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Cancer Chemotherapy and Pharmacology

, Volume 80, Issue 5, pp 999–1004 | Cite as

Efficacy and safety of retreatment with nivolumab in metastatic melanoma patients previously treated with nivolumab

  • Motoo Nomura
  • Atsushi Otsuka
  • Tomohiro Kondo
  • Hiroki Nagai
  • Yumi Nonomura
  • Yo Kaku
  • Shigemi Matsumoto
  • Manabu Muto
Original Article

Abstract

Background

Nivolumab is a monoclonal antibody directed against programmed death-1 that has been shown to improve survival in patients with metastatic melanoma. However, the efficacy of nivolumab and other agents in melanoma remains limited. The objective of this study was to evaluate the efficacy and safety of retreatment with nivolumab in metastatic melanoma patients who previously progressed on nivolumab.

Patients and methods

A retrospective review was performed on eight consecutive metastatic melanoma patients retreated with nivolumab who progressed on previous nivolumab. These patients received nivolumab 2 mg/kg every 3 weeks. Best responses to each treatment were assessed using RECIST 1.1.

Results

Of eight metastatic melanoma patients, three patients received chemotherapy before first nivolumab. The median first nivolumab treatment period was 4.1 months. During first nivolumab, 3 (37.5%) patients achieved a partial response and 3 (37.5%) patients achieved stable disease as their best response. First nivolumab was discontinued due to disease progression in seven patients and grade 3 colitis in 1 patient. Patients were subsequently treated with ipilimumab (n = 6), vemurafenib (n = 1), or no other medical treatment (n = 1). The median treatment period between first and second nivolumab was 3.0 months. Four patients received radiation therapy between first and second nivolumab. The median second nivolumab treatment period was 4.3 months. Among the eight patients who received second nivolumab, 2 (25%) patients achieved a partial response and 3 (37.5%) patients achieved stable disease as their best response. Second nivolumab was discontinued due to disease progression in seven patients. One patient continues to receive second nivolumab. Among the four patients treated with ipilimumab and radiotherapy between first and second nivolumab, the response rate was 50% and the disease control rate was 75%.

Conclusions

This study showed that retreatment with nivolumab is an option for select metastatic melanoma patients after previous nivolumab treatment.

Keywords

Metastatic melanoma Chemotherapy Immune checkpoint inhibitor 

Notes

Compliance with ethical standards

Funding

None of the authors have financial disclosures or funding support.

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.

Conflict of interest

None of the authors have conflicts of interest to declare.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB,et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    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 16:375–384CrossRefPubMedGoogle Scholar
  3. 3.
    Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L et al (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320–330CrossRefPubMedGoogle Scholar
  4. 4.
    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD et al (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23–34CrossRefPubMedGoogle Scholar
  5. 5.
    Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff CL Jr, Lawrence DP et al (2016) Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol 17:943–955CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Lebbé C, Weber JS, Maio M, Neyns B, Harmankaya K, Hamid O et al (2014) Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies. Ann Oncol 25:2277–2284CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Chiarion-Sileni V, Pigozzo J, Ascierto PA, Simeone E, Maio M, Calabrò L et al (2014) Ipilimumab retreatment in patients with pretreated advanced melanoma: the expanded access programme in Italy. Br J Cancer 110:1721–1726CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Robert C, Schadendorf D, Messina M, Hodi FS, O’Day S,et al (2013) Efficacy and safety of retreatment with ipilimumab in patients with pretreated advanced melanoma who progressed after initially achieving disease control. Clin Cancer Res 19:2232–2239CrossRefPubMedGoogle Scholar
  9. 9.
    Amann VC, Hoffmann D, Mangana J, Dummer R, Goldinger SM (2017) Successful retreatment with combined BRAF/MEK inhibition in metastatic BRAFV600-mutated melanoma. J Eur Acad Dermatol Venereol. doi: 10.1111/jdv.14268 PubMedGoogle Scholar
  10. 10.
    Blasig H, Bender C, Hassel JC, Eigentler TK, Sachse MM, Hiernickel J et al (2017) Reinduction of PD1-inhibitor therapy: first experience in eight patients with metastatic melanoma. Melanoma Res 27:321–325CrossRefPubMedGoogle Scholar
  11. 11.
    Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK et al (2006) Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med 203:1259–1271CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Burnette BC, Liang H, Lee Y, Chlewicki L, Khodarev NN, Weichselbaum RR et al (2011) The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Cancer Res 71:2488–2496CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Lugade AA, Moran JP, Gerber SA, Rose RC, Frelinger JG, Lord EM (2005) Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J Immunol 174:7516–7523CrossRefPubMedGoogle Scholar
  14. 14.
    Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR et al (2014) Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 124:687–695CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Qin R, Olson A, Singh B et al (2016) Safety and efficacy of radiation therapy in advanced melanoma patients treated with ipilimumab. Int J Radiat Oncol Biol Phys 96:72–77CrossRefPubMedGoogle Scholar
  16. 16.
    Koller KM, Mackley HB, Liu J et al (2017) Improved survival and complete response rates in patients with advanced melanoma treated with concurrent ipilimumab and radiotherapy versus ipilimumab alone. Cancer Biol Ther 18:36–42CrossRefPubMedGoogle Scholar
  17. 17.
    Zak KM, Grudnik P, Magiera K et al (2017) Structural biology of the immune checkpoint receptor PD-1 and its ligands PD-L1/PD-L2. Structure 25:1163–1174CrossRefPubMedGoogle Scholar
  18. 18.
    Reck M, Rodríguez-Abreu D, Robinson AG et al (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375:1823–1833CrossRefPubMedGoogle Scholar
  19. 19.
    Gettinger S, Rizvi NA, Chow LQ et al (2016) Nivolumab monotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 34:2980–2987CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    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 35:226–235CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Department of Therapeutic OncologyKyoto University Graduate School of MedicineKyotoJapan
  2. 2.Department of DermatologyKyoto University Graduate School of MedicineKyotoJapan
  3. 3.Translational Research Department for Skin and Brain DiseasesKyoto University Graduate School of MedicineKyotoJapan

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