Melanoma and Immune Checkpoint Inhibitors

  • Masutaka Furue
  • Takamichi Ito
  • Naoko Wada
  • Maiko Wada
  • Takafumi Kadono
  • Hiroshi Uchi
Melanoma (RJ Sullivan, Section Editor)
  • 314 Downloads
Part of the following topical collections:
  1. Topical Collection on Melanoma

Abstract

Purpose of Review

Prognosis of patients with advanced melanoma is dismal with a median overall survival of about 8 months and 5-year overall survival from a diagnosis of metastatic disease of roughly 10%. However, immune checkpoint inhibitors have brought indispensable benefits to melanoma patients. Here we will review the recent clinical efficacy and adverse events of immune checkpoint inhibitors for melanoma patients.

Recent Findings

The immune checkpoint inhibitors increase confirmed objective response and prolong progression-free and overall survival of the afflicted patients in association with maintaining their quality of life. Although diverse immune-related adverse events occur, most of them are manageable by appropriate immunomodulating agents. Clinical efficacy of immune checkpoint inhibitors continues even after discontinuation of drugs.

Summary

Compared with conventional therapeutic options, the immune checkpoint inhibitors appear to prolong the survival of patients with advanced melanoma. Further clinical trials are warranted to determine whether their combinatory use with other treatment options may augment benefits or not.

Keywords

Melanoma Immune checkpoint inhibitors Ipilimumab Nivolumab Pembrolizumab 

Notes

Compliance with Ethical Standards

Conflict of Interest

Masutaka Furue, Takamichi Ito, Naoko Wada, Maiko Wada, Takafumi Kadono, and Hiroshi Uchi declare they have no conflict of interest.

