Targeted Oncology

, Volume 13, Issue 5, pp 611–619 | Cite as

Immediate Progressive Disease in Patients with Metastatic Renal Cell Carcinoma Treated with Nivolumab: a Multi-Institution Retrospective Study

  • Hiroki Ishihara
  • Tsunenori KondoEmail author
  • Toshio Takagi
  • Hidekazu Tachibana
  • Hironori Fukuda
  • Kazuhiko Yoshida
  • Junpei Iizuka
  • Hirohito Kobayashi
  • Kazunari Tanabe
Original Research Article



Investigations on rapid disease progression in patients with urologic malignancies treated with immune checkpoint inhibitors are currently lacking.


The objective of this study was to assess cases of rapid disease progression/immediate development of progressive disease (immediate PD) in patients with pretreated metastatic renal cell carcinoma (mRCC) treated with nivolumab.

Patients and Methods

Forty patients were retrospectively evaluated. Immediate PD within the initial two cycles of nivolumab therapy was clinically or objectively diagnosed. Clinical diagnosis was defined as an acceleration of symptoms directly caused by tumor growth or systematic worsening of the general condition, such as cachexia. Objective diagnosis was based on imaging evaluation using the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).


Seven patients (17.5%) developed immediate PD. For these patients, the median time from the initiation of nivolumab treatment to PD was 14 days; all seven patients subsequently died from the cancer. Progression-free survival (0.66 vs. 10.5 months; p < 0.0001) and overall survival (1.41 months vs. not reached; p < 0.0001) were significantly shorter in patients with immediate PD than in those without immediate PD. Further, female sex (p = 0.0434), poor Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score (p = 0.0263), and shorter prior-line time to progression (p = 0.0218) were associated with immediate PD.


The development of immediate PD in mRCC patients treated with nivolumab can severely worsen patient prognosis. Sex, MSKCC score, and prior-line time to progression may be involved in the development of immediate PD. Prospective studies are needed to further assess these findings.



The authors thank Dr. Kana Iwamoto (Department of Urology, Tokyo Women’s Medical University Medical Center East) for assisting with the data collection and Nobuko Hata (Department of Urology, Tokyo Women’s Medical University) for secretarial work.

Compliance with Ethical Standards


No external funding was used in the preparation of this manuscript.

Disclosure of Conflict of Interest

Tsunenori Kondo received honoraria from Pfizer, Bayer, and Novartis. Hiroki Ishihara, Toshio Takagi, Hidekazu Tachibana, Hironori Fukuda, Kazuhiko Yoshida, Junpei Iizuka, Hirohito Kobayashi, and Kazunari Tanabe declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

Supplementary material

11523_2018_591_MOESM1_ESM.pdf (76 kb)
ESM 1 (PDF 76 kb)


