Advertisement

International Journal of Clinical Oncology

, Volume 24, Issue 12, pp 1508–1514 | Cite as

Recent advances in therapeutic strategies for unresectable or metastatic melanoma and real-world data in Japan

  • Hisashi UharaEmail author
Invited Review Article

Abstract

New therapeutic strategies including immunotherapy and selective molecular target inhibitors have brought about a new era in the treatment of patients with advanced melanoma. In Japan, the immune checkpoint inhibitors ipilimumab, nivolumab and pembrolizumab, the BRAF inhibitor (BRAFi) vemurafenib, dabrafenib and MEK inhibitor (MEKi) trametinib have been available for the treatment of unresectable and metastatic melanoma. The BRAFi + MEKi combination shows high response rates (60–70%) and rapid response induction associated with symptom control, with a progression-free survival of 12 months. Nivolumab and pembrolizumab offer moderate response rates (30–40%) and long survival (3- to 5-year survival: 30–50%). In Japan, treatment options for the first-line setting frequently include nivolumab or pembrolizumab monotherapy and BRAFi + MEKi combinations (for patients with BRAF-mutant melanoma). Ipilimumab is included in the second-line setting, and the nivolumab + ipilimumab combination has not been approved yet in Japan. Although these medications have demonstrated impressive efficacy, the clinical trials and real-world data have shown that the clinical benefit is not fully satisfactory. We have to carefully manage a new class of adverse events due to these medicines. Moreover, biomarkers are emerging with which we can identify a population that would experience more benefits without severe adverse events.

Keywords

Melanoma Japan Immune checkpoint inhibitors BRAF inhibitors MEK inhibitors Biomarker 

Notes

Acknowledgements

This work was partially supported by JSPS KAKENHI Grant Number JP16K10150.

Compliance with ethical standards

Conflict of interest

Funds and Grant for research: ONO PHARMACEUTICAL CO., LTD, Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd. Novartis, MSD, TAIHO Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Kyowa Hakko Kirin Company, Limited, Mitsubishi Tanabe Pharma Corporation, Esai, AbbVie, Maruho, DAIICHI SANKYO COMPANY, LIMITED, Tsumura, Porafarma, Mochida, Nihonkayaku, Acterion, Torii, KAKEN PHARMACEUTICAL CO., LTD. Consultancy fee: ONO PHARMACEUTICAL CO., LTD, Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd. Novartis, MSD, Kyowa Hakko Kirin Company, Limited: Fee for speaking. ONO PHARMACEUTICAL CO., LTD, Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd. Novartis, MSD, TAIHO Pharmaceutical Co., Ltd. Porafarma, Mitsubishi Tanabe Pharma Corporation, Maruho.

