Assessment of Efficacy of Systemic Therapy in Patients with Metastatic Melanoma

  • Philip FriedlanderEmail author
  • William Simpson
  • Cora Cajulis


The prognosis of patients with stage IV melanoma is improving through the use of molecularly targeted therapy that inhibits the activity of the BRAF protein and the use of immunotherapies that block regulatory checkpoints. Interval performance of imaging studies is needed to determine treatment efficacy. Traditionally, enlargement of a metastasis or the development of new lesions would signify tumor progression and insufficient treatment efficacy. Immunotherapy can cause immune cells to infiltrate tumors leading to initial enlargement of metastases on imaging termed pseudo-progression. This chapter reviews advances in systemic treatment of metastatic melanoma and novel strategies to monitor for efficacy in the context of immunotherapy and molecularly targeted therapy.


Melanoma BRAF Immunotherapy PD-1 CTLA-4 


  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30.CrossRefGoogle Scholar
  2. 2.
    Gershenwald JE, 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(6):472–92.CrossRefGoogle Scholar
  3. 3.
    Morton DL, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599–609.CrossRefGoogle Scholar
  4. 4.
    Chapman PB, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999;17(9):2745–51.CrossRefGoogle Scholar
  5. 5.
    Atkins MB, et al. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000;6(Suppl 1):S11–4.PubMedGoogle Scholar
  6. 6.
    Hodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.CrossRefGoogle Scholar
  7. 7.
    Schadendorf D, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015;33(17):1889–94.CrossRefGoogle Scholar
  8. 8.
    Hamid O, et al. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol. 2019;30:582–8.CrossRefGoogle Scholar
  9. 9.
    Schachter J, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017;390(10,105):1853–62.CrossRefGoogle Scholar
  10. 10.
    Topalian SL, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.CrossRefGoogle Scholar
  11. 11.
    Larkin J, et al. Overall survival in patients with advanced melanoma who received nivolumab versus investigator’s choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018;36(4):383–90.CrossRefGoogle Scholar
  12. 12.
    Weber JS, 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(4):375–84.CrossRefGoogle Scholar
  13. 13.
    Ascierto PA, et al. Survival outcomes in patients with previously untreated BRAF wild-type advanced melanoma treated with nivolumab therapy: three-year follow-up of a randomized phase 3 trial. JAMA Oncol. 2018;
  14. 14.
    Hodi FS, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19(11):1480–92.CrossRefGoogle Scholar
  15. 15.
    Hu JC, et al. A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. Clin Cancer Res. 2006;12(22):6737–47.CrossRefGoogle Scholar
  16. 16.
    Andtbacka RH, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33(25):2780–8.CrossRefGoogle Scholar
  17. 17.
    Covington MF, et al. FDG-PET/CT for monitoring response of melanoma to the novel oncolytic viral therapy talimogene laherparepvec. Clin Nucl Med. 2017;42(2):114–5.CrossRefGoogle Scholar
  18. 18.
    Solus JF, Kraft S. Ras, Raf, and MAP kinase in melanoma. Adv Anat Pathol. 2013;20(4):217–26.CrossRefGoogle Scholar
  19. 19.
    Davies H, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54.CrossRefGoogle Scholar
  20. 20.
    Wan PT, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116(6):855–67.CrossRefGoogle Scholar
  21. 21.
    Sondergaard JN, et al. Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032. J Transl Med. 2010;8:39.CrossRefGoogle Scholar
  22. 22.
    Flaherty KT, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809–19.CrossRefGoogle Scholar
  23. 23.
    Chapman PB, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.CrossRefGoogle Scholar
  24. 24.
    McArthur GA, 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(3):323–32.CrossRefGoogle Scholar
  25. 25.
    Hauschild A, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358–65.CrossRefGoogle Scholar
  26. 26.
    Ascierto PA, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17(9):1248–60.CrossRefGoogle Scholar
  27. 27.
    Dummer R, et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19(10):1315–27.CrossRefGoogle Scholar
  28. 28.
    Schadendorf D, et al. Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials. Eur J Cancer. 2017;82:45–55.CrossRefGoogle Scholar
  29. 29.
    Simard JL, Smith M, Chandra S. Pseudoprogression of Melanoma Brain Metastases. Curr Oncol Rep. 2018;20(11):91.CrossRefGoogle Scholar
  30. 30.
    Zamora C, et al. Imaging manifestations of pseudoprogression in metastatic melanoma nodes injected with talimogene laherparepvec: initial experience. AJNR Am J Neuroradiol. 2017;38(6):1218–22.CrossRefGoogle Scholar
  31. 31.
    Litiere S, et al. RECIST—learning from the past to build the future. Nat Rev Clin Oncol. 2017;14(3):187–92.CrossRefGoogle Scholar
  32. 32.
    Nishino M, et al. Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements. Clin Cancer Res. 2013;19(14):3936–43.CrossRefGoogle Scholar
  33. 33.
    Seymour L, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):e143–52.CrossRefGoogle Scholar
  34. 34.
    Wolchok JD, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23):7412–20.CrossRefGoogle Scholar
  35. 35.
    Hodi FS, et al. Immune-modified response evaluation criteria in solid tumors (imRECIST): refining guidelines to assess the clinical benefit of cancer immunotherapy. J Clin Oncol. 2018;36(9):850–8.CrossRefGoogle Scholar
  36. 36.
    Hodi FS, et al. Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab. J Clin Oncol. 2016;34(13):1510–7.CrossRefGoogle Scholar
  37. 37.
    Ito K, et al. F-18 FDG PET/CT for monitoring of ipilimumab therapy in patients with metastatic melanoma. J Nucl Med. 2019;60:335–41.CrossRefGoogle Scholar
  38. 38.
    Sachpekidis C, et al. Predictive value of early 18F-FDG PET/CT studies for treatment response evaluation to ipilimumab in metastatic melanoma: preliminary results of an ongoing study. Eur J Nucl Med Mol Imaging. 2015;42(3):386–96.CrossRefGoogle Scholar
  39. 39.
    Cho SY, et al. Prediction of response to immune checkpoint inhibitor therapy using early-time-point (18)F-FDG PET/CT imaging in patients with advanced melanoma. J Nucl Med. 2017;58(9):1421–8.CrossRefGoogle Scholar
  40. 40.
    Perng P, Marcus C, Subramaniam RM. (18)F-FDG PET/CT and melanoma: staging, immune modulation and mutation-targeted therapy assessment, and prognosis. AJR Am J Roentgenol. 2015;205(2):259–70.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Philip Friedlander
    • 1
    Email author
  • William Simpson
    • 2
  • Cora Cajulis
    • 3
  1. 1.Division of Hematology and Medical OncologyTisch Cancer Institute, Icahn School of Medicine, Mount Sinai HospitalNew YorkUSA
  2. 2.Department of RadiologyThe Mount Sinai HospitalNew YorkUSA
  3. 3.The Mount Sinai HospitalNew YorkUSA

Personalised recommendations