced melanoma in adults who have received prior therapy;8 †Approved for metastatic melanoma in the USA.6 IL-2 is not for patients with poor performance status or active brain metastases;11 ‡Approved as adjuvant to surgical treatment;13 while not FDA or EMA approved for metastatic melanoma, IFN-α-2b is one of several preferred systemic regimens for treatment of unresectable stage III and IV melanoma, 11 however the NCCN melanoma panel does not recommend the use of adjuvant interferon alpha for completely resected stage IV disease. 11

6. Bhatia S, et al. Oncology 2009;23:488–96; 7. Yervoy Prescribing Information, March 2011 ; 8. Yervoy Summary of Product Characteristics, July 2011; 11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V.2.2013. Available from www.nccn.org (last accessed December 18, 2013); 12. Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii91; 13. Garbe C, et al. Eur J Cancer 2010;46:270–83.

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


Metastatic Melanoma (Unresectable Stage IIIC and Stage IV)

• Prior to recent developments in the treatment od metastatic melanoma, many agents showed modest response rates in metastatic melanoma patients6,11

• Response rates to DTIC monotherapy range between 5.3% and 28%20

• IL-2 induces prolonged CR in approximately 5% of a selected group of patients21

• Approved in the US and Europe, ipilimumab demonstrated a BORR of 10.9% and a median OS of approximately 10 months in previously-treated patients22 and a BORR of 15.2%, a 24% reduction in risk of disease progression and a median OS of approximately 11 months in treatment-naïve patients24*

• Zelboraf is an FDA and EMA approved targeted therapy indicated for use in BRAFV600E9 and BRAFV60010 mutation-positive patients, respectively

– In the February 2012 post-hoc survival update of the Phase 3 trial, Zelboraf demonstrated an overall response rate of 57% and a median OS of 13.6 months compared with 10.3 months with DTIC (p<0.01) in treatment-naïve patients23

*Ipilimumab + DTIC compared with patients receiving placebo + DTIC (median OS 9.1 months; 95% CI: 7.8–10.5)BORR = best overall response rate; CI = confidence interval; CR = complete response.

6. Bhatia S, et al. Oncology 2009;23:488–96; 9. Zelboraf Prescribing Information, August 2011; 10. Zelboraf Summary of Product Characteristics, March 2012; 11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Melanoma V.2.2013. Available from www.nccn.org (last accessed December 18, 2012); 20. Lui P, et al. Cancer Treat Rev 2007;33:665–80; 21. Sznol M. Curr Oncol Rep 2009;11:397–404; 22. Hodi FS, et al. N Engl J Med 2010;363:711; 23. Chapman P, et al. Presented at the ASCO Annual Meeting 2012; Oral Presentation 8502; 24. Robert C, et al. N Engl J Med 2012;365:2517–26.



Case study:

A 59-year-old male presents with stage IV resectable metastatic melanoma with no brain involvement. Based on the knowledge you have gained from the Treatment Options Overview chapter, which of the four treatment options presented below would be best suited for this patient?

1. Palliative radiotherapy

2. Resection, followed by clinical trial as second-line therapy

3. Best supportive care

4. Isolated limb perfusion



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



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


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


Chemotherapy for Metastatic Melanoma


Learning objectives


• Recall approval status, key efficacy and safety data for the following chemotherapy classes:

– Alkylating agents– Platinum agents– Antimitotic agents


Chemotherapy

• Cytotoxic chemotherapy has been used for the treatment of metastatic melanoma for over 3 decades6

• Cytotoxic agents with modest antitumor efficacy in metastatic melanoma include:6

– Alkylating agents (e.g. DTIC, TMZ)– Nitrosoureas (e.g. carmustine, lomustine, fotemustine)– Platinum analogs (e.g. cisplatin, carboplatin)– Antimitotic toxins (e.g. vindesine, vinblastine, paclitaxel)

• These agents have been used alone or in combination– DTIC; FDA and EMA approved as monotherapy6,25

– TMZ; off-label used as monotherapy or in combination in metastatic melanoma26

– Fotemustine; not FDA approved in metastatic melanoma but available in Europe6

6. Bhatia S, et al. Oncology 2009;23:488–96.25. European Medicines Agency. Available from www.ema.europa.eu (last accessed December 18, 2012).26. Temodar [package insert]. Whitehouse Station, NJ: Merck + Co, Inc; 2011.


