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Cancer Immunology, Immunotherapy

, Volume 66, Issue 9, pp 1153–1162 | Cite as

The experience of immune checkpoint inhibitors in Chinese patients with metastatic melanoma: a retrospective case series

  • Xizhi Wen
  • Ya Ding
  • Jingjing Li
  • Jingjing Zhao
  • Ruiqing Peng
  • Dandan Li
  • Baoyan Zhu
  • Yao Wang
  • Xing Zhang
  • Xiaoshi ZhangEmail author
Original Article

Abstract

Melanomas in Chinese patients show relatively higher rates of acral and mucosal types than in other populations. However, the efficacy of checkpoint inhibitor therapies against these melanoma subtypes is not well defined. We analyzed 52 patients treated with ipilimumab, pembrolizumab, or a combination of both to evaluate the efficacy and safety of checkpoint inhibitors in Chinese patients with advanced melanoma, particularly those with acral and mucosal types. The objective response rates (ORRs) were 0, 25, and 20% for ipilimumab, pembrolizumab, and pembrolizumab plus ipilimumab, respectively. Pembrolizumab contained therapy was as effective in acral and mucosal melanoma patients (ORR 26.7 and 20%, respectively) as in non-acral cutaneous melanoma patients (ORR 26.7%). Baseline lactate dehydrogenase levels and relative lymphocyte counts were independent prognostic factors for PFS and OS. The incidences of grade 3–4 adverse events were 14% in the two monotherapy groups and 30% in the combined therapy group. The most frequent adverse events were elevation of aminotransferase, skin toxicity, thyroid dysfunction, pyrexia, and fatigue. Treatment-related rash or vitiligo was associated with a better prognosis. In summary, pembrolizumab-based therapy resulted in meaningful efficacy and good tolerability in Chinese patients with melanoma, including those with acral and mucosal types.

Keywords

Ipilimumab Pembrolizumab Chinese patients Acral melanoma Mucosal melanoma Biomarkers 

Abbreviations

ASTA

Spartate aminotransferase

ALT

Alanine aminotransferase

CSD

Chronic sun-derived

CR

Completeremission

CTCAE

National Cancer Institute Common Terminology Criteria for Adverse Events

DCR

Disease control rate

ECOG

Eastern Cooperative Group

Ipi

Ipilimumab

NR

Not reached

OS

Overall survival

ORR

Objective response rate

Pem

Pembrolizumab

PR

Partial remission

PFS

Progression-free survival

RECIST

Response evaluation criteria in solid tumors

RLC

Relative lymphocyte count

REC

Relative eosinophil count

SD

Stable disease

ULN

Upper limit of normal

Notes

Compliance with ethical standards

Funding

This study received support from the National Natural Science Foundation of China (Grant No. 81272341).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The institutional review board at our hospital approved this study.

Informed consent

All patients provided written informed consent for this study.

Supplementary material

262_2017_1989_MOESM1_ESM.pdf (729 kb)
Supplementary material 1 (PDF 729 KB)

