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Cancer Immunology, Immunotherapy

, Volume 68, Issue 7, pp 1171–1178 | Cite as

Evaluation of the efficacy of immunotherapy for non-resectable mucosal melanoma

  • Antoine Moya-PlanaEmail author
  • Ruth Gabriela Herrera Gómez
  • Caroline Rossoni
  • Laurent Dercle
  • Samy Ammari
  • Isabelle Girault
  • Séverine Roy
  • Jean-Yves Scoazec
  • Stephan Vagner
  • François Janot
  • Alexander M. M. Eggermont
  • Caroline Robert
Original Article

Abstract

Background

Immune checkpoint inhibitors are now standard-of-care treatments for metastatic cutaneous melanoma. However, for rare sub-groups, such as mucosal melanomas, few published data are available, and with no established therapeutic guidelines. Our objective was to assess the response to anti-CTLA4 and anti-PD1 immunotherapy in patients with mucosal melanomas.

Methods

We performed a single-center, prospective cohort analysis of patients with non-surgical locally advanced and/or metastatic mucosal melanoma receiving anti-CTLA4 and/or anti-PD1 immunotherapy from 2010 to 2016.

Results

Forty-four patients were enrolled, including 18 (40.9%) with head and neck, 12 (27.3%) with vulvo-vaginal and 14 (31.8%) with ano-rectal primary tumours. Eleven (25%) patients had stage 3 disease, and 11 (25%) had distant metastases. The first-line immunotherapy was ipilimumab in 24 patients and pembrolizumab in 20. The objective response rate (ORR) was 8.2% (one complete response) for ipilimumab and 35% (four complete responses) for pembrolizumab. No significant difference was observed for primary tumour location. The median follow-up was 24 months (range 4–73). The median progression-free survival (PFS) in the first-line ipilimumab and pembrolizumab groups was 3 months [95% confidence interval (CI) 2.5–4.6] and 5 months (95% CI 2.6–33.1), respectively (p = 0.0147).

Conclusion

In the patients with unresectable and/or metastatic mucosal melanoma, we found ORR and PFS rates comparable to those in patients with cutaneous melanoma, with no significant differences in the types of mucosal surfaces involved. Anti-PD1 therapy has a more favorable benefit-risk ratio than ipilimumab and should be used preferentially.

Keywords

Mucosal melanoma Immunotherapy Ipilimumab Pembrolizumab Anti-PD1 Anti-CTLA4 

Abbreviations

BRAF

B-Raf proto-oncogene, serine/threonine kinase

BRCA1

Breast cancer 1

cKIT

KIT proto-oncogene, receptor tyrosine kinase

CR

Complete response

DCR

Disease control rate

DOR

Duration of response

iRECIST

Immune response evaluation criteria in solid tumours

irRC

Immune-related response criteria

MBD4

Methyl-CpG-binding domain 4

NF1

Neurofibromin 1

NRAS

NRAS proto-oncogene, GTPase

ORR

Objective response rate

PD

Progressive disease

SD

Stable disease

SF3B1

Splicing factor 3b subunit 1

SNV

Somatic nucleotide variants

TG

Tumour growth

TGR

Tumor growth rate

V0

Tumour volume at baseline

Vt

Tumour volume at time t

Notes

Author contributions

AM-P, FJ, AMME, LD and CR conceptualized the manuscript, harmonized and edited the text and references and produced the figures. CR and IG performed statistical analysis. RGHG, SA, SR, J-YS and SV were responsible for data collection and analysis. All the authors contributed to the writing and editing of the manuscript. All the authors approved the final version.

Funding

No relevant funding.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The translational research study NCT02105168 was approved by the Institutional Review Board at Gustave Roussy Cancer Campus on April 7, 2014. All the methods and procedures associated with this study were conducted in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

All the patients have given their written authorization to perform research on their tumour samples by signing the Institutional Tumor Bank form (before April 2014) or the form of the translational research study NCT02105168. All the patients provided written informed consent to the use of their anonymized data in scientific studies.

