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Treatment of Melanoma

Recommendations for treatment of melanoma are summarized in the National Comprehensive Cancer Network (NCCN) guidelines.1  These provide a general guide for therapy, although recommendations for individual patients need to be tailored to the particular case.

Searching the Internet for therapeutic options can be confusing.  It is important to distinguish between therapy when all known sites of disease have been surgically excises (called “Adjuvant Therapy”) and when there is metastatic disease that cannot be surgically excised.  The drugs used in these may be quite different. 

Adjuvant Therapy

Adjuvant therapy is considered when all known sites of melanoma have been surgically excised and the patient is a high risk for recurrence.  It is a treatment that may offered in addition to surgery (therefore the name adjuvant) in an effort to provide clinical benefit.  Patients who are candidates for adjuvant therapy are those with a primary melanoma that is 4 mm or more in thickness (Stage IIB or IIC) or with involvement of regional lymph nodes (Stage IIIA, IIIB, or IIIC).  Patients with a thin primary melanoma (Stage IA, IB, or IIA) are not candidates because the prognosis for these patients is so good with surgery alone.2  This includes primary melanomas up to 2 mm in thickness with or without ulceration and up to 4 mm in thickness without ulceration.  Patients with distant metastases (Stage IV melanoma) that have been surgically excised would be candidates for adjuvant therapy because they are at high risk for recurrence, but clinical trials of adjuvant therapy in this patient population have been limited.

Following is a summary of agents that are candidates for use in adjuvant therapy of melanoma and the status as of July, 2016:

FDA-Approved

  • Intron A (IFNα, IFN alfa-2b,Interferon alfa-2b)
  • Sylatron  (Pegylated interferon, pegIFN-α2b, Peginterferon alfa -2b)
  • Yervoy (ipilimumab)

Pivotal Trials – Accrual ongoing

  • Vaccine: Polyvalent Melanoma Vaccine (POL-103A) vs placebo
  • Ipilimumab vs interferon

Intron A, Sylatron, Yervoy

The only drugs approved in the US and Canada for the postsurgical adjuvant treatment of melanoma are Intron A, Sylatron, and Yervoy.  The approval of Intron A was based on a clinical trial by the Eastern Cooperative Oncology Group (ECOG, E1684), in which patients were randomized to high-dose interferon for 1 year of therapy or observation.  Results showed improvement in progression-free and overall survival.3  In a subsequent trial by the same group (E1690), patients were randomly assigned to one of three arms: high-dose interferon, low-dose interferon, or observation.4  Results showed that there was no survival benefit in patients receiving high-dose interferon compared with those receiving low-dose interferon or observation.  Thus, this was a negative study and failed to confirm clinical benefit of high-dose interferon therapy.  In a third study by this group (E1694), patients were randomized to receive high-dose interferon or a vaccine called GMK.5  Since there was no observation only control group in this study, no conclusions can be drawn about the efficacy of the interferon treatment.  Yervoy was approved on the basis of a randomized trial in which patients were randomized to Yervoy or placebo.  Although progression-free survival was improved in the patients who received Yervoy, there were 5 treatment-related deaths in patients who received Yervoy in the adjuvant setting.  There have been numerous other studies of adjuvant therapy of patients with melanoma who are at high risk for recurrence. 6-12  

Therapy of Unresectable Metastatic Melanoma

Treatment options for patients with unresectable metastatic melanoma are changing rapidly.  Before 2011, the only drugs approved for this indication were a chemotherapy, DTIC (dacarbazine) and an immunotherapy, IL-2 (interleukin-2).  In 2011, 2 novel, first–in-kind drugs were approved, an immunotherapy, ipilimumab (Yervoy) and a small molecule B-RAF inhibitor, vemurafenib (Zelboraf).  The B-RAF inhibitor is only appropriate if the patient’s tumor harbors a mutation in the B-RAF gene, which is present in about 50% of the patients.  These treatments represent a dramatic step forward in therapeutic options and potential efficacy, but further improvement is needed.  Yervoy has a low response rate (~10%) but offers the potential for durable disease control.  Zelboraf offers a high response rate, but the responses are not durable and the disease usually recurs despite ongoing treatment.  In 2013, two additional drugs were approved for therapy of patients with tumors harboring the B-RAF mutation: dabrafenib (Tafinlar) and trametinib (Mekinist).  They were initially approved for use alone, and later for use together.  The combination is associated with a higher response rate and longer responses than therapy with Zelboraf or Tafinlar alone.  Dramatic results have been reported with immunotherapy with anti-PD1 (programmed death 1) monoclonal antibodies, pembrolizumab and nivolumab.  Pembrolizumab (Keytruda) was approved by the FDA in September, 2014 and nivolumab (Opdivo) was approved in December, 2014.  Many other drugs are being developed for therapy of unresectable metastatic melanoma and it is anticipated that one or more of these will be approved within the next few years and that there will be much new information about proper sequencing and combinations of these drugs.

References

  1. NCCN Guidelines Version 1.2013. Melanoma V.1.2013, www.nccn.org 2013: www.nccn.org.
  2. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010.
  3. Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684 [see comments]. J. Clin. Oncol. 1996;14(1):7-17.
  4. Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and Low-Dose Interferon Alfa-2b in High-Risk Melanoma: First Analysis of Intergroup Trial E1690/S9111/C9190. J. Clin. Oncol. 2000;18(12):2444-2458.
  5. Kirkwood JM, Ibrahim JG, Sosman JA, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J. Clin. Oncol. 2001;19(9):2370-2380.
  6. Cameron DA, Cornbleet MC, Mackie RM, et al. Adjuvant interferon alpha 2b in high risk melanoma - the Scottish study. Br. J. Cancer. May 4 2001;84(9):1146-1149.7.  Cascinelli N, Belli F, MacKie RM, Santinami M, Bufalino R, Morabito A. Effect of long-term adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: a randomised trial. Lancet. Sep 15 2001;358(9285):866-869.
  7. Cascinelli N, Bufalino R, Morabito A, Mackie R. Results of adjuvant interferon study in WHO melanoma programme. Lancet. Apr 9 1994;343(8902):913-914.
  8. Creagan ET, Dalton RJ, Ahmann DL, et al. Randomized, surgical adjuvant clinical trial of recombinant interferon alfa-2a in selected patients with malignant melanoma. J. Clin. Oncol. 1995;13(11):2776-2783.
  9. Eggermont AM, Suciu S, MacKie R, et al. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet. Oct 1 2005;366(9492):1189-1196.
  10. Pehamberger H, Soyer HP, Steiner A, et al. Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group [see comments]. J. Clin. Oncol. 1998;16(4):1425-1429.
  11. Punt CJA, Eggermont AMM. Adjuvant interferon-alfa for melanoma revisited: News from old and new studies. Ann. Oncol. 2001;12:1663-1666.