  1. 1.
    Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–13.CrossRefGoogle Scholar
  2. 2.
    Escudier B, Sharma P, McDermott DF, George S, Hammers HJ, Srinivas S, et al. CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol. 2017;72(6):962–71.Google Scholar
  3. 3.
    Cella D, Grunwald V, Nathan P, Doan J, Dastani H, Taylor F, et al. Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):994–1003.CrossRefGoogle Scholar
  4. 4.
    Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, et al. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup analysis from the CheckMate 025 study. Jpn J Clin Oncol. 2017;47(7):639–46CrossRefGoogle Scholar
  5. 5.
    Motzer RJ, Jonasch E, Agarwal N, Bhayani S, Bro WP, Chang SS, et al. Kidney Cancer, version 2.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2017;15(6):804–34.CrossRefGoogle Scholar
  6. 6.
    Clarke JM, George DJ, Lisi S, Salama AKS. Immune checkpoint blockade: the new frontier in Cancer treatment. Target Oncol. 2018;13(1):1–20.CrossRefGoogle Scholar
  7. 7.
    Champiat S, Dercle L, Ammari S, Massard C, Hollebecque A, Postel-Vinay S, et al. Hyperprogressive disease is a new pattern of progression in Cancer patients treated by anti-PD-1/PD-L1. Clin Cancer Res. 2017;23(8):1920–8.CrossRefGoogle Scholar
  8. 8.
    Saada-Bouzid E, Defaucheux C, Karabajakian A, Coloma VP, Servois V, Paoletti X, et al. Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol. 2017;28(7):1605–11.CrossRefGoogle Scholar
  9. 9.
    Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017;23(15):4242–50.CrossRefGoogle Scholar
  10. 10.
    Brower V. Hyperprogressive disease with anti-PD-1 and anti-PD-L1. Lancet Oncol. 2016;17(12):e527.CrossRefGoogle Scholar
  11. 11.
    Ishihara H, Kondo T, Fukuda H, Yoshida K, Omae K, Takagi T, et al. Evaluation of renal function change during first-line tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma. Jpn J Clin Oncol. 2017;47(12):1175–81.CrossRefGoogle Scholar
  12. 12.
    Ishihara H, Kondo T, Yoshida K, Omae K, Takagi T, Iizuka J, et al. Time to progression after first-line tyrosine kinase inhibitor predicts survival in patients with metastatic renal cell carcinoma receiving second-line molecular-targeted therapy. Urol Oncol. 2017;35(9):542.e1–.e9.CrossRefGoogle Scholar
  13. 13.
    Ishihara H, Takagi T, Kondo T, Tachibana H, Yoshida K, Omae K, et al. Efficacy and safety of third-line molecular-targeted therapy in metastatic renal cell carcinoma resistant to first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor and second-line therapy. Int J Clin Oncol. 2018;23(3):559–67.CrossRefGoogle Scholar
  14. 14.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.CrossRefGoogle Scholar
  15. 15.
    Motzer RJ, Bacik J, Schwartz LH, Reuter V, Russo P, Marion S, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol. 2004;22(3):454–63.CrossRefGoogle Scholar
  16. 16.
    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.CrossRefGoogle Scholar
  17. 17.
    Seidel C, Busch J, Weikert S, Steffens S, Fenner M, Ganser A, et al. Progression free survival of first line vascular endothelial growth factor-targeted therapy is an important prognostic parameter in patients with metastatic renal cell carcinoma. Eur J Cancer. 2012;48(7):1023–30.CrossRefGoogle Scholar
  18. 18.
    Wells JC, Stukalin I, Norton C, Srinivas S, Lee JL, Donskov F, et al. Third-line targeted therapy in metastatic renal cell carcinoma: results from the international metastatic renal cell carcinoma database consortium. Eur Urol. 2017;71(2):204–9.CrossRefGoogle Scholar
  19. 19.
    Conforti F, Pala L, Bagnardi V, De Pas T, Martinetti M, Viale G, et al. Cancer immunotherapy efficacy and patients’ sex: a systematic review and meta-analysis. Lancet Oncol. 2018;19(6):737–46.CrossRefGoogle Scholar
  20. 20.
    Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16(10):626–38.CrossRefGoogle Scholar
  21. 21.
    Lin PY, Sun L, Thibodeaux SR, Ludwig SM, Vadlamudi RK, Hurez VJ, et al. B7-H1-dependent sex-related differences in tumor immunity and immunotherapy responses. J Immunol. 2010;185(5):2747–53.CrossRefGoogle Scholar
  22. 22.
    Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus Ipilimumab versus Sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277–90.CrossRefGoogle Scholar
  23. 23.
    Kanai O, Fujita K, Okamura M, Nakatani K, Mio T. Severe exacerbation or manifestation of primary disease related to nivolumab in non-small-cell lung cancer patients with poor performance status or brain metastases. Ann Oncol. 2016;27(7):1354–6.CrossRefGoogle Scholar
  24. 24.
    Iacovelli R, Massari F, Albiges L, Loriot Y, Massard C, Fizazi K, et al. Evidence and clinical relevance of tumor flare in patients who discontinue tyrosine kinase inhibitors for treatment of metastatic renal cell carcinoma. Eur Urol. 2015;68(1):154–60.CrossRefGoogle Scholar
  25. 25.
    Chaft JE, Oxnard GR, Sima CS, Kris MG, Miller VA, Riely GJ. Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design. Clin Cancer Res. 2011;17(19):6298–303.CrossRefGoogle Scholar
  26. 26.
    Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541(7637):321–30.CrossRefGoogle Scholar
  27. 27.
    Manson G, Norwood J, Marabelle A, Kohrt H, Houot R. Biomarkers associated with checkpoint inhibitors. Ann Oncol. 2016;27(7):1199–206.CrossRefGoogle Scholar
  28. 28.
    Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4(1):71–8.CrossRefGoogle Scholar
  29. 29.
    DeNardo DG, Andreu P, Coussens LM. Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity. Cancer Metastasis Rev. 2010;29(2):309–16.CrossRefGoogle Scholar
  30. 30.
    Sen DR, Kaminski J, Barnitz RA, Kurachi M, Gerdemann U, Yates KB, et al. The epigenetic landscape of T cell exhaustion. Science. 2016;354(6316):1165–9.CrossRefGoogle Scholar
  31. 31.
    Miao D, Margolis CA, Gao W, Voss MH, Li W, Martini DJ, et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science. 2018;359(6377):801–6.CrossRefGoogle Scholar
  32. 32.
    Pan D, Kobayashi A, Jiang P, Ferrari de Andrade L, Tay RE, Luoma AM, et al. A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science. 2018;359(6377):770–5.CrossRefGoogle Scholar
  33. 33.
    Tazdait M, Mezquita L, Lahmar J, Ferrara R, Bidault F, Ammari S, et al. Patterns of responses in metastatic NSCLC during PD-1 or PDL-1 inhibitor therapy: comparison of RECIST 1.1, irRECIST and iRECIST criteria. Eur J Cancer. 2018;88:38–47.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Hiroki Ishihara
    • 1
  • Tsunenori Kondo
    • 2
    Email author
  • Toshio Takagi
    • 1
  • Hidekazu Tachibana
    • 2
  • Hironori Fukuda
    • 1
  • Kazuhiko Yoshida
    • 1
  • Junpei Iizuka
    • 1
  • Hirohito Kobayashi
    • 1
  • Kazunari Tanabe
    • 1
  1. 1.Department of UrologyTokyo Women’s Medical UniversityTokyoJapan
  2. 2.Department of UrologyTokyo Women’s Medical University Medical Center EastTokyoJapan

Personalised recommendations