Skip to main content

Advertisement

SpringerLink
Log in

Long-term survival with modern therapeutic agents against metastatic melanoma—vemurafenib and ipilimumab in a daily life setting

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Despite new therapeutic options, metastatic melanoma remains to be one of the most fatal tumors. With the development of BRAF inhibitors and immune checkpoint inhibitors, overall survival could be prolonged significantly for the first time. Clinical studies implied that even long-term survival is possible with both types of drugs, but predictive markers are so far missing. In this study, we analyzed survival data from patients that received the first-in-class substances vemurafenib and ipilimumab, respectively, during the time period from registration of the drugs until availability of combination treatments. We aimed to evaluate the possibility of long-term survival in a daily life setting and to characterize patients that benefit from these drugs in order to gain insight into predictive attributes. Eighty patients were evaluated who were treated with either vemurafenib (n = 40) or ipilimumab (n = 40), and overall survival was analyzed. Subgroup analysis was performed for patients who were still alive 24 months after induction of therapy (long-term survival). Median overall survival (OS) was 8.0 months for patients treated with vemurafenib and 10.0 months for patients treated with ipilimumab (log-rank P value = 0.689). Long-term survival was achieved in 32.5% of patients (42.3% vemurafenib, 57.7% ipilimumab). Negative predictors of long-term survival in the vemurafenib group were brain and liver metastases, as well as elevated LDH, S100ß and liver enzymes. For ipilimumab, an increase in lymphocytes and eosinophils during course of treatment correlated with long-term survival. Our real-life experience shows that long-term survival is possible with using both therapeutic agents, vemurafenib and ipilimumab. Pattern of metastases and laboratory values might be of interest in decision making for a specific therapeutic approach. Combination of drugs and observational studies in larger patient cohorts are necessary to further validate our findings.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidences and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013;49:1374–403.

    Article  CAS  PubMed  Google Scholar 

  2. Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. N Engl J Med. 2004;351:998–1012.

    Article  CAS  PubMed  Google Scholar 

  3. Eigentler TK, Caroli UM, Radny P, Garbe C. Palliative therapy of disseminated malignant melanoma: a systematic review of 41 randomized clinical trials. Lancet Oncol. 2003;4(12):748–59.

    Article  CAS  PubMed  Google Scholar 

  4. Schadendorf D, Fisher DE, Garbe C, et al. Melanoma. Nat Rev Dis Primers. 2015;1:15003.

    Article  PubMed  Google Scholar 

  5. Eggermont AM, Spatz A, Robert C. Cutaneous melanoma. Lancet. 2011;383(9919):816–27.

    Article  Google Scholar 

  6. Rudolph BM, Groffik A, Stanger C, Loquai C, Grabbe S. Systemic therapy for malignant melanoma. Hautarzt. 2012;63(11):885–98.

    Article  CAS  PubMed  Google Scholar 

  7. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600 K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;15:323–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Menzies AM, Wilmott JS, Drummond M, et al. Clinicopathologic Features Associated with efficacy and long-term survival in metastatic melanoma patients treated with BRAF of combined BRAF and MEK inhibitors. Cancer. 2015;121(21):3826–35.

    Article  CAS  PubMed  Google Scholar 

  10. Hodi FS, O`Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–26.

    Article  CAS  PubMed  Google Scholar 

  12. Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kelderman S, Heemskerk B, van Tinteren H, et al. Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. Cancer Immunol Immunother. 2014;63:449–58.

    CAS  PubMed  Google Scholar 

  14. Gebhardt C, Sevko A, Jiang H. Myeloid cells and related chronic inflammatory factors as novel predictive markers in melanoma treatment with ipilimumab. Clin Cancer Res. 2015;21(24):5453–9.

    Article  CAS  PubMed  Google Scholar 

  15. Diem S, Kasenda B, Martin-Liberal J, et al. Prognostic score for patients with advanced melanoma treated with ipilimumab. Eur J Cancer. 2015;51(18):2785–91.

    Article  CAS  PubMed  Google Scholar 

  16. Martens A, Wistuba-Hamprecht K, Yuan J, et al. Increases in absolute lymphocytes and circulating CD4þ and CD8þ T Cells are associated with positive clinical outcome of melanoma patients treated with ipilimumab. Clin Cancer Res. 2016;22(19):4848–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Martens A, Wistuba-Hamprecht K, Geukes Foppen M. Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin Cancer Res. 2016;22(12):2908–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wilgenhof S, Du Four S, Vandenbroucke F, et al. Single-center experience with ipilimumab in an expanded access program for patients with pretreated advanced melanoma. J Immunother. 2013;36:215–22.

    Article  CAS  PubMed  Google Scholar 

  19. Abusaif S, Jradi Z, Held L, et al. S100B and lactate dehydrogenase as response and progression markers during treatment with vemurafenib in patients with advanced melanoma. Melanoma Res. 2013;23(5):396–401.