References

  1. 1.
    Garbe C, Eigentler TK, Keilholz U, Hauschild A, Kirkwood JM (2011) Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist 16:5–24CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, Patt D, Chen TT, Berman DM, Wolchok JD (2015) Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumabin unresectable or metastatic melanoma. J ClinOncol 33:1889–1894CrossRefGoogle Scholar
  3. 3.
    Hamid O, Robert C, Daud A et al (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369:134–144CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    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 ClinOncol 32:1020–1030CrossRefGoogle Scholar
  5. 5.
    Wolchok JD, Kluger H, Callahan MK et al (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369:122–133CrossRefPubMedGoogle Scholar
  6. 6.
    Larkin J, Chiarion-Sileni V, Gonzalez R et al (2015) Combined nivolumaband ipilimumabor monotherapy in untreated melanoma. N Engl J Med 373:23–34CrossRefPubMedGoogle Scholar
  7. 7.
    Long GV, Atkinson V, Cebon JS et al (2016) Pembrolizumab (pembro) plus ipilimumab (ipi) for advanced melanoma: Results of the KEYNOTE-029 expansion cohort. J ClinOncol 34(suppl 15):9506 (ASCO Annual Meeting abstract) Google Scholar
  8. 8.
    Chi Z, Li S, Sheng X, Si L, Cui C, Han M, Guo J (2011) Clinical presentation, histology, and prognoses of malignant melanoma in ethnic Chinese: a study of 522 consecutive cases. BMC Cancer 11:85CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Curtin JA, Fridlyand J, Kageshita T et al (2005) Distinct sets of genetic alterations in melanoma. N Engl J Med 353:2135–2147CrossRefPubMedGoogle Scholar
  10. 10.
    Furney SJ, Turajlic S, Stamp G et al (2013) Genome sequencing of mucosal melanomas reveals that they are driven by distinct mechanisms from cutaneous melanoma. J Pathol 230:261–269CrossRefPubMedGoogle Scholar
  11. 11.
    Furney SJ, Turajlic S, Stamp G et al (2014) The mutational burden of acral melanoma revealed by whole-genome sequencing and comparative analysis. Pigment Cell. Melanoma Res 27:835–838CrossRefGoogle Scholar
  12. 12.
    Shoushtari AN, Munhoz RR, Kuk D et al (2016) The efficacy of anti-PD-1 agents in acral and mucosal melanoma. Cancer 22:3354–3362CrossRefGoogle Scholar
  13. 13.
    Wu P, Wu D, Li L, Chai Y, Huang J (2015) PD-L1 and survival in solid tumors: a meta-analysis. PLoS One 10:e0131403. doi: 10.1371/journal.pone.0131403 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Ribas A, Puzanov I, Dummer R et al (2015) Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 16:908–918CrossRefPubMedGoogle Scholar
  15. 15.
    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 384:1109–1117CrossRefPubMedGoogle Scholar
  16. 16.
    Daud AI, Wolchok JD, Robert C et al (2016) Programmed death-ligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma. J Clin Oncol 34:4102–4109CrossRefPubMedGoogle Scholar
  17. 17.
    Festino L, Botti G, Lorigan P, Masucci GV, Hipp JD, Horak CE, Melero I, Ascierto PA (2016) Cancer treatment with anti-PD-1/PD-L1 agents: Is PD-L1 expression a biomarker for patient selection? Drugs 76:925–945CrossRefPubMedGoogle Scholar
  18. 18.
    Madore J, Vilain RE, Menzies AM et al (2015) PD-L1 expression in melanoma shows marked heterogeneity within and between patients: implications for anti-PD-1/PD-L1 clinical trials. Pigment Cell. Melanoma Res 28:245–253CrossRefGoogle Scholar
  19. 19.
    Diem S, Kasenda B, Spain L, Martin-Liberal J, Marconcini R, Gore M, Larkin J (2016) Serum lactate dehydrogenase as an early marker for outcome in patients treated with anti-PD-1 therapy in metastatic melanoma. Br J Cancer 114:256–261CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Weide B, Martens A, Hassel JC et al (2016) Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-16-0127 Google Scholar
  21. 21.
    Hua C, Boussemart L, Mateus C et al (2016) Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol 152:45–51CrossRefPubMedGoogle Scholar
  22. 22.
    Sanlorenzo M, Vujic I, Daud A, Algazi A, Gubens M, Luna SA, Lin K, Quaglino P, Rappersberger K, Ortiz-Urda S (2015) Pembrolizumabcutaneous adverse events and their association with disease progression. JAMA Dermatol 151:1206–1212CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ferrucci PF, Ascierto PA, Pigozzo J et al (2016) Baseline neutrophils and derived neutrophil-to-lymphocyte ratio: prognostic relevance in metastatic melanoma patients receiving ipilimumab. Ann Oncol 27:732–738CrossRefPubMedGoogle Scholar
  24. 24.
    Boutros C, Tarhini A, Routier E et al (2016) Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol 13:473–486CrossRefPubMedGoogle Scholar
  25. 25.
    Wen X, Wang Y, Ding Y, Li D, Li J, Guo Y, Peng R, Zhao J, Zhang X, Zhang XS (2016) Safety of immune checkpoint inhibitors in Chinese patients with melanoma. Melanoma Res 26:284–289CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Xizhi Wen
    • 1
  • Ya Ding
    • 1
  • Jingjing Li
    • 1
  • Jingjing Zhao
    • 1
  • Ruiqing Peng
    • 1
  • Dandan Li
    • 1
  • Baoyan Zhu
    • 1
  • Yao Wang
    • 1
  • Xing Zhang
    • 1
  • Xiaoshi Zhang
    • 1
    Email author
  1. 1.Biotherapy Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhouPeople’s Republic of China

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