Skip to main content

Advertisement

SpringerLink
Log in

How to optimize the use of adjuvant pembrolizumab in renal cell carcinoma: which patients benefit the most?

  • Original Article
  • Published:
World Journal of Urology Aims and scope Submit manuscript

Abstract

Purpose

The KEYNOTE-564 trial showed improved disease-free survival (DFS) for patients with high-risk renal cell carcinoma (RCC) receiving adjuvant pembrolizumab as compared to placebo. However, if systematically administered to all high-risk patients, it might lead to the overtreatment in a non-negligible proportion of patient. Therefore, we aimed to determine the optimal candidate for adjuvant pembrolizumab.

Methods

Within a prospectively maintained database we selected patients who fulfilled the inclusion criteria of the KEYNOTE-564. We compared baseline characteristics and oncologic outcomes in this cohort with those of the placebo arm of the KEYNOTE-564. Regression tree analyses was used to generate a risk stratification tool to predict 1-year DFS after surgery.

Results

In the off-trial setting, patients had worse tumor characteristics then in the KEYNOTE-564 placebo arm, i.e. there were more pT4 (5.4 vs. 2.7%, p = 0.046) and pN1 (15 vs. 6.3%, p < 0.001) cases. Median DFS was 29 (95% CI 21–35) months as compared to value not reached in KEYNOTE-564 and 1-year DFS was 64.2% (95% CI 59.6–69.2) as compared to 76.2% (95% CI 72.2–79.7), respectively. Patients with pN1 were at the highest risk of 1-year recurrence (1-year DFS 28.6% [95% CI 20.2–40.3]); patients without LNI, but necrosis were at intermediate risk (1-year DFS 62.5% [95% CI 56.9–68.8]); those without LNI and necrosis were at the lowest risk (1-year DFS 83.8% [95% CI 79.1–88.9]). LVI substratification furtherly improved the accuracy in the prediction of early recurrence.

Conclusions

Patients potentially eligible for adjuvant pembrolizumab have worse characteristics and DFS in the off-trial setting as compared to the placebo arm of the KEYNOTE-564. Patients with either LNI or necrosis were at the highest risk of early-recurrence, which make them the ideal candidate to adjuvant pembrolizumab.

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

Similar content being viewed by others

References

  1. Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Chang Y-H et al (2021) Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. New Engl J Med 385:683–694. https://doi.org/10.1056/nejmoa2106391

    Article  CAS  PubMed  Google Scholar 

  2. Network NCC (n.d.) Kidney Cancer Version 4.2022. https://www.nccn.org/login?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf (accessed Decr 26, 2021).

  3. Powles T, Albiges L, Bex A, Grünwald V, Porta C, Procopio G et al (2021) ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma. Ann Oncol 32:1511–1519. https://doi.org/10.1016/j.annonc.2021.09.014

    Article  CAS  PubMed  Google Scholar 

  4. Bedke J, Albiges L, Capitanio U, Giles RH, Hora M, Lam TB et al (2021) 2021 Updated European Association of Urology guidelines on the use of adjuvant pembrolizumab for renal cell carcinoma. Eur Urol 81:134–137. https://doi.org/10.1016/j.eururo.2021.11.022

    Article  CAS  PubMed  Google Scholar 

  5. Capitanio U, Montorsi F (2016) Renal cancer. Lancet 387:894–906. https://doi.org/10.1016/s0140-6736(15)00046-x

    Article  PubMed  Google Scholar 

  6. Martini A, Fallara G, Pellegrino F, Cirulli GO, Larcher A, Necchi A et al (2021) Neoadjuvant and adjuvant immunotherapy in renal cell carcinoma. World J Urol. https://doi.org/10.1007/s00345-020-03550-z

    Article  PubMed  Google Scholar 

  7. Bristol Myers Squibb Provides Update on CheckMate -914 Trial Evaluating Opdivo (nivolumab) Plus Yervoy (ipilimumab) as Adjuvant Treatment of Localized Renal Cell Carcinoma. Bristol Myers Squibb Provides Update on CheckMate -914 Trial Evaluating Opdivo (Nivolumab) Plus Yervoy (Ipilimumab) as Adjuvant Treatment of Localized Renal Cell Carcinoma 2022. https://news.bms.com/news/details/2022/Bristol-Myers-Squibb-Provides-Update-on-CheckMate--914-Trial-Evaluating-Opdivo-nivolumab-Plus-Yervoy-ipilimumab-as-Adjuvant-Treatment-of-Localized-Renal-Cell-Carcinoma/default.aspx (accessed Aug 16, 2022)

  8. Roche’s Tecentriq flunks in postsurgery kidney cancer as early-stage liver, lung cancer readouts draw near 2022. https://www.fiercepharma.com/pharma/roches-tecentriq-flunks-postsurgery-kidney-cancer-early-stage-liver-lung-cancer-readout-draw (accessed Aug 16, 2022)