    Article  CAS  PubMed  Google Scholar 

  20. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27:6199–206.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Gibney GT, Gauthier G, Ayas C. Treatment patterns and outcomes in BRAF V600E-mutant melanoma patients with brain metastases receiving vemurafenib in the real-world setting. Cancer Med. 2015;4(8):1205–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Harding JJ, Catalanotti F, Munhoz RR. A retrospective evaluation of vemurafenib as treatment for BRAF-mutant melanoma brain metastases. Oncologist. 2015;20(7):789–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Khoja L, Atenafu EG, Ye Q, et al. Real-world efficacy, toxicity and clinical management of ipilimumab treatment in metastatic melanoma. Oncology letters. 2016;11:1581–5.

    Article  PubMed  Google Scholar 

  24. Puzanov I, Amaravadi RK, McArthur GA, et al. Long-term outcome in BRAFV600E melanoma patients treated with vemurafenib: patterns of disease progression and clinical management of limited progression. Eur J Cancer. 2015;51(11):1435–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zimmer L, Eigentler TK, Kiecker F, et al. Open-label, multicenter, single-arm phase II DeCOG-study of ipilimumab in pretreated patients with different subtypes of metastatic melanoma. Transl Med. 2015;13:351.

    Article  Google Scholar 

  26. Di Giacomo AM, Calabro L, Danielli R, et al. Long-term survival and immunological parameters in metastatic melanoma patients who responded to ipilimumab 10 mg/kg within an expanded access programme. Cancer Immunol Immunother. 2013;62:1021–8.

    Article  PubMed  Google Scholar 

  27. Fennira F, Page C, Schneider P, et al. Vemurafenib in the French temporary authorization for use metastatic melanoma cohort: a single-centre trial. Melanoma Res. 2014;24:75–82.

    Article  CAS  PubMed  Google Scholar 

  28. Larkin J, Del Vecchio M, Ascierto PA, et al. Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet Oncol. 2014;15(4):436–44.

    Article  CAS  PubMed  Google Scholar 

  29. Uguel S, Loquai C, Kahler K, et al. A multicenter DeCOG study on predictors of vemurafenib therapy outcome in melanoma: pretreatment impacts survival. Ann Oncol. 2015;26:573–82.

    Article  Google Scholar 

  30. Schilling B, Sondermann W, Zhao F, et al. Differential influence of vemurafenib and dabrafenib on patients’ lymphocytes despite similar clinical efficacy in melanoma. Ann Oncol. 2015;25:747–53.

    Article  Google Scholar 

  31. Simeone E, Gentilcore G, Romano A, Daponte A, Caraco C, Grimaldi AM, et al. Immunological and biological changes during ipilimumab (Ipi) treatment and their correlation with clinical response and survival. J Clin Oncol 2012;30:abstr 8573(suppl).

  32. Gebhardt C, Lichtenberger R, Utikal J. Biomarker value and pitfalls of serum S100B in the follow-up of high-risk melanoma patients. J Dtsch Dermatol Ges. 2016;14(2):158–64.

    PubMed  Google Scholar 

  33. Ku GY, Yuan J, Page DB, Schroeder SE, Panageas KS, Carvajal RD, et al. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer. 2010;116:1767–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Berman D, Wolchok JD, Weber J, Hamid O, O’Day S, Chasalow S. Association of peripheral blood absolute lymphocyte count (ALC) and clinical activity in patients (pts) with advanced melanoma treated with ipilimumab. J Clin Oncol. 2009;27(15):3020.

    Google Scholar 

  35. Delyon J, Mateus C, Lefeuvre D, et al. Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival. Ann Oncol. 2013;24(6):1697–703.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany

    B. M. Lang, A. Peveling-Oberhag, D. Faidt, S. Grabbe & C. Loquai

  2. Department of Radiology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany

    A. M. Hötker

  3. Institute for Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany

    V. Weyer-Elberich

Authors
  1. B. M. Lang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Peveling-Oberhag
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Faidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. M. Hötker
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. V. Weyer-Elberich
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S. Grabbe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C. Loquai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B. M. Lang.

Ethics declarations

Conflict of interest

BML received speaker honoraria from Roche, Novartis and BMS and travel expenses from BMS and Novartis. SG received honoraria for advisory boards, oral presentations and travel expenses from Roche, Novartis, MSD and BMS. CL received honoraria for advisory boards and oral presentations from Amgen, MSD, Roche, BMS, Novartis, Leo, Pierre Fabre; consultant for Roche-Posay, Roche, BMS and Biontech; travel expenses from Roche, Amgen, BMS, MSD and Novartis. APO, DF, AMH and VWE 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. For this type of study, formal consent is not required.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lang, B.M., Peveling-Oberhag, A., Faidt, D. et al. Long-term survival with modern therapeutic agents against metastatic melanoma—vemurafenib and ipilimumab in a daily life setting. Med Oncol 35, 24 (2018). https://doi.org/10.1007/s12032-018-1084-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-018-1084-9

Keywords

Search

Navigation