Melanoma Treatment Regimens

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MELANOMA TREATMENT REGIMENS

Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment.

Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The melanoma cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These melanoma cancer treatment regimens are only provided to supplement the latest treatment strategies.

These Cancer Treatment Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Systemic Therapy Options for Metastatic or Unresectable Melanoma1

Note: All recommendations are category 2A unless otherwise indicated.

First-line Immunotherapy Regimens

(Revised 3/2017)

© 2017 Haymarket Media, Inc.

REGIMEN

DOSING

Nivolumab (Category 1)2,3abcd

Nivolumab 3mg/kg IV every 2 weeks.

Nivolumab + ipilimumab4,5abcdef

Day 1: Nivolumab 1mg/kg followed by ipilimumab 3mg/kg IV every 3 weeks for 4 cycles; then, nivolumab 3mg/kg every 2 weeks.

Pembrolizumab (Category 1)6-9acd

Pembrolizumab 2mg/kg IV every 3 weeks.

First-line Targeted Therapy for BRAF-Mutant Melanoma

Preferred Regimens

Dabrafenib + trametinib (Category 1)10-13ghi

Dabrafenib 150mg orally twice daily + trametinib 2mg/day orally.

Vemurafenib + cobimetinib (Category 1)14-16ghij

Vemurafenib 960mg orally twice daily on days 1–28 + cobimetinib 60mg/day orally on days 1–21.

Repeat cycle every 28 days.

Other Active Regimens

Vemurafenib (Category 1)17,18ghi

Vemurafenib 960mg orally twice daily.

Dabrafenib (Category 1)19,20ghi

Dabrafenib 150mg orally twice daily.

Second-line or Subsequent Therapy (PS 0-2)k

Pembrolizumab6-9acdl

Pembrolizumab 2mg/kg IV every 3 weeks.

Nivolumab2,3abcd

Nivolumab 3mg/kg IV every 2 weeks.

Nivolumab + ipilimumab4,5abcdefl

Day 1: Nivolumab 1mg/kg followed by ipilimumab 3mg/kg IV every 3 weeks for 4 cycles; then, nivolumab 3mg/kg every 2 weeks.

Ipilimumab (Category 1)21-24cdelm

Day 1: Ipilimumab 3mg/kg IV. Repeat cycle every 3 weeks for 4 cycles.

High-dose IL-225-28no

Days 1–5: IL-2 22mcg/kg (360,000 IU/kg), 33mcg/kg (540,000 IU/kg),

36mcg/kg (600,000 IU/kg), or 44mcg/kg (720,000mcg/kg) IV every 8 hours

for up to 14 consecutive doses as clinically tolerated.

Dacarbazine29

Day 1: Dacarbazine 2–4.5mg/kg/day IV for 10 days.

Repeat cycle every 4 weeks.

OR

Days 1–5: Dacarbazine 250mg/m2/day IV.

Repeat cycle every 3 weeks.

Temozolomide30

Days 1–5: Temozolomide 200mg/m2/day orally for 5 days.

Repeat cycle every 4 weeks.

Paclitaxel31

Paclitaxel 250mg/m2 continuous IV infusion for 24 hours.

Repeat cycle every 21 days.

Albumin-bound paclitaxel32,33

Nab-paclitaxel 100mg/m2 (in previously treated patients) or 150mg/m2 (in

chemotherapy-naive patients) IV.

Repeat every week for 3–4 cycles.

Carboplatin + paclitaxel34-37

Days 1, 8, and 15: Paclitaxel 100mg/m2 IV + carboplatin AUC 2mg·min/mL IV.

Repeat cycle every 4 weeks until disease progression

Biochemotherapy for metastatic disease (Category 2B)38-42o

Dacarbazine or temozolomide, + cisplatin or carboplatin, ± vinblastine or nitrosourea, + IL-2 + IFN-alpha-2b

Biochemotherapy for adjuvant treatment of high-risk disease (Category 2B)43o

Dacarbazine, cisplatin, vinblastine, IL-2, and interferon alfa-2b

Imatinib44,45p

Imatinib 400mg orally twice daily.

Second-Line or Subsequent Therapy for BRAF-Mutant Melanoma (PS 0-2)

Preferred Regimens

Dabrafenib + trametinib10-13ghi

Dabrafenib 150mg orally twice daily + trametinib 2mg/day orally.

Vemurafenib + cobimetinib14-16ghij

Vemurafenib 960mg orally twice daily on days 1–28 + cobimetinib 60mg/day orally on days 1–21.

Repeat cycle every 28 days.

Other Active Regimens

Vemurafenib17,18ghi

Vemurafenib 960mg orally twice daily.