References

  1. 1.
    Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R et al (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369:134–144.  https://doi.org/10.1056/NEJMoa1305133 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454.  https://doi.org/10.1056/NEJMoa1200690 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH et al (2014) Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 32:1020–1030.  https://doi.org/10.1200/JCO.2013.53.0105 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R 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 384:1109–1117.  https://doi.org/10.1016/S0140-6736(14)60958-2 CrossRefPubMedGoogle Scholar
  5. 5.
    Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L et al (2015) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372:2521–2532.  https://doi.org/10.1056/NEJMoa1503093 CrossRefGoogle Scholar
  6. 6.
    Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C et al (2015) Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 16:908–918.  https://doi.org/10.1016/S1470-2045(15)00083-2 CrossRefPubMedGoogle Scholar
  7. 7.
    Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B 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 16:375–384.  https://doi.org/10.1016/S1470-2045(15)70076-8 CrossRefGoogle Scholar
  8. 8.
    McLaughlin CC, Wu XC, Jemal A, Martin HJ, Roche LM, Chen VW (2005) Incidence of noncutaneous melanomas in the U.S. Cancer 103:1000–1007.  https://doi.org/10.1002/cncr.20866 CrossRefPubMedGoogle Scholar
  9. 9.
    Patrick RJ, Fenske NA, Messina JL (2007) Primary mucosal melanoma. J Am Acad Dermatol 56:828–834.  https://doi.org/10.1016/j.jaad.2006.06.017 CrossRefPubMedGoogle Scholar
  10. 10.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T et al (2008) Cancer statistics, 2008. CA Cancer J Clin 58:71–96.  https://doi.org/10.3322/CA.2007.0010 CrossRefGoogle Scholar
  11. 11.
    Chang AE, Karnell LH, Menck HR (1998) The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 83:1664–1678.  https://doi.org/10.1002/(sici)1097-0142(19981015)83:8%3c1664:aid-cncr23%3e3.0.co;2-g CrossRefPubMedGoogle Scholar
  12. 12.
    Kuk D, Shoushtari AN, Barker CA, Panageas KS, Munhoz RR, Momtaz P et al (2016) Prognosis of mucosal, uveal, acral, non acral cutaneous, and unknown primary melanoma from the time of first metastasis. Oncologist 21:848–854.  https://doi.org/10.1634/theoncologist.2015-0522 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Yamazaki N, Takenouchi T, Fujimoto M, Ihn H, Uchi H, Inozume T et al (2017) Phase 1b study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced melanoma (KEYNOTE-041). Cancer Chemother Pharmacol 79:651–660.  https://doi.org/10.1007/s00280-016-3237-x CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    D’Angelo SP, Larkin J, Sosman JA, Lebbé C, Brady B, Neyns B et al (2017) Efficacy and safety of nivolumab alone or in combination with ipilimumab in patients With mucosal melanoma: a pooled analysis. J Clin Oncol 35:226–235.  https://doi.org/10.1200/JCO.2016.67.9258 CrossRefPubMedGoogle Scholar
  15. 15.
    Shoushtari AN, Munhoz RR, Kuk D, Ott PA, Johnson DB, Tsai KK et al (2016) The efficacy of anti-PD-1 agents in acral and mucosal melanoma. Cancer 122:3354–3362.  https://doi.org/10.1002/cncr.30259 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Del Vecchio M, Di Guardo L, Ascierto PA, Grimaldi AM, Sileni VC, Pigozzo J et al (2014) Efficacy and safety of ipilimumab 3 mg/kg in patients with pretreated, metastatic, mucosal melanoma. Eur J Cancer 50:121–127.  https://doi.org/10.1016/j.ejca.2013.09.007 CrossRefPubMedGoogle Scholar
  17. 17.
    Champiat S, Dercle L, Ammari S, Massard C, Hollebecque A, Postel-Vinay S et al (2017) Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. Clin Cancer Res 23:1920–1928.  https://doi.org/10.1158/1078-0432.CCR-16-1741 CrossRefPubMedGoogle Scholar
  18. 18.
    Robert C, Ribas A, Hamid O, Daud A, Wolchok JD, Joshua AM et al (2018) Durable complete response after discontinuation of pembrolizumab in patients with metastatic melanoma. J Clin Oncol 36:1668–1674.  https://doi.org/10.1200/JCO.2017.75.6270 CrossRefGoogle Scholar
  19. 19.
    Wolchock JD, Chiaron-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL et al (2017) Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 377:1345–1356CrossRefGoogle Scholar
  20. 20.
    Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF et al (2016) 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 17:1558–1568.  https://doi.org/10.1016/S1470-2045(16)30366-7 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Zimmer L, Apuri S, Eroglu Z, Kottschade LA, Forschner A, Gutzmer R (2017) Ipilimumab alone or in combination with nivolumab after progression on anti-PD1 therapy in advanced melanoma. Eur J Cancer 75:47–55CrossRefPubMedGoogle Scholar
