Clinical and Translational Oncology

, Volume 19, Issue 6, pp 761–768

Pembrolizumab for advanced melanoma: experience from the Spanish Expanded Access Program

  • M. González-Cao
  • A. Arance
  • J. M. Piulats
  • I. Marquez-Rodas
  • J. L. Manzano
  • A. Berrocal
  • G. Crespo
  • D. Rodriguez
  • E. Perez-Ruiz
  • M. Berciano
  • A. Soria
  • A. G. Castano
  • E. Espinosa
  • C. Montagut
  • L. Alonso
  • T. Puertolas
  • C. Aguado
  • M. A. Royo
  • R. Blanco
  • J. F. Rodríguez
  • E. Muñoz
  • P. Mut
  • F. Barron
  • S. Martin-Algarra
  • Spanish Melanoma Group
Research Article

Abstract

Background

The programmed death (PD-1) inhibitor pembrolizumab has been recently approved for the treatment of advanced melanoma. We evaluated the clinical activity of pembrolizumab in melanoma patients treated under the Spanish Expanded Access Program.

Methods

Advanced melanoma patients who failed to previous treatment lines were treated with pembrolizumab 2 mg/kg every three weeks. Patients with brain metastases were not excluded if they were asymptomatic. Data were retrospectively collected from 21 centers in the Spanish Melanoma Group.

Results

Sixty-seven advanced melanoma patients were analyzed. Most patients were stage M1c (73.1%), had high LDH levels (55.2%) and had ECOG PS 1 or higher (59.7%). For cutaneous melanoma patients, median overall survival was 14.0 months; the 18-month overall survival rate was 47.1%. Overall response rate was 27%, including three patients with complete responses (6.5%). Median response duration was not reached, with 83.3% of responses ongoing (3.5 m+ to 20.4 m+). From ten patients included with brain metastases, four (40%) had an objective response, two (20%) of them achieved a complete response. Significant prognostic factors for overall survival were LDH level, ECOG PS and objective response. There were no serious adverse events.

Conclusion

Although this was a heavily pretreated cohort, pembrolizumab activity at the approved dose and schedule was confirmed in the clinical setting with long-term responders, also including patients with brain metastases.

Keywords

Expanded access program Melanoma Pembrolizumab Survival CNS metastases 

Supplementary material

12094_2016_1602_MOESM1_ESM.docx (13 kb)
Supplementary material 1 (DOCX 12 kb)

References

  1. 1.
    Weber J, Thompson JA, Hamid O, Minor D, Amin A, Ron I, et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009;15(17):5591–8 epub 2009/08/13.CrossRefPubMedGoogle Scholar
  2. 2.
    Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11(2):155–64 epub 2009/12/17.CrossRefPubMedGoogle Scholar
  3. 3.
    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 epub 2010/06/08.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33 epub 2013/06/04.CrossRefPubMedGoogle Scholar
  5. 5.
    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 epub 2015/04/22.CrossRefPubMedGoogle Scholar
  6. 6.
    Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540–50 epub 2015/12/30.CrossRefPubMedGoogle Scholar
  7. 7.
    Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123–35 epub 2015/06/02.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627–39 epub 2015/09/29.CrossRefPubMedGoogle Scholar
  9. 9.
    Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909–20 epub 2016/03/10.CrossRefPubMedGoogle Scholar
  10. 10.
    Luke JJ, Ott PA. PD-1 pathway inhibitors: the next generation of immunotherapy for advanced melanoma. Oncotarget. 2015;6(6):3479–92 epub 2015/02/17.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–71 epub 2014/11/28.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384(9948):1109–17 epub 2014/07/19.CrossRefPubMedGoogle Scholar
  13. 13.
    Daud A, Blank CU, Robert C, Puzanov I, Richtig E, Margolin KA, et al. KEYNOTE-006 study of pembrolizumab (pembro) versus ipilimumab (ipi) for advanced melanoma: Efficacy by PD-L1 expression and line of therapy. J Clin Oncol. 2016;34:9513.CrossRefGoogle Scholar
  14. 14.
    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 epub 2015/06/28.CrossRefPubMedGoogle Scholar
  15. 15.
    Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23):7412–20.CrossRefPubMedGoogle Scholar
  16. 16.
    Daud A, Ribas A, Robert C, Hodi FS, Wolchok JD, Joshua AM, et al. Long-term efficacy of pembrolizumab (pembro; MK-3475) in a pooled analysis of 655 patients (pts) with advanced melanoma (MEL) enrolled in KEYNOTE-001. J Clin Oncol. 2016;33(15):9005.Google Scholar
  17. 17.
    Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016;315(15):1600–9 epub 2016/04/20.CrossRefPubMedGoogle Scholar
  18. 18.
    Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2016;17(7):976–83 epub 2016/06/09.CrossRefPubMedGoogle Scholar
  19. 19.
    Rosell R, Karachaliou N. Trends in immunotherapy for brain metastases. Lancet Oncol. 2016;17(7):859–60 epub 2016/06/09.CrossRefPubMedGoogle Scholar
  20. 20.
    Aya F, Fernandez-Martinez A, Gaba L, Victoria I, Tosca M, Carrera C, et al. Pembrolizumab in a BRAF-mutant metastatic melanoma patient following a severe immune-related adverse event with ipilimumab. Immunotherapy. 2016;8(6):687–92 epub 2016/04/27.CrossRefPubMedGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2016

