Advertisement

Current Oncology Reports

, 21:106 | Cite as

The Evolution of Adjuvant Therapy for Melanoma

  • Justine V. CohenEmail author
  • Elizabeth I. Buchbinder
Melanoma (RJ Sullivan, Section Editor)
  • 139 Downloads
Part of the following topical collections:
  1. Topical Collection on Melanoma

Abstract

Purpose of Review

The past decade has been a time of remarkable advancement in the field of adjuvant therapy for patients with resected high-risk melanoma. Here, we review the data for adjuvant melanoma and raise questions about the best choice of therapy for an individual patient.

Recent Findings

There have been several new adjuvant approvals including immunotherapy and targeted therapy approaches. Nivolumab is approved for patients with nodal involvement or metastatic disease after resection. Pembrolizumab is approved for patients with nodal involvement after resection. In addition, the combination of dabrafenib and trametinib is approved in patients’ nodal involvement after resection whose tumors harbor BRAFV600E/K mutations.

Summary

New therapeutic opportunities have provided promising options for patients with high-risk disease. These advances have significantly challenged the previous standard-of-care for this population of patients. Data is still forthcoming regarding durability of benefit and safety of these new treatments.

Keywords

Melanoma Adjuvant Immunotherapy BRAF 

Notes

Compliance with Ethical Standards

Conflict of Interest

Justine V. Cohen has received compensation from Sanofi-Genzyme and Bristol-Myers Squibb for service as a consultant. Elizabeth I. Buchbinder has received compensation from Bristol-Myers Squibb, Trieza Therapeutics, and Novartis for service as a consultant.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67:472–92.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Ding S, Byrd DR, et al. Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases. J Clin Oncol. 2010;28:2452–9.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    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. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1996;14:7–17.CrossRefGoogle Scholar
  5. 5.
    Mocellin S, Lens MB, Pasquali S, Pilati P, Chiarion Sileni V. Interferon alpha for the adjuvant treatment of cutaneous melanoma. Cochrane Database Syst Rev. 2013:CD008955.Google Scholar
  6. 6.
    Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst. 2010;102:493–501.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Kirkwood JM, Manola J, Ibrahim J, et al. A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res. 2004;10:1670–7.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Kirkwood JM, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernstoff MS, 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;18:2444–58.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Pectasides D, Dafni U, Bafaloukos D, Skarlos D, Polyzos A, Tsoutsos D, et al. Randomized phase III study of 1 month versus 1 year of adjuvant high-dose interferon alfa-2b in patients with resected high-risk melanoma. J Clin Oncol. 2009;27:939–44.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Eggermont AM, Suciu S, Testori A, Santinami M, Kruit WH, Marsden J, et al. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol. 2012;30:3810–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Coit DG, Andtbacka R, Anker CJ, Bichakjian CK, Carson WE 3rd, Daud A, et al. Melanoma. J Natl Compr Cancer Netw. 2012;10:366–400.CrossRefGoogle Scholar
  12. 12.
    Cole BF, Gelber RD, Kirkwood JM, Goldhirsch A, Barylak E, Borden E. Quality-of-life-adjusted survival analysis of interferon alfa-2b adjuvant treatment of high-risk resected cutaneous melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol. 1996;14:2666–73.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Kilbridge KL, Weeks JC, Sober AJ, Haluska FG, Slingluff CL, Atkins MB, et al. Patient preferences for adjuvant interferon alfa-2b treatment. J Clin Oncol. 2001;19:812–23.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16:522–30.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375:1845–55.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    • Eggermont AMM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial. Eur J Cancer. 2019;119:1–10 Long-term follow-up results from the phase III EORTC 18071 trial of adjuvant ipilimumab 10 mg/kg versus placebo. This 5-year follow-up showed sustained improvement in RFS, distant metastasis free survival and OS. PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Coens C, Suciu S, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, et al. Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol. 2017;18:393–403.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Tarhini AA, Lee SJ, Hodi FS, et al. A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma (U.S. Intergroup E1609): preliminary safety and efficacy of the ipilimumab arms. J Clin Oncol. 2017;35:9500.CrossRefGoogle Scholar
  19. 19.
    Tarhini AA, Lee SJ, Hodi FS, et al. United States Intergroup E1609: A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon-α2b for resected high-risk melanoma. J Clin Oncol. 2019;37:9504.CrossRefGoogle Scholar
  20. 20.