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

  1. 1.
    Ernst DS, Petrella T, Joshua AM, Hamou A, Thabane M, Vantyghem S, et al. Burden of illness for metastatic melanoma in Canada, 2011-2013. Curr Oncol. 2016;23(6):e563–e70.  https://doi.org/10.3747/co.23.3161.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Gwadry-Sridhar F, Nikan S, Hamou A, Seung SJ, Petrella T, Joshua AM, et al. Resource utilization and costs of managing patients with advanced melanoma: a Canadian population-based study. Curr Oncol. 2017;24(3):168–75.  https://doi.org/10.3747/co.24.3432.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Szczepaniak Sloane RA, Gopalakrishnan V, Reddy SM, Zhang X, Reuben A, Wargo JA. Interaction of molecular alterations with immune response in melanoma. Cancer. 2017;123(S11):2130–42.  https://doi.org/10.1002/cncr.30681.CrossRefPubMedGoogle Scholar
  4. 4.
    World Health Organization, International Agency on Cancer Research (iarc). GLOBOCAN 2008: Cancer incidence and mortality worldwide in 2008 [Web resource]. Lyon, France: iarc: 2008. [Current version (2012) available online at: http://globocan.iarc.fr/Default.aspx; cited 5 Mar 2016].
  5. 5.
    Garbe C, Eigentler TK, Keilholz U, Hauschild A, Kirkwood JM. Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist. 2011;16(1):5–24.  https://doi.org/10.1634/theoncologist.2010-0190.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Farnetani F, Scope A, Coco V, Guida S, Cesinaro AM, Piana S, et al. Paradigmatic cases of pigmented lesions: how to not miss melanoma. J Dermatol. 2016;43(12):1433–7.  https://doi.org/10.1111/1346-8138.13522.CrossRefPubMedGoogle Scholar
  7. 7.
    Yamamura K, Otsuka A, Kaku Y, Seidel JA, Nomura M, Nagai H, et al. Dermoscopic changes in malignant melanoma after successful treatment with nivolumab: a case report. J Dermatol. 2017;44(5):547–8.  https://doi.org/10.1111/1346-8138.13501.CrossRefPubMedGoogle Scholar
  8. 8.
    Woltsche N, Schmid-Zalaudek K, Deinlein T, Rammel K, Hofmann-Wellenhof R, Zalaudek I. Abundance of the benign melanocytic universe: dermoscopic-histopathological correlation in nevi. J Dermatol. 2017;44(5):499–506.  https://doi.org/10.1111/1346-8138.13808.CrossRefPubMedGoogle Scholar
  9. 9.
    Sakai H, Ando Y, Ikinaga K, Tanaka M. Estimating melanin location in the pigmented skin lesions by hue-saturation-lightness color space values of dermoscopic images. J Dermatol. 2017;44(5):490–8.  https://doi.org/10.1111/1346-8138.13725.CrossRefPubMedGoogle Scholar
  10. 10.
    Russo T, Piccolo V, Ferrara G, Agozzino M, Alfano R, Longo C, et al. Dermoscopy pathology correlation in melanoma. J Dermatol. 2017;44(5):507–14.  https://doi.org/10.1111/1346-8138.13629.CrossRefPubMedGoogle Scholar
  11. 11.
    Floristán Muruzábal U, Gamo Villegas R, Pampín Franco A, Pinedo Moraleda F, Pérez Fernández E, López-Estebaranz JL. Combined in vivo reflectance confocal microscopy and digital dermoscopy for follow up of patients at high risk of malignant melanoma: a prospective case series study. J Dermatol. 2017;44(6):681–9.  https://doi.org/10.1111/1346-8138.13743.CrossRefPubMedGoogle Scholar
  12. 12.
    Asahara M, Hoashi T, Shirakawa N, Matano Y, Funasaka Y, Saeki H. Case of nodular melanoma on the upper eyelid dermoscopically mimicking pigmented basal cell carcinoma. J Dermatol. 2017;44(5):543–5.  https://doi.org/10.1111/1346-8138.13615.CrossRefPubMedGoogle Scholar
  13. 13.
    Wada M, Ito T, Tsuji G, Nakahara T, Hagihara A, Furue M, et al. Acral lentiginous melanoma versus other melanoma: a single-center analysis in Japan. J Dermatol. 2017;44(8):932–8.  https://doi.org/10.1111/1346-8138.13834.CrossRefPubMedGoogle Scholar
  14. 14.
    Hoashi T, Funasaka Y, Shirakawa N, Matano Y, Ansai SI, Saeki H. Case of subungual malignant melanoma showing the subtle clinical features and unexpected typical histopathological findings of melanoma in situ. J Dermatol. 2016;43(11):1361–2.  https://doi.org/10.1111/1346-8138.13391.CrossRefPubMedGoogle Scholar
  15. 15.