Dabrafenib19,20ghi

Dabrafenib 150mg orally twice daily.

a Nivolumab or pembrolizumab may cause immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, hypophysitis, nephritis, and hyperthyroidism. For moderate to severe immune-mediated toxicities, discontinue therapy and administer systemic steroids.

b Clinically significant (grade 3 and 4) immune-related adverse events are seen more commonly with nivolumab/ipilimumab combination therapy compared with iplimumab or nivolumab monotherapy. This emphasizes the need for careful patient education, selection, and monitoring.

c Immune-mediated dermatitis sometimes responds to topical corticosteroids. For patients who do not respond, consider referral to a dermatologist or provider experienced in diagnosing and management cutaneous manifestations of immunotherapy.

d Infliximab 5 mg/kg is preferred for treatment of severe immune- related colitis that does not resolve with high-dose steroids. A single dose of infliximab is sufficient to resolve immune-related colitis in most patients.

e Ipilimumab has the potential for significant immune-mediated complications. Although no longer required by the FDA, the Risk Evaluation and Mitigation Strategy program and/or experience in use of the drug as well as resources to follow the patient closely are essential for safe use of ipilimumab. It should be used with extreme caution, if at all, in patients with underlying immune disorders.

f Nivolumab/ipilimumab combination therapy was associated with better relapse-free survival than either agent used alone in a phase 3 trial, but the combination significantly increased toxicity. The combination's effect on overall survival (OS) is undetermined.

g Vemurafenib, dabrafenib, and trametinib are recommended only for patients with V600 mutation of the BRAF gene documented by an FDA-approved or Clinical Laboratory Improvement Amendments (CLIA)-approved facility.

h Regular dermatologic evaluation and referral to a dermatologist or provider experienced in the diagnosis and management of cutaneous manifestations of targeted therapy is recommended. BRAF inhibitors are associated with cutaneous squamous cell carcinoma, extreme photosensitivity, and other dermatologic toxicities, which occur much less often with concurrent MEK inhibitors.

i Pyrexia (defined as a temperature of 38.5°C or greater) is a common (~55%) side effect of combining BRAF and MEK inhibitors and occurs less frequently with BRAF monotherapy (~20%). The pyrexia is episodic, and onset is often 2 to 4 weeks following the start of therapy with a median duration of 9 days. Pyrexia may be associated with chills, night sweats, rash, dehydration, electrolyte abnormalities, and hypotension. Stopping or holding dabrafenib and trametinib at the onset of pyrexia will often interrupt the episode, and treatment can be resumed with full-dose dabrafenib and trametinib upon cessation of pyrexia and pyrexia-related symptoms. Upon re-exposure to dabrafenib and trametinib, repeat pyrexia events can occur, but grade >3 events are uncommon (21%). In occasional instances of prolonged or severe pyrexia not responsive to discontinuation of dabrafenib and trametinib, low-dose steroids (prednisone 10 mg/day) can be used. Patients with pyrexia should be advised to use antipyretics as needed and increase fluid intake.

j Vemurafenib/cobimetinib combination therapy was associated with better PFS and a better response rate than vemurafenib monotherapy in previously untreated patients with unresectable stage IIIC or stage IV disease. The combination's effect on OS compared to single-agent vemurafenib is unknown.

k Consider second-line agents that were not used in first-line therapy and that are not of the same class.

l For patients with preexistent hypophysitis due to iplimumab, pembrolizumab may be administered if patients are on appropriate physiologic replacement endocrine therapy.

m Ipilimumab reintroduction may be considered for select patients who did not experience significant systemic toxicity during prior ipilimumab therapy and who relapse after initial clinical response or have progression after stable disease > 3 months.

n High-dose IL should not be used in patients with inadequate organ reserve, poor performance status, or untreated or active brain metastases. IL-2 may be considered for patients with small brain metastases and without significant peritumoral edema.

o Administration of multiagent regimens and high-dose IL-2 is complex and associated with significant toxicities. Therapy should only be administered at an institution with medical staff experienced in the administration and management of these regimens.

p For tumors with activating mutations of C-KIT.

References

1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology™. Melanoma. v 1.2017. Available at: http://www.nccn.org/professionals/physician_gls/pdf/ melanoma.pdf. Accessed March 10, 2017.

2. Weber JS, D'Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16:375–384.

3. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–330.

4. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.

5. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006–2017.

6. Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16:908–918.

7. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521–2532.

8. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab- refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384:1109–1117.

9. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (Anti-PD-1) in Melanoma. N Eng J Med. 2013;369:134–144.

10. Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386:444–451.

11. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372:30–39.

12. Johnson DB, Flaherty KT, Weber JS, et al. Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAF V600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. J Clin Oncol. 2014;32:3697–3704.