Authors and Affiliations

  • M. González-Cao
    • 1
  • A. Arance
    • 2
  • J. M. Piulats
    • 3
  • I. Marquez-Rodas
    • 4
  • J. L. Manzano
    • 5
  • A. Berrocal
    • 6
  • G. Crespo
    • 7
  • D. Rodriguez
    • 8
  • E. Perez-Ruiz
    • 9
  • M. Berciano
    • 10
  • A. Soria
    • 11
  • A. G. Castano
    • 12
  • E. Espinosa
    • 13
  • C. Montagut
    • 14
  • L. Alonso
    • 15
  • T. Puertolas
    • 16
  • C. Aguado
    • 17
  • M. A. Royo
    • 18
  • R. Blanco
    • 19
  • J. F. Rodríguez
    • 20
  • E. Muñoz
    • 21
  • P. Mut
    • 22
  • F. Barron
    • 23
  • S. Martin-Algarra
    • 24
  • Spanish Melanoma Group
  1. 1.Translational Cancer Research Unit, Dr. Rosell Oncology InstituteQuiron Dexeus University HospitalBarcelonaSpain
  2. 2.Hospital Clinic I ProvincialBarcelonaSpain
  3. 3.Catalan Institute of OncologyBarcelonaSpain
  4. 4.Gregorio Marañón Institute of Health ResearchMadridSpain
  5. 5.Germans Trias I Pujol University HospitalBarcelonaSpain
  6. 6.General University HospitalValenciaSpain
  7. 7.Burgos University HospitalBurgosSpain
  8. 8.Insular University Hospital of Gran CanariaCanary IslandsSpain
  9. 9.Costa del Sol HospitalMarbellaSpain
  10. 10.Regional University Hospital of MalagaMalagaSpain
  11. 11.Ramony Cajal HospitalMadridSpain
  12. 12.Marqués de Valdecilla University HospitalSantanderSpain
  13. 13.La Paz University HospitalMadridSpain
  14. 14.Del Mar University HospitalBarcelonaSpain
  15. 15.Virgen de la Victoria HospitalMalagaSpain
  16. 16.Miguel Servet University HospitalZaragozaSpain
  17. 17.San Carlos HospitalMadridSpain
  18. 18.Dr. Peset HospitalValenciaSpain
  19. 19.Consorci Sanitari de TerrassaBarcelonaSpain
  20. 20.Clara Campal HospitalMadridSpain
  21. 21.Valld’Hebron University HospitalBarcelonaSpain
  22. 22.Son Llatzer University HospitalMallorcaSpain
  23. 23.National Cancer InstituteMexico CityMexico
  24. 24.Navarra University ClinicPamplonaSpain

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