Monotherapy for the Treatment of Metastatic Melanoma

• Monotherapy is relatively ineffective in treatment of melanoma27

*Approved for metastatic melanoma in Europe.25 †Approved for metastatic melanoma in the US.6

6. Bhatia S, et al. Oncology 2009;23:488–96. 20. Lui P, et al. Cancer Treat Rev 2007;33:665–80. 25. European Medicines Agency. Available from www.ema.europa.eu (last accessed December 18, 2012).28. Middleton MR, et al. J Clin Oncol 2000;18:158–66. 29. Bleehen NM, et al. J Clin Oncol 1995;13:910–3.

30. Jacquillat C, et al. Cancer 1990;66:1873–8.31. Avril MF, et al. J Clin Oncol 2004;22:1118–25.32. Mornex F, et al. Melanoma Res 2003;13:97–103.33. Nelimark RA, et al. Am J Clin Oncol 1983;6:561–4.34. Carmichael J, et al. Eur J Cancer Clin Oncol 1982;18:1293–5.

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

http://www.ema.europa.eu/


Alkylating Agents: DTIC

ORR = objective response rate; PR = partial response.6. Bhatia S, et al. Oncology 2009;23:488–96; 11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™.Melanoma V.2.2013. Available from www.nccn.org (last accessed December 18, 2012); 12. Dummer R, et al. Ann Oncol 2012;23(suppl 7):vii86–vii91; 23. Chapman P, et al. Presented at the ASCO Annual Meeting 2012; Oral Presentation 8502; 31. Avril MF, et al. J Clin Oncol 2004;22:1118–25; 35. Hauschild A, et al. Lancet 2012;380:358–65; 36. Flaherty KT, et al.N Engl J Med 2012;367:107–14.

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

• DTIC is one of the alkylating agents included in cytotoxic agents with modest anti-tumour efficacy


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

26. Temodar [package insert]. Whitehouse Station, NJ: Merck + Co, Inc; 2011.28. Middleton MR, et al. J Clin Oncol 2000;18:158–66.

Events Patients Number of patients at risk Treatment

398 430 148 93 50 27 17 11 8 DTIC

401 429 187 109 47 25 17 11 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

HR=0.92, 95% Cl (0.80–1.06)Median (months) = 2.30 (TMZ) vs. 2.17 (DTIC)p=0.27

0 3 6 9 12 15 18 21 240

102030

5060

Months

40

70

90100

80

0 6 12 18 24 30 360

102030

5060

Months

40

70

90100

80 HR=1.00, 95% Cl (0.86–1.17)Median (months) = 9.13 (TMZ) vs. 9.36 (DTIC)p=1.0

DTIC TMZ

PFS OS


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.


Platinum Agents

• Single-agent platinum-based therapy shows modest activity in patients with metastatic melanoma6

– Mostly prescribed as combination regimens6,11

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.

Approval status

Activity

Safety Ototoxicity, neurotoxicity, nephrotoxicity38

Thrombocytopenia and leukopenia39

Cisplatin CarboplatinNot 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


• 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

Activity• In a Phase 2 study, it led to a median OS of 7.8 months in stage IV

metastatic melanoma32

Safety • Paclitaxel is associated with fatigue, alopecia, myelosuppression, neuropathy, myalgias and hypersensitivity reactions6

6. Bhatia S, et al. Oncology 2009;23:488–96. 32. O’Day S, et al. J Clin Oncol 2009;27:5452–58.

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



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



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


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


Immunotherapy for Metastatic Melanoma


Learning Objectives


• 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


Proof of Concept for Immunotherapy in Metastatic Melanoma

• Attempting to modulate the immune response has been a popular strategy in melanoma

– Strategies previously used in immune modulation trials include the use of cytokines (IFN-α, IL-2), vaccines (gp100), antibodies (ipilimumab, tremelimumab) and adoptive immunotherapy21

• Key advances suggested potential to manipulate and disrupt immune activation checkpoints and tumor defense mechanisms:21

– Immune activation by antigen presentation (e.g. vaccines)– New antigen-specific T-cell expansions in vitro and in vivo– Gene transfer to alter lymphocyte specificity and function – Discovery of new predictive biomarkers

• There are currently a number of immunotherapies in the pipeline for melanoma, some of which are in late-phase development21,40,41

• The use of immunotherapy has been associated with only modest response rates, with high-dose cytokine therapies leading to prolonged responses in a minority of patients21

• While the response rate with ipilimumab was limited, median OS was significantly improved when used as monotherapy and in combination with the peptide vaccine gp100 compared with gp100 alone22

– A recent evaluation of Phase 2 ipilimumab trials in patients with metastatic melanoma demonstrates 5-year survival in up to 18% of pretreated patients42

21. Sznol M. Curr Oncol Rep 2009;11:397–404; 22. Hodi SF, et al. N Engl J Med 2010;363:711–23;40. Schadendorf D, et al. Ann Oncol 2012;23(suppl):x104–x108; 41. Sapoznik S, et al. Clin Dev Immunol 2012; [Epub ahead of print] doi:10.1155/2012/818214; 42. Lebbe C, et al. Presented at ESMO 2012; Poster Presentation 1116PD.