    Shoushtari AN, Munhoz RR, Kuk D, Ott PA, Johnson DB, Tsai KK, et al. The efficacy of anti-PD-1 agents in acral and mucosal melanoma. Cancer. 2016;122(21):3354–62.  https://doi.org/10.1002/cncr.30259.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Furue M, Kadono T. Melanoma therapy: check the checkpoints. J Dermatol. 2016;43(2):121–4.  https://doi.org/10.1111/1346-8138.13257.CrossRefPubMedGoogle Scholar
  17. 17.
    Achkar T, Tarhini AA. The use of immunotherapy in the treatment of melanoma. J Hematol Oncol. 2017;10(1):88.  https://doi.org/10.1186/s13045-017-0458-3.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Yamazaki N, Uhara H, Wada H, Matsuda K, Yamamoto K, Shimamoto T, et al. Phase I study of pegylated interferon-alpha-2b as an adjuvant therapy in Japanese patients with malignant melanoma. J Dermatol. 2016;43(10):1146–53.  https://doi.org/10.1111/1346-8138.13338.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Rivas-Tolosa N, Ortiz-Brugués A, Toledo-Pastrana T, Baradad M, Traves V, Soriano V, et al. Local cryosurgery and imiquimod: a successful combination for the treatment of locoregional cutaneous metastasis of melanoma: a case series. J Dermatol. 2016;43(5):553–6.  https://doi.org/10.1111/1346-8138.13197.CrossRefPubMedGoogle Scholar
  20. 20.
    Shain AH, Yeh I, Kovalyshyn I, Sriharan A, Talevich E, Gagnon A, et al. The genetic evolution of melanoma from precursor lesions. N Engl J Med. 2015;373(20):1926–36.  https://doi.org/10.1056/NEJMoa1502583.CrossRefPubMedGoogle Scholar
  21. 21.
    Tokuzumi A, Fukushima S, Miyashita A, Nakahara S, Kubo Y, Yamashita J, et al. Cell division cycle-associated protein 1 as a new melanoma-associated antigen. J Dermatol. 2016;43(12):1399–405.  https://doi.org/10.1111/1346-8138.13436.CrossRefPubMedGoogle Scholar
  22. 22.
    Umemura H, Yamasaki O, Kaji T, Otsuka M, Asagoe K, Takata M, et al. Usefulness of serum 5-S-cysteinyl-dopa as a biomarker for predicting prognosis and detecting relapse in patients with advanced stage malignant melanoma. J Dermatol. 2017;44(4):449–54.  https://doi.org/10.1111/1346-8138.13651.CrossRefPubMedGoogle Scholar
  23. 23.
    Mori M, Funakoshi T, Kameyama K, Kawakami Y, Sato E, Nakayama E, et al. Lack of XAGE-1b and NY-ESO-1 in metastatic lymph nodes may predict the potential survival of stage III melanoma patients. J Dermatol. 2017;44(6):671–80.  https://doi.org/10.1111/1346-8138.13730.CrossRefPubMedGoogle Scholar
  24. 24.
    Fukumoto T, Sakaguchi M, Oka M, Nishimura M, Mukohara T, Nishigori C. Malignant melanoma with bone marrow involvement diagnosed from hypercalcemia: development of a neural cell adhesion molecule stain. J Dermatol. 2017;44(5):e105–e6.  https://doi.org/10.1111/1346-8138.13718.CrossRefPubMedGoogle Scholar
  25. 25.
    Volpe VO, Klufas DM, Hegde U, Grant-Kels JM. The new paradigm of systemic therapies for metastatic melanoma. J Am Acad Dermatol. 2017;77(2):356–68.  https://doi.org/10.1016/j.jaad.2017.04.1126.CrossRefPubMedGoogle Scholar
  26. 26.
    Furudate S, Fujimura T, Kambayashi Y, Hidaka T, Sato Y, Tanita K, et al. Keratoacanthoma, palmoplantar keratoderma developing in an advanced melanoma patient treated with vemurafenib regressed by blockade of mitogen-activated protein kinase kinase signaling. J Dermatol. 2017;44(9):e226–e7.  https://doi.org/10.1111/1346-8138.13898.CrossRefPubMedGoogle Scholar
  27. 27.
    Long GV, Weber JS, Infante JR, Kim KB, Daud A, Gonzalez R, et al. Overall survival and durable responses in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib combined with trametinib. J Clin Oncol. 2016;34(8):871–8.  https://doi.org/10.1200/JCO.2015.62.9345.CrossRefPubMedGoogle Scholar
  28. 28.
    Leal L, Agut-Busquet E, Romani J, Sabat M, Yebenes M, Saez A, et al. Cutaneous granulomatous panniculitis and sarcoidal granulomatous papular eruption in a patient with metastatic melanoma treated with a BRAF inhibitor. J Dermatol. 2016;43(6):715–6.  https://doi.org/10.1111/1346-8138.13255.CrossRefPubMedGoogle Scholar
  29. 29.
    Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27(4):450–61.  https://doi.org/10.1016/j.ccell.2015.03.001.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Walker LSK. PD-1 and CTLA4: two checkpoints, one pathway? Sci Immunol. 2017;2(11):eaan3864.  https://doi.org/10.1126/sciimmunol.aan3864.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, et al. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res. 2004;64(3):1140–5.  https://doi.org/10.1158/0008-5472.CAN-03-3259.CrossRefPubMedGoogle Scholar