    Mangana J, Dimitriou F, Braun R, Ludwig S, Dummer R, Barysch MJ. Single-center real-life experience with low-dose ipilimumab monotherapy in adjuvant setting for patients with stage III melanoma. Melanoma Res. 2019;29(6):648–54.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    •• Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377:1824–35 This phase III trial (CheckMate 238) randomized patients with resected melanoma to adjuvant nivolumab vs ipilimumab. Patients who received nivolumab had improved RFS and fewer immune-related adverse effects. PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521–32.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    •• Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378:1789–801 This phase III trial (EORTC 1325; Keynote 054) randomized patients with resected melanoma to adjuvant pembrolizumab vs placebo. Patients who received pembrolizumab had prolonged RFS. PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Maio M, Lewis K, Demidov L, Mandalà M, Bondarenko I, Ascierto PA, et al. Adjuvant vemurafenib in resected, BRAF(V600) mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. 2018;19:510–20.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    •• Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377:1813–23 This phase III trial (COMBI-AD) randomized patients with resected BRAF V600E/K mutated melanoma to dabrafenib and trametinib vs two matched placebos. Patients who received the targeted therapy combination had an improved RFS and distant metastases-free survival. PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Hauschild A, Dummer R, Schadendorf D, et al. Longer follow-up confirms relapse-free survival benefit with adjuvant dabrafenib plus trametinib in patients with resected BRAF V600-mutant stage III melanoma. J Clin Oncol. 2018:JCO1801219.Google Scholar
  28. 28.
    Larkin JMG, Hauschild A, Santinami M, et al. Dabrafenib plus trametinib (D + T) as adjuvant treatment of resected BRAF-mutant stage III melanoma: findings from the COMBI-AD trial analyzed based on AJCC 8 classification. J Clin Oncol. 2018;36:9591.CrossRefGoogle Scholar
  29. 29.
    Schadendorf D, Hauschild A, Santinami M, et al. Effect on health-related quality of life (HRQOL) of adjuvant treatment (tx) with dabrafenib plus trametinib (D + T) in patients (pts) with resected stage III BRAF-mutant melanoma. J Clin Oncol. 2018;36:9590.CrossRefGoogle Scholar
  30. 30.
    Gerbasi ME, Stellato D, Ghate SR, et al. Cost-effectiveness of dabrafenib and trametinib in combination as adjuvant treatment of BRAF V600E/K mutation-positive melanoma from a US healthcare payer perspective. J Med Econ. 2019:1–10.Google Scholar
  31. 31.
    Goldstein DA. Adjuvant ipilimumab for melanoma-the $1.8 million per patient regimen. JAMA Oncol. 2017;3:1628–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Freeman ML, Shoushtari AN, Betts KA, et al. Assessing the value of nivolumab (NIVO) versus placebo (PBO) and ipilimumab (IPI) as adjuvant therapy for resected melanoma. J Clin Oncol. 2018;36:9594.CrossRefGoogle Scholar
  33. 33.
    Momtaz P, Harding JJ, Ariyan C, Coit DG, Merghoub T, Gasmi B, et al. Four-month course of adjuvant dabrafenib in patients with surgically resected stage IIIC melanoma characterized by a BRAFV600E/K mutation. Oncotarget. 2017;8:105000–10.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Hindie E. What is the role of dabrafenib plus trametinib adjuvant therapy in stage IIIA melanoma? J Clin Oncol. 2019;37:1355–6.PubMedCrossRefGoogle Scholar
  35. 35.
    • Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med. 2017;376:2211–22 The MSLT2 trial presented data showing completion lymph node dissections improves local control and guides prognostication however does not increase survival in patients with sentinel lymph node metastases from melanoma. PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Rapisuwon S, Patel SP, Carvajal RD, et al. Phase II single-arm multicenter study of adjuvant ipilimumab in combination with nivolumab in subjects with high-risk ocular melanoma. J Clin Oncol. 2019;37:TPS9604-TPS.CrossRefGoogle Scholar
  37. 37.
    Constantinou M, Vezeridis MP, Weinstock MA, et al. BrUOG 324: Adjuvant nivolumab and low-dose ipilimumab for stage IIC, III, and resected stage IV melanoma: a phase II Brown University Oncology Research Group trial. J Clin Oncol. 2018;36:TPS202-TPS.CrossRefGoogle Scholar
  38. 38.
    Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124–8.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Ribas A. Adaptive immune resistance: how cancer protects from immune attack. Cancer Discov. 2015;5:915–9.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Tarhini AA, Zahoor H, Yearley JH, et al. Tumor associated PD-L1 expression pattern in microscopically tumor positive sentinel lymph nodes in patients with melanoma. J Transl Med. 2015;13:319.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Jacquelot N, Roberti MP, Enot DP, et al. Predictors of responses to immune checkpoint blockade in advanced melanoma. Nat Commun. 2017;8:592.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Jacquelot N, Roberti MP, Enot DP, et al. Immunophenotyping of stage III melanoma reveals parameters associated with patient prognosis. J Invest Dermatol. 2016;136:994–1001.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Davis JL, Langan RC, Panageas KS, Zheng J, Postow MA, Brady MS, et al. Elevated blood neutrophil-to-lymphocyte ratio: a readily available biomarker associated with death due to disease in high risk nonmetastatic melanoma. Ann Surg Oncol. 2017;24:1989–96.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Lee RJ, Gremel G, Marshall A, et al. Circulating tumor DNA predicts survival in patients with resected high risk stage II/III melanoma. Ann Oncol. 2018 Feb 1;29(2):490–496.PubMedCentralCrossRefGoogle Scholar
  45. 45.
    Corrie P, Marshall A, Lorigan P, et al. Adjuvant bevacizumab as treatment for melanoma patients at high risk of recurrence: final results for the AVAST-M trial. J Clin Oncol. 2017;35:9501.CrossRefGoogle Scholar
  46. 46.
    Corrie PG, Marshall A, Dunn JA, et al. Adjuvant bevacizumab in patients with melanoma at high risk of recurrence (AVAST-M): preplanned interim results from a multicentre, open-label, randomised controlled phase 3 study. Lancet Oncol. 2014;15:620–30.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Long GV, Eroglu Z, Infante J, Patel S, Daud A, Johnson DB, et al. Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma who received dabrafenib combined with trametinib. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2018;36:667–73.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Pennsylvania HospitalUniversity of Pennsylvania Abramson Cancer CenterPhiladelphiaUSA
  2. 2.Dana Farber Cancer InstituteBostonUSA

Personalised recommendations