Advertisement

Journal of Cancer Research and Clinical Oncology

, Volume 145, Issue 2, pp 511–521 | Cite as

Immune-related adverse events correlate with improved survival in patients undergoing anti-PD1 immunotherapy for metastatic melanoma

  • Alice IndiniEmail author
  • Lorenza Di Guardo
  • Carolina Cimminiello
  • Michele Prisciandaro
  • Giovanni Randon
  • Filippo De Braud
  • Michele Del Vecchio
Original Article – Clinical Oncology

Abstract

Background

Therapeutic chances for metastatic melanoma have consistently changed over the last years with the advent of antibodies targeting the programmed cell death protein-1 (PD-1). Onset of immune-related adverse events (irAEs) during treatment can be a source of concern, and the association with survival outcome is yet to be defined.

Patients and methods

Data of consecutive patients treated with anti-PD1 (nivolumab or pembrolizumab) for metastatic melanoma between July 2013 and January 2018 were retrospectively reviewed. Baseline factors, together with onset of irAEs and vitiligo during treatment, were evaluated to identify predictors of progression-free (PFS) and overall (OS) survival. PFS and OS were assessed using Kaplan–Meier and Cox models.

Results

Overall, 173 patients were included in the present analysis, and 102 patients (59%) experienced irAEs. Disease control rate was 51%. Median (interquartile range) PFS and OS were 4.9 (2.6–13.3) and 8.6 (3.5–18.3) months, respectively. At multivariate analysis, irAEs occurrence was independently associated with improved PFS [HR 0.47 (95% CI 0.26, 0.86); p = 0.016], and correlated with better OS [HR 0.39 (95% CI 0.18, 0.81); p = 0.007]. Among various irAEs, the occurrence of vitiligo was associated with a trend toward a non-significant improved OS in comparison with other irAEs (p = 0.061). Median OS was undefined for patients experiencing vitiligo vs. 21.9 months for patients with other irAEs vs. 9.7 months for patients who had no irAEs (p = 0.003).

Conclusions

Our study underlines the association between irAEs and survival outcomes from anti-PD1 therapy. Careful management of treatment-related toxicity can lead to achieve maximum clinical benefit from this therapy.

Keywords

Melanoma Immunotherapy Anti-PD1 IrAEs Vitiligo Toxicity 

Notes

Funding

No fundings were received for the present investigation.

Compliance with ethical standards

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.

Human rights and animal participants

This article does not contain any studies with animals performed by any of the authors.

Informed consent

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

Supplementary material

432_2018_2819_MOESM1_ESM.docx (16 kb)
Supplementary material 1 (DOCX 16 KB)

References

  1. Boasberg PD, Hoon DS, Piro LD et al (2006) Enhanced survival associated with vitiligo expression during maintenance biotherapy for metastatic melanoma. J Invest Dermatol 126:2658–2663CrossRefGoogle Scholar
  2. Boudewijns S, Westdorp H, Koornstra RH et al (2016) Immune-related adverse events of dendritic cell vaccination correlate with immunologic and clinical outcome in stage III and IV melanoma patients. J Immunother 39:241–248CrossRefGoogle Scholar
  3. Bouwhuis MG, Ten Hagen TL, Suciu S, Eggermont AM (2011) Autoimmunity and treatment outcome in melanoma. Curr Opin Oncol 23:170–176CrossRefGoogle Scholar
  4. Brahmer JR, Lacchetti C, Schneider BJ et al (2018) Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 36:1714–1768CrossRefGoogle Scholar
  5. Downey SG, Klapper JA, Smith FO et al (2007) Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res 12:6681–6688CrossRefGoogle Scholar
  6. Eggermont AMM, Christian UB, Blank MD et al (2018) Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med 378:1789–1801CrossRefGoogle Scholar
  7. Feng Y, Roy A, Masson E et al (2013) Exposure-response relationships of the efficacy and safety of ipilimumab in patients with advanced melanoma. Clin Cancer Res 19:3977–3986CrossRefGoogle Scholar
  8. Freeman-Keller M, Kim Y, Cronin H (2016) Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res 22:886–894CrossRefGoogle Scholar
  9. Gogas H, Ioannovich J, Dafni U et al (2006) Prognostic significante of autoimmunity during treatment of melanoma with interferon. N Engl J Med 354:709–718CrossRefGoogle Scholar
  10. Heidelberger V, Goldwasser F, Kramkimel N et al (2017) Clinical parameters associated with anti-programmed death-1 (PD-1) inhibitors-induced tumor response in melanoma patients. Invest New Drugs 35:842–847CrossRefGoogle Scholar
  11. Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723CrossRefGoogle Scholar
  12. Hu Y, Smolkin ME, White EJ et al (2014) Inflammatory adverse events are associated with disease-free survival after vaccine therapy among patients with melanoma. Ann Surg Oncol 21:3978–3984CrossRefGoogle Scholar
  13. Hua C, Boussemart L, Mateus C (2016) Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol 152:45–51CrossRefGoogle Scholar
  14. Ku G, Yuan J, Page D et al (2010) Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting. Cancer 116:1767–1775CrossRefGoogle Scholar
  15. Larkin J, Chiarion-Sileni V, Gonzalez R et al (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23–34CrossRefGoogle Scholar
  16. Nakamura Y, Kitano S, Takahashi A et al (2016) Nivolumab for advanced melanoma: pretreatment prognostic factors and early outcome markers during therapy. Oncotarget 7:77404–77415Google Scholar
  17. Nakamura Y, Tanaka R, Asami Y et al (2017) Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: A multi-institutional retrospective study. J Dermatol 44:117–122CrossRefGoogle Scholar
  18. Nosrati A, Tsai KK, Goldinger SM et al (2017) Evaluation of clinicopathological factors in PD-1 response: derivation and validation of a prediction scale for response to PD-1 monotherapy. Br J Cancer 116:1141–1147CrossRefGoogle Scholar
  19. 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 16:908–918CrossRefGoogle Scholar
  20. Robert C, Schachter J, Long GV et al (2015) Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 372:2521–2532CrossRefGoogle Scholar
  21. Teulings HE, Limpens J, Jansen SN et al (2015) Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol 33:773–781CrossRefGoogle Scholar
  22. Toi Y, Sugawara S, Kawashima Y et al (2018) Association of immune-related adverse events with clinical benefit in patients with advanced non-small-cell lung cancer treated with nivolumab. Oncologist 23:1358–1365CrossRefGoogle Scholar
  23. Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454CrossRefGoogle Scholar
  24. Wang DY, Salem JE, Cohen JV et al (2018) Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol.  https://doi.org/10.1001/jamaoncol.2018.3923 Google Scholar
  25. Weber JS, D’Angelo SP, Minor D 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 16:375–384CrossRefGoogle Scholar
  26. Weber J, Mandala M, Del Vecchio M et al (2017a) Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 377:1824–1835CrossRefGoogle Scholar
  27. Weber JS, Hodi FS, Wolchok JD et al (2017b) Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol 35:785–792CrossRefGoogle Scholar
  28. Weide B, Martens A, Hassel JC et al (2016) baseline biomarkers for outcome of melanoma patients treated with pembrolizumab. Clin Cancer Res 22:5487–5496CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Melanoma Medical Oncology Unit, Department of Medical Oncology and HematologyFondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
  2. 2.Department of Medical Oncology and HematologyFondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
  3. 3.Università degli studi di MilanoFondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly

Personalised recommendations