  32. 32.
    Oba J, Nakahara T, Abe T, Hagihara A, Moroi Y, Furue M. Expression of programmed death receptor ligand 1 in melanoma may indicate tumor progression and poor patient survival. J Am Acad Dermatol. 2014;70(5):954–6.  https://doi.org/10.1016/j.jaad.2014.01.880.CrossRefPubMedGoogle Scholar
  33. 33.
    Daud AI, Wolchok JD, Robert C, Hwu WJ, Weber JS, Ribas A, et al. Programmed death-ligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma. J Clin Oncol. 2016;34(34):4102–9.  https://doi.org/10.1200/JCO.2016.67.2477.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Kraft S, Fernandez-Figueras MT, Richarz NA, Flaherty KT, Hoang MP. PDL1 expression in desmoplastic melanoma is associated with tumor aggressiveness and progression. J Am Acad Dermatol. 2017;77(3):534–42.  https://doi.org/10.1016/j.jaad.2017.05.007.CrossRefPubMedGoogle Scholar
  35. 35.
    • 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(1):23–34. This report shows that combinatory nivolumab and ipilimumab treatment prolongs the patient survival than monotherapy.  https://doi.org/10.1056/NEJMoa1504030.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006–17.  https://doi.org/10.1056/NEJMoa1414428.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    • Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345–56.  https://doi.org/10.1056/NEJMoa1709684. This report shows that combinatory nivolumab and ipilimumab treatment prolongs the patient survival than monotherapy.CrossRefPubMedGoogle Scholar
  38. 38.
    • Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016;17(11):1558–68. This report shows that nivolumab prolongs the patient survival more than ipilimumab.  https://doi.org/10.1016/S1470-2045(16)30366-7.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    • Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, 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(10105):1853–62.  https://doi.org/10.1016/S0140-6736(17)31601-X. This report shows that pembrolizumab prolongs the patient survival more than ipilimumab.CrossRefPubMedGoogle Scholar
  40. 40.
    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(26):2521–32.  https://doi.org/10.1056/NEJMoa1503093.CrossRefPubMedGoogle Scholar
  41. 41.
    Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16(8):908–18.  https://doi.org/10.1016/S1470-2045(15)00083-2.CrossRefPubMedGoogle Scholar
  42. 42.
    Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377(19):1824–35.  https://doi.org/10.1056/NEJMoa1709030.CrossRefPubMedGoogle Scholar
  43. 43.
    Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, 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. 2017:JCO2016718023. doi:  https://doi.org/10.1200/JCO.2016.71.8023.
  44. 44.
    Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, 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.  https://doi.org/10.1016/S1470-2045(15)70076-8.CrossRefPubMedGoogle Scholar
  45. 45.
    Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30.  https://doi.org/10.1056/NEJMoa1412082.CrossRefPubMedGoogle Scholar
  46. 46.
    Ascierto PA, Del Vecchio M, Robert C, Mackiewicz A, Chiarion-Sileni V, Arance A, et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2017;18(5):611–22.  https://doi.org/10.1016/S1470-2045(17)30231-0.CrossRefPubMedGoogle Scholar
  47. 47.
    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(19):1845–55.  https://doi.org/10.1056/NEJMoa1611299.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517–26.  https://doi.org/10.1056/NEJMoa1104621.CrossRefPubMedGoogle Scholar
  49. 49.
    Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.  https://doi.org/10.1056/NEJMoa1003466.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, et al. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015;33(10):1191–6.  https://doi.org/10.1200/JCO.2014.56.6018.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Long GV, Atkinson V, Ascierto PA, Robert C, Hassel JC, Rutkowski P, et al. Effect of nivolumab on health-related quality of life in patients with treatment-naïve advanced melanoma: results from the phase III CheckMate 066 study. Ann Oncol. 2016;27(10):1940–6.  https://doi.org/10.1093/annonc/mdw265.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, et al. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016;67:46–54.  https://doi.org/10.1016/j.ejca.2016.07.018.CrossRefPubMedGoogle Scholar