  9. Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 40:373–383. https://doi.org/10.1016/0021-9681(87)90171-8

    Article  CAS  PubMed  Google Scholar 

  10. Paner GP, Stadler WM, Hansel DE, Montironi R, Lin DW, Amin MB (2018) Updates in the eighth edition of the Tumor-Node-Metastasis staging classification for urologic cancers. Eur Urol 73:560–569. https://doi.org/10.1016/j.eururo.2017.12.018

    Article  PubMed  Google Scholar 

  11. Guyot P, Ades A, Ouwens MJ, Welton NJ (2012) Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan−Meier survival curves. Bmc Med Res Methodol 12:9. https://doi.org/10.1186/1471-2288-12-9

    Article  PubMed  PubMed Central  Google Scholar 

  12. Gul A, Rini BI (2019) Adjuvant therapy in renal cell carcinoma. Cancer 125:2935–2944. https://doi.org/10.1002/cncr.32144

    Article  PubMed  Google Scholar 

  13. Verma V, Sprave T, Haque W, Simone CB, Chang JY, Welsh JW et al (2018) A systematic review of the cost and cost-effectiveness studies of immune checkpoint inhibitors. J Immunother Cancer 6:128. https://doi.org/10.1186/s40425-018-0442-7

    Article  PubMed  PubMed Central  Google Scholar 

  14. Marchioni M, Bandini M, Pompe RS, Martel T, Tian Z, Shariat SF et al (2018) The impact of lymph node dissection and positive lymph nodes on cancer-specific mortality in contemporary pT2-3 non-metastatic renal cell carcinoma treated with radical nephrectomy. Bju Int 121:383–392. https://doi.org/10.1111/bju.14024

    Article  PubMed  Google Scholar 

  15. Capitanio U, Becker F, Blute ML, Mulders P, Patard J-J, Russo P et al (2011) Lymph node dissection in renal cell carcinoma. Eur Urol 60:1212–1220. https://doi.org/10.1016/j.eururo.2011.09.003

    Article  PubMed  Google Scholar 

  16. Capitanio U, Stewart GD, Larcher A, Ouzaid I, Akdogan B, Roscigno M et al (2017) European temporal trends in the use of lymph node dissection in patients with renal cancer. Eur J Surg Oncol 43:2184–2192. https://doi.org/10.1016/j.ejso.2017.07.016

    Article  CAS  PubMed  Google Scholar 

  17. Bandini M, Smith A, Zaffuto E, Pompe RS, Marchioni M, Capitanio U et al (2017) Effect of pathological high-risk features on cancer-specific mortality in non-metastatic clear cell renal cell carcinoma: a tool for optimizing patient selection for adjuvant therapy. World J Urol 36:51–57. https://doi.org/10.1007/s00345-017-2093-6

    Article  PubMed  Google Scholar 

  18. Rosiello G, Larcher A, Fallara G, Giancristofaro C, Martini A, Re C et al (2022) Head-to-head comparison of all the prognostic models recommended by the European Association of Urology Guidelines to predict oncologic outcomes in patients with renal cell carcinoma. Urol Oncol Semin Orig Investig. https://doi.org/10.1016/j.urolonc.2021.12.010

    Article  Google Scholar 

  19. Capitanio U, Larcher A, Montorsi F (2021) Re: Toni K. Choueiri, Piotr Tomczak, Se Hoon Park, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med 2021;385:683–94 Adjuvant pembrolizumab after nephrectomy: a plea to reconsider the need for lymph node dissection. Eur Urol. https://doi.org/10.1016/j.eururo.2021.09.034

    Article  PubMed  Google Scholar 

  20. Marconi L, Sun M, Beisland C, Klatte T, Ljungberg B, Stewart GD et al (2021) Prevalence, disease-free, and overall survival of contemporary patients with renal cell carcinoma eligible for adjuvant checkpoint inhibitor trials. Clin Genitourin Cancer 19:e92–e99. https://doi.org/10.1016/j.clgc.2020.12.005

    Article  PubMed  Google Scholar 

  21. Palumbo C, Mazzone E, Mistretta FA, Knipper S, Perrotte P, Shariat SF et al (2020) A plea for optimizing selection in current adjuvant immunotherapy trials for high-risk nonmetastatic renal cell carcinoma according to expected cancer-specific mortality. Clin Genitourin Cancer 18:314-321.e1. https://doi.org/10.1016/j.clgc.2019.11.010

    Article  PubMed  Google Scholar 

  22. Harshman LC, Xie W, Moreira RB, Bossé D, Ares GJR, Sweeney CJ et al (2018) Evaluation of disease-free survival as an intermediate metric of overall survival in patients with localized renal cell carcinoma: a trial-level meta-analysis. Cancer 124