References

  1. 1.
    Mangana J, Cheng PF, Kaufmann C et al (2017) Multicenter, real-life experience with checkpoint inhibitors and targeted therapy agents in advanced melanoma patients in Switzerland. Melanoma Res 27(4):358–368PubMedPubMedCentralGoogle Scholar
  2. 2.
    CANCER STATISTICS IN JAPAN '16. Cancer information service NCC, Japan. https://ganjoho.jp/en/professional/statistics/brochure/2016_en.html
  3. 3.
    Nishi M (2016) Epidemiology of skin cancer in Japan. J Tumor 4(2):369–373Google Scholar
  4. 4.
    Fujisawa Y, Fujimoto M (2014) Statistics for malignant melanoma in Japan: a nation wide survey from 2005 to 2013. Skin Cancer 29(2):189–194Google Scholar
  5. 5.
    Curtin JA, Fridlyand J, Kageshita T et al (2005) Distinct sets of genetic alterations in melanoma. N Engl J Med 353(20):2135–2147PubMedGoogle Scholar
  6. 6.
    Menzies AM, Haydu LE, Visintin L et al (2012) Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res 18(12):3242–3249PubMedGoogle Scholar
  7. 7.
    Jiveskog S, Ragnarsson-Olding B, Platz A et al (1998) N-ras mutations are common in melanomas from sun-exposed skin of humans but rare in mucosal membranes or unexposed skin. J Investig Dermatol 111(5):757–761PubMedGoogle Scholar
  8. 8.
    Curtin JA, Busam K, Pinkel D et al (2006) Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 24(26):4340–4346PubMedGoogle Scholar
  9. 9.
    Cancer Genome Atlas Network (2015) Genomic classification of cutaneous melanoma. Cell 161(7):1681–1696Google Scholar
  10. 10.
    Sakaizawa K, Ashida A, Uchiyama A et al (2015) Clinical characteristics associated with BRAF, NRAS and KIT mutations in Japanese melanoma patients. J Dermatol Sci 80(1):33–37PubMedGoogle Scholar
  11. 11.
    Uhara H, Ashida A, Koga H et al (2014) NRAS mutations in primary and metastatic melanomas of Japanese patients. Int J Clin Oncol 19(3):544–548PubMedGoogle Scholar
  12. 12.
    Flaherty KT, Infante JR, Daud A et al (2012) Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367(18):1694–1703PubMedPubMedCentralGoogle Scholar
  13. 13.
    Long GV, Stroyakovskiy D, Gogas H et al (2015) Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 386(9992):444–451PubMedGoogle Scholar
  14. 14.
    Long GV, Eroglu Z, Infante J et al (2017) Long-Term outcomes in patients with BRAF V600-mutant metastatic melanoma who received dabrafenib combined with trametinib. J Clin Oncol 2017:JCO2017741025Google Scholar
  15. 15.
    Uhara H, Kiyohara Y, Tsuda A et al (2018) Characteristics of adverse drug reactions in a vemurafenib early post-marketing phase vigilance study in Japan. Clin Transl Oncol 20(1):169–175PubMedGoogle Scholar
  16. 16.
    Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723PubMedPubMedCentralGoogle Scholar
  17. 17.
    Robert C, Thomas L, Bondarenko I et al (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364(26):2517–2526PubMedGoogle Scholar
  18. 18.
    Schadendorf D, Hodi FS, Robert C et al (2015) Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 33(17):1889–1894PubMedPubMedCentralGoogle Scholar
  19. 19.
    Bertrand A, Kostine M, Barnetche T et al (2015) Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med 13:211PubMedPubMedCentralGoogle Scholar
  20. 20.
    Fujisawa Y, Yoshino K, Otsuka A et al. (2018) Retrospective study of advanced melanoma patients treated with ipilimumab after nivolumab: Analysis of 60 Japanese patients. J Dermatol Sci 89(1):60–66PubMedGoogle Scholar
  21. 21.
    Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454PubMedPubMedCentralGoogle Scholar
  22. 22.
    Topalian SL, Sznol M, McDermott DF et al (2014) Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 32(10):1020–1030PubMedPubMedCentralGoogle Scholar
  23. 23.
    Robert C, Ribas A, Wolchok JD et al (2014) Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 384(9948):1109–1117PubMedGoogle Scholar
  24. 24.
    Larkin J, Chiarion-Sileni V, Gonzalez R et al (2015) Combined nivolumab and ipilimumab or monotherapy in untreated Melanoma. N Engl J Med 373(1):23–34PubMedPubMedCentralGoogle Scholar
  25. 25.
    Robert C, Schachter J, Long GV et al (2015) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372(26):2521–2532PubMedGoogle Scholar
  26. 26.
    Khoja L, Day D, Wei-Wu Chen T et al (2017) Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review. Ann Oncol 28(10):2377–2385PubMedGoogle Scholar
  27. 27.
    Hughes J, Vudattu N, Sznol M et al (2015) Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy. Diabetes Care 38(4):e55–e57PubMedPubMedCentralGoogle Scholar
  28. 28.
    Shirai T, Sano T, Kamijo F et al (2016) Acetylcholine receptor binding antibody-associated myasthenia gravis and rhabdomyolysis induced by nivolumab in a patient with melanoma. Jpn J Clin Oncol 46(1):86–88PubMedGoogle Scholar