  53. 53.
    De Velasco G, Je Y, Bossé D, Awad MM, Ott PA, Moreira RB, et al. Comprehensive meta-analysis of key immune-related adverse events from CTLA-4 and PD-1/PD-L1 inhibitors in cancer patients. Cancer Immunol Res. 2017;5(4):312–8.  https://doi.org/10.1158/2326-6066.CIR-16-0237.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Heinzerling L, Ott PA, Hodi FS, Husain AN, Tajmir-Riahi A, Tawbi H, et al. Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy. J Immunother Cancer. 2016;4(1):50.  https://doi.org/10.1186/s40425-016-0152-y.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Nakamura Y, Tanaka R, Asami Y, Teramoto Y, Imamura T, Sato S, et al. Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: a multi-institutional retrospective study. J Dermatol. 2017;44(2):117–22.  https://doi.org/10.1111/1346-8138.13520.CrossRefPubMedGoogle Scholar
  56. 56.
    Arai T, Harada K, Usui Y, Irisawa R, Tsuboi R. Case of acute anterior uveitis and Vogt-Koyanagi-Harada syndrome-like eruptions induced by nivolumab in a melanoma patient. J Dermatol. 2017;44(8):975–6.  https://doi.org/10.1111/1346-8138.13612.CrossRefPubMedGoogle Scholar
  57. 57.
    Fujimura T, Kambayashi Y, Furudate S, Kakizaki A, Hidaka T, Haga T, et al. Isolated adrenocorticotropic hormone deficiency possibly caused by nivolumab in a metastatic melanoma patient. J Dermatol. 2017;44(3):e13–e4.  https://doi.org/10.1111/1346-8138.13532.CrossRefPubMedGoogle Scholar
  58. 58.
    Tanaka A, Ikinaga K, Kiyohara E, Tanemura A, Wataya-Kaneda M, Fujimura R, et al. Critical renal adverse event induced by nivolumab therapy in a stage IV melanoma patient. J Dermatol. 2017;44(6):727–8.  https://doi.org/10.1111/1346-8138.13538.CrossRefPubMedGoogle Scholar
  59. 59.
    Teramoto Y, Nakamura Y, Asami Y, Imamura T, Takahira S, Nemoto M, et al. Case of type 1 diabetes associated with less-dose nivolumab therapy in a melanoma patient. J Dermatol. 2017;44(5):605–6.  https://doi.org/10.1111/1346-8138.13486.CrossRefPubMedGoogle Scholar
  60. 60.
    Wada N, Uchi H, Furue M. Case of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome induced by nivolumab in a patient with advanced malignant melanoma. J Dermatol. 2017;44(8):e196–e7.  https://doi.org/10.1111/1346-8138.13840.CrossRefPubMedGoogle Scholar
  61. 61.
    Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, Larkin J, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol. 2017;35(7):785–92.  https://doi.org/10.1200/JCO.2015.66.1389.CrossRefPubMedGoogle Scholar
  62. 62.
    Schadendorf D, Wolchok JD, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, et al. Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol. 2017:JCO2017732289. doi:  https://doi.org/10.1200/JCO.2017.73.2289.
  63. 63.
    Fujimura T, Furudate S, Kakizaki A, Kambayashi Y, Haga T, Hashimoto A, et al. Contact immunotherapy enhances the therapeutic effects of nivolumab in treating in-transit melanoma: two cases reports. J Dermatol. 2016;43(6):686–9.  https://doi.org/10.1111/1346-8138.13229.CrossRefPubMedGoogle Scholar
  64. 64.
    Fujimura T, Kambayashi Y, Furudate S, Hidaka T, Sato Y, Tanita K, et al. Successful treatment of multiple in-transit melanomas on the leg with intensity-modulated radiotherapy and immune checkpoint inhibitors: report of two cases. J Dermatol. 2017;44(5):592–5.  https://doi.org/10.1111/1346-8138.13707.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Masutaka Furue
    • 1
  • Takamichi Ito
    • 1
  • Naoko Wada
    • 1
  • Maiko Wada
    • 1
  • Takafumi Kadono
    • 2
  • Hiroshi Uchi
    • 1
  1. 1.Department of DermatologyKyushu UniversityFukuokaJapan
  2. 2.Department of DermatologySt. Marianna University School of MedicineKawasakiJapan

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