Immunotherapy as Monotherapy for the Treatment of Metastatic Melanoma

*Not FDA or EMA approved in metastatic melanoma. †Approved by the FDA for the treatment of advanced (unresectable or metastatic) melanoma 7 and by the EMA for the treatment of advanced melanoma in adults who have received prior therapy.8

‡Previously treated patients.7. Yervoy Prescribing Information, March 2011.8. Yervoy Summary of Product Characteristics, July 2011. 22. Hodi SF, et al. N Engl J Med 2010;363:711–23.43. Miller RL, et al. Cancer Res 1989;49:1871–6.44. Robison WA, et al. Immunobiology 1986;172:275–82.45. Legha SS, et al. Cancer 1996;77:89–96.46. Atkins MB, et al. Clin Oncol 1999;17:2105–16.

Immunotherapies Response Rate

Interferon-α-2b* 13–25%43,44

Interleukin-2 16–22%45,46

Ipilimumab† 10.9% (median OS: ≈10 months)22‡


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

0 10 20 30 40 50 60 70 800.0

0.2

0.4

0.6

0.8

1.0

Duration of response (months)

Prob

abili

ty o

f con

tinui

ng re

spon

se

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.


High-dose IFN-α-2b

FDA approved

Activity

Safety

6. Bhatia S, et al. Oncology 2009;23:488–96.14. Intron-A Product Information. Available from www.introna.com (last accessed December 18, 2012).15. Intron-A Summary of product characteristics, December 2011.

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


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 20118. Yervoy Summary of Product Characteristics, July 2011.22. Hodi SF, et al. N Engl J Med 2010;363:711–23.49. Weber JS, et al. J Clin Oncol 2008;26(36);5950–6.50. Ipilimumab in metastatic melanoma. Available from www.clinicaltrials.gov (last accessed December 18, 2012)

http://www.clinicaltrials.gov/


Ipilimumab Phase 3 Pivotal Clinical Trials: Trial Design and Results

• 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.

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

Ipilimumab showed long-term survival benefit in both previously-treated and in treatment naïve patients with metastatic melanoma22,24


Ipilimumab Phase 3 Pivotal Clinical Trials: Trial Design and Results

• 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.

Ipilimumab showed long-term survival benefit in both previously-treated and in treatment naïve patients with metastatic melanoma22,24

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)

Phase 3Patients with treatment-naïve unresectable stage III/IV melanoma (N=502)

Week 24Induction therapy Maintenance therapy

Patients with SD or an objective response and no

dose-limiting adverse events: Ipilimumab 10 mg/kg q12w

Placebo q12w


Treatment Combinations for Metastatic Melanoma

• Combination regimens are also relatively ineffective and poorly tolerated3

Select Therapy Combinations Stage IV Median OSDTIC + 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.



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


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


Targeted Therapies


Learning Objectives


• 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


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 9.7 months for DTIC

• Median PFS was 6.9 months compared with 1.6 months with DTIC

• ORR of 57% with Zelboraf compared with 8.6% with DTIC

Zelboraf showed a consistent safety profile and adverse drug reactions caused by Zelboraf were generally manageable.23 Further targeted therapies are currently being investigated, including dabrafenib and trametinib for patients with BRAFV600 mutations and nilotinib for patients with c-KIT mutations.35,36,62,63

*February 2012 post-hoc survival update.10. Zelboraf Summary of Product Characteristics, March 2012; 23. Chapman P, et al. Presented at the ASCO Annual Meeting 2012; OralPresentation 8502; 35. Hauschild A, et al. Lancet 2012;380:358–65 ; 36. Flaherty KT, et al. N Engl J Med 2012;367:107–14; 61. Flaherty KT, et al. Cancer 2010;116:4902–13; 62. A Study of AMNN107 Against DTIC. NCT01028222. Available from www.clinicaltrials.gov(last accessed December 18, 2012); 63. Falchook GS, et al. Lancet 2012;379:1893–1901.