  29. 29.
    Suzuki S, Ishikawa N, Konoeda F et al (2017) Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan. Neurology 89(11):1127–1134PubMedGoogle Scholar
  30. 30.
    Weber JS, D’Angelo SP, Minor D et al (2015) 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 16(4):375–384PubMedGoogle Scholar
  31. 31.
    Kanameishi S, Otsuka A, Nonomura Y et al (2016) Idiopathic thrombocytopenic purpura induced by nivolumab in a metastatic melanoma patient with elevated PD-1 expression on B cells. Ann Oncol 27(3):546–547PubMedGoogle Scholar
  32. 32.
    Wolchok JD, Chiarion-Sileni V, Gonzalez R et al (2017) Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 377(14):1345–1356PubMedPubMedCentralGoogle Scholar
  33. 33.
    Hayward NK, Wilmott JS, Waddell N et al (2017) Whole-genome landscapes of major melanoma subtypes. Nature 545(7653):175–180PubMedGoogle Scholar
  34. 34.
    Long GV, Grob JJ, Nathan P et al (2016) Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol 17(12):1743–1754PubMedGoogle Scholar
  35. 35.
    Davies MA, Saiag P, Robert C et al (2017) Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 18(7):863–873PubMedPubMedCentralGoogle Scholar
  36. 36.
    Long GV AV, Menzies AM et al (2017) Randomized phase II study of nivolumab (nivo) or nivo plus ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets): anti-PD-1 brain collaboration (ABC). Presented at: 2017 World Congress of Melanoma; October 18–21, 2017; Brisbane, Australia 2017;SMR09-6Google Scholar
  37. 37.
    Ahmed KA, Stallworth DG, Kim Y et al (2016) Clinical outcomes of melanoma brain metastases treated with stereotactic radiation and anti-PD-1 therapy. Ann Oncol 27(3):434–441PubMedGoogle Scholar
  38. 38.
    Eggermont AM, Chiarion-Sileni V, Grob JJ et al (2015) Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 16(5):522–530PubMedGoogle Scholar
  39. 39.
    Weber J, Mandala M, Del Vecchio M et al (2017) Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 377(19):1824–1835PubMedPubMedCentralGoogle Scholar
  40. 40.
    Long GV, Hauschild A, Santinami M et al (2017) Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med 377(19):1813–1823PubMedGoogle Scholar
  41. 41.
    Watanabe D, Goshima F, Mori I et al (2008) Oncolytic virotherapy for malignant melanoma with herpes simplex virus type 1 mutant HF10. J Dermatol Sci 50(3):185–196PubMedGoogle Scholar
  42. 42.
    Chesney J, Puzanov I, Collichio F et al (2017) Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma. J Clin Oncol 2017:JCO2017737379Google Scholar
  43. 43.
    Long GV, Flaherty KT, Stroyakovskiy D et al (2017) Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol 28(7):1631–1639PubMedPubMedCentralGoogle Scholar
  44. 44.
    Sakaizawa K, Goto Y, Kiniwa Y et al (2012) Mutation analysis of BRAF and KIT in circulating melanoma cells at the single cell level. Br J Cancer 106(5):939–946PubMedPubMedCentralGoogle Scholar
  45. 45.
    Ashida A, Sakaizawa K, Mikoshiba A et al (2016) Quantitative analysis of the BRAF V600E mutation in circulating tumor-derived DNA in melanoma patients using competitive allele-specific TaqMan PCR. Int J Clin Oncol 21(5):981–988PubMedGoogle Scholar
  46. 46.
    Manson G, Norwood J, Marabelle A et al (2016) Biomarkers associated with checkpoint inhibitors. Ann Oncol 27(7):1199–1206PubMedGoogle Scholar
  47. 47.
    Van Allen EM, Miao D, Schilling B et al (2015) Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350(6257):207–211PubMedPubMedCentralGoogle Scholar
  48. 48.
    Inoue H, Park JH, Kiyotani K et al (2016) Intratumoral expression levels of PD-L1, GZMA, and HLA-A along with oligoclonal T cell expansion associate with response to nivolumab in metastatic melanoma. Oncoimmunology 5(9):e1204507PubMedPubMedCentralGoogle Scholar
  49. 49.
    Fujisawa Y, Yoshino K, Otsuka A et al (2017) Fluctuations in routine blood count might signal severe immune-related adverse events in melanoma patients treated with nivolumab. J Dermatol Sci 88(2):225–231PubMedGoogle Scholar
  50. 50.
    Nakamura Y, Kitano S, Takahashi A et al (2016) Nivolumab for advanced melanoma: pretreatment prognostic factors and early outcome markers during therapy. Oncotarget 7(47):77404–77415PubMedPubMedCentralGoogle Scholar
  51. 51.
    Freeman-Keller M, Kim Y, Cronin H et al (2016) Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res 22(84):886–894PubMedGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2018

Authors and Affiliations

  1. 1.Department of DermatologySapporo Medical University School of MedicineSapporoJapan

Personalised recommendations