13. Sanlorenzo M, Choudhry A, Vujic I, et al. Comparative profile of cutaneous adverse events: BRAF/MEK inhibitor combination therapy versus BRAF monotherapy in melanoma. J Am Acad Dermatol. 2014;71:1102–1109;e1101.

14. Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867–1876.

15. Ribas A, Gonzalez R, Pavlick A, et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. Lancet Oncol. 2014;15:954–965.

16. Pavlick AC, Ribas A, Gonzalez R, et al. Extended follow-up results of phase Ib study (BRIM7) of vemurafenib (VEM) with cobimetinib (COBI) in BRAF-mutant melanoma. J Clin Oncol. 2015;33:(suppl; abstr 9020).

17. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707–714.

18. McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;15:323–332.

19. Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAKMB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:1087–1095.

20. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358–365.

21. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13:459–465.

22. Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691–2697.

23. Hodi FS, O'Day SJ, McDermott DF, Weber RW, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Eng J Med. 2010;363:711–723.

24. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–2526.

25. Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. J Am Med Assoc. 1994;271:907–913.

26. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17:2105–2116.

27. Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000;6 Suppl 1:S11–14.

28. Smith FO, Downey SG, Klapper JA, et al. Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines. Clin Cancer Res. 2008;14:5610–5618.

29. Serrone L, Zeuli M, Sega FM, et al. Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview. J Exp Clin Cancer Res. 2000;19:21–34.

30. Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000;18:158–166.

31. Wiernik PH, Einzig AI. Taxol in malignant melanoma. J Natl Cancer Inst Monogr. 1993;15:185–187.

32. Hersh EM, O'Day SJ, Ribas A, et al. A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. Cancer. 2010;116:155–163.

33. Kottschade LA, Suman VJ, Amatruda T, et al. A phase II trial of nabpaclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma: a North Central cancer treatment group study, N057E(1). Cancer. 2011;117:1704–1710.

34. Rao RD, Holtan SG, Ingle JN, et al. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer. 2006;106:375–382.

35. Agarwala SS, Keilholz U, Hogg D, et al. Randomized phase III study of paclitaxel plus carboplatin with or without sorafenib as second-line treatment in patients with advanced melanoma. J Clin Oncol. 2007;25(18_suppl):8510.

36. Hauschild A, Agarwala SS, Trefzer U, et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009;27:2823–2830.

37. Flaherty KT, Lee SJ, Schuchter LM, et al. Final results of E2603: A double-blind, randomized phase III trial comparing carboplatin (C)/paclitaxel (P) with or without sorafenib (S) in metastatic melanoma. J Clin Oncol. 2010. 28:(suppl; abstr 8511).

38. Legha SS, Ring S, Eton O, et al. Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma. J Clin Oncol. 1998;16:1752–1759.

39. Eton O, Legha SS, Bedikian AY, et al. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol. 2002;20:2045–2052.

40. O'Day SJ, Boasberg PD, Piro L, et al. Maintenance biotherapy for metastatic melanoma with interleukin-2 and granulocyte macrophage-colony stimulating factor improves survival for patients responding to induction concurrent biochemotherapy. Clin Cancer Res. 2002;8:2775–2781.

41. Ives NJ, Stowe RL, Lorigan P, Wheatley K. Chemotherapy compared with biochemotherapy for the treatment of metastatic melanoma: a meta-analysis of 18 trials involving 2,621 patients. J Clin Oncol. 2007;25:5426–5434.

42. Atkins MB, Hsu J, Lee S, et al. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2008;26:5748–5754.

43. Flaherty LE, Othus M, Atkins MB, et al. Southwest Oncology Group S0008: a phase III trial of high-dose interferon alfa-2b versus cisplatin, vinblastine, and dacarbazine, plus interleukin-2 and interferon in patients with high-risk melanoma—an intergroup study of cancer and leukemia Group B, Children's Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. J Clin Oncol. 2014;32:3771–3778.

44. Hodi FS, Corless CL, Giobbie-Hurder A, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol. 2013;31:3182–3190.

45. Carvajal RD, Antonescu CR, Wolchok, JD, et al. KIT as a therapeutic target in metastatic melanoma. J Am Med Assoc. 2011;395:2327–2334.


Skin Cancer Drug Monographs

Melanoma And Other Skin Cancers

BAVENCIO COTELLIC DTIC-DOME
EFUDEX EFUDEX CREAM ERIVEDGE
GLEEVEC IMLYGIC INTRON A
INTRON A SOLN KEYTRUDA MEKINIST
ODOMZO OPDIVO PROLEUKIN
SYLATRON TAFINLAR YERVOY
ZELBORAF


Data provided by the Monthly Prescribing Reference (MPR) Hematology/Oncology Edition.

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