  22. 22.
    Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A et al (2014) Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371:2189–2199.  https://doi.org/10.1056/NEJMoa1406498 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV et al (2013) Signatures of mutational processes in human cancer. Nature 500:415–421.  https://doi.org/10.1038/nature12477 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Eroglu Z, Zaretsky JM, Hu-Lieskovan S, Kim DW, Algazi A, Johnson DB et al (2018) High response rate to PD-1 blockade in desmoplastic melanomas. Nature 553:347–350.  https://doi.org/10.1038/nature25187 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Furney SJ, Turajlic S, Stamp G, Nohadani M, Carlisle A, Thomas JM et al (2013) Genome sequencing of mucosal melanomas reveals that they are driven by distinct mechanisms from cutaneous melanoma. J Pathol 230:261–269.  https://doi.org/10.1002/path.4204 CrossRefPubMedGoogle Scholar
  26. 26.
    Furney SJ, Turajlic S, Stamp G, Thomas JM, Hayes A, Strauss D et al (2014) The mutational burden of acral melanoma revealed by whole-genome sequencing and comparative analysis. Pigment Cell Melanoma Res 27:835–838.  https://doi.org/10.1111/pcmr.12279 CrossRefPubMedGoogle Scholar
  27. 27.
    Hayward NK, Wilmott JS, Waddell N, Johansson PA, Field MA, Nones K et al (2017) Whole-genome landscapes of major melanoma subtypes. Nature 545:175–180.  https://doi.org/10.1038/nature22071 CrossRefPubMedGoogle Scholar
  28. 28.
    Hintzsche JD, Gorden NT, Amato CM, Kim J, Wuensch KE, Robinson SE et al (2017) Whole-exome sequencing identifies recurrent SF3B1 R625 mutation and comutation of NF1 and KIT in mucosal melanoma. Melanoma Res 27:189–199.  https://doi.org/10.1097/CMR.0000000000000345 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Van Engen-van Grunsven AC, Baar MP, Pfundt R, Rijntjes J, Küsters-Vandevelde HV, Delbecq AL et al (2015) Whole-genome copy-number analysis identifies new leads for chromosomal aberrations involved in the oncogenesis and metastastic behavior of uveal melanomas. Melanoma Res 25:200–209.  https://doi.org/10.1097/CMR.0000000000000152 CrossRefPubMedGoogle Scholar
  30. 30.
    Furney SJ, Pedersen M, Gentien D, Dumont AG, Rapinat A, Desjardins L et al (2013) SF3B1 mutations are associated with alternative splicing in uveal melanoma. Cancer Discov 2013(3):1122–1129.  https://doi.org/10.1158/2159-8290.CD-13-0330 CrossRefGoogle Scholar
  31. 31.
    Heppt MV, Heinzerling L, Kähler KC, Forschner A, Kirchberger MC, Loquai C et al (2017) Prognostic factors and outcomes in metastatic uveal melanoma treated with programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4 inhibition. Eur J Cancer 82:56–65.  https://doi.org/10.1016/j.ejca.2017.05.038 CrossRefPubMedGoogle Scholar
  32. 32.
    Algazi AP, Tsai KK, Shoushtari AN, Munhoz RR, Eroglu Z, Piulats JM et al (2016) Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer 122:3344–3353.  https://doi.org/10.1002/cncr.30258 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Rodrigues M, Mobuchon L, Houy A, Fiévet A, Gardrat S, Barnhill RL et al (2018) Outlier response to anti-pd1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors. Nat Commun. 9(1):1866.  https://doi.org/10.1038/s41467-018-04322-5 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Antoine Moya-Plana
    • 1
    • 6
    Email author
  • Ruth Gabriela Herrera Gómez
    • 2
  • Caroline Rossoni
    • 3
  • Laurent Dercle
    • 4
  • Samy Ammari
    • 5
  • Isabelle Girault
    • 6
  • Séverine Roy
    • 6
  • Jean-Yves Scoazec
    • 6
    • 7
  • Stephan Vagner
    • 6
  • François Janot
    • 1
  • Alexander M. M. Eggermont
    • 8
    • 9
  • Caroline Robert
    • 6
    • 9
    • 10
  1. 1.Head and Neck Surgery DepartmentGustave Roussy Cancer CampusVillejuif CedexFrance
  2. 2.Medical Oncology DepartmentGustave Roussy Cancer CampusVillejuifFrance
  3. 3.Biostatistics DepartmentGustave Roussy Cancer CampusVillejuifFrance
  4. 4.Radiology DepartmentColumbia University Medical Center, New York Presbyterian HospitalNew YorkUSA
  5. 5.Radiology DepartmentGustave Roussy Cancer CampusVillejuifFrance
  6. 6.Inserm U981, Melanoma Group, Gustave Roussy Cancer CampusVillejuifFrance
  7. 7.Pathology DepartmentGustave Roussy Cancer CampusVillejuifFrance
  8. 8.Gustave Roussy Cancer CampusVillejuifFrance
  9. 9.Université Paris-SaclayVillejuifFrance
  10. 10.Onco-dermatology DepartmentGustave Roussy Cancer CampusGrand ParisFrance

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