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.


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.


Novel Therapies

Molecule Name Mechanism of ActionCytotoxic agentsAlbumin-bound paclitaxel65 Microtubule inhibitor6

DHA-paclitaxel66 Microtubule inhibitor6

Immunotherapy agentsMage-A3 ASCI (astuprotimut-r)67 MAGE-A3 vaccine68

OncoVEX GM-CSF69 Oncolytic HSV-170

BMS-93655870 Anti-PD-1 antibody70

Velimugene aliplasmid71 HLA-B772

Targeted agentsNilotinib62,74 Bcr-Abl/c-KIT/PDGFR inhibitor62,74

Oblimersen75 Bcl-2 antisense75

Dabrafenib35,63 BRAF inhibitor35,63

Tramtenib36 MEK inhibitor36

6. Bhatia S, et al. Oncology 2009;23:488–96; 65. ABI-007 versus DTIC. Available from www.clinicaltrials.gov (last accessed December 2012); 35. Hauschild A, et al.Lancet 2012;380:358–65; 36. Flaherty KT, et al. N Engl J Med 2012;367:107–14; 63. Falchook GS, et al. Lancet 2012;379:1893–901; 66. DHA-paclitaxel versus DTIC.Available from www.clinicaltrials.gov (last accessed December 2012); 67. MAGE-A3 Phase III clinical trial. Available from www.clinicaltrials.gov (last accessed December 18,2012); 68. MAGE-A3 in NSCLC. Available from www.drugs.com (last accessed December 18, 2012); 69. OncoVEXGM-CSF efficacy and safety study. Available fromwww.clinicaltrials.gov (last accessed December 2012). 70. OncoVEX Phase II results. Available from www.drugs.com (last accessed December 2012); 71. Allovectin-7 versuschemotherapy. Available from www.clinicaltrials.gov (last accessed December 18, 2012); 72. Allovectin-7 Phase III press release. Available from www.drugs.com;73. Tropalin SL, et al. N Engl J Med 2012;366:2443–54; 74. Tasigna prescribing information. Available from www.drugs.com (last accessed December 18, 2012); 75. Genasense Phase III update. Available from www.drugs.com (last accessed December 18, 2012).


The Emerging Future of Targeted Therapy for Melanoma76

CDK = cyclin-dependent kinase; mTOR = mammalian target of rapamycin; PTEN = phosphotase and tensin hemolog.

76. Sosman J, et al. Oral presentation at Melanoma 2010, Sydney, Australia. www.melanoma2010.com.

NRASCRAF

MEK

BRAF PTEN

PI3K

AKT

mTOR

CDK2CDK4

CyclinDp16

GDC-0941XL147

VQD002MK2206GSK 690693

TemsirolimusEverolimusAP23573OSI-027

PD032991CYC202

BMS-387032

GSK 2118436RAF-265XL281

GSK 1120212GDC-0973AZD-6244

Emerging targeted therapies aim to inhibit mutated proteins that up-regulate signaling pathways known to promote uncontrolled melanocyte growth and survival



Which of the following is not a targeted therapy?

• Vemurafenib

• Ipilimumab

• Dabrafenib (GSK2118436)

• Tasigna (nilotinib)



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%



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%


Reference List

1. Roguin A, et al. Rene Theophile Hyacinthe Laënnec (1781-1826): The Man Behind the Stethoscope. Clin Med Research 2006;4;1:230–5. PMID: 17048358

2. Burke PJ et al. Imidazole carboxamide therapy in advanced malignant melanoma. Cancer 1971;27:744–50. PMID: 5549505

3. Mouawad R, et al. Treatment for metastatic malignant melanoma: old drugs and new strategies. Crit Rev Oncol Hematol 2010;74:27–39. PMID: 19781957

4. Khayat D, et al. Fotemustine in the treatment of brain primary tumors and metastases. Cancer Invest 1994;12:414–20. PMID: 8032964

5. National Cancer Institute. Available from www.cancer.gov (last accessed on February 18, 2012).

6. Bhatia S, et al. Treatment of metastatic melanoma: an overview. Oncology 2009;23:488–96. PMID: 19544689

7. Yervoy Prescribing Information, March 2011 (last accessed December 18, 2012).

8. Yervoy Summary of Product Characteristics, July 2011 (last accessed December 18, 2012).

9. Zelboraf Prescribing Information, August 2011 (last accessed December 18, 2012).

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confidential – for internal use only chapter 2: therapeutic options in metastatic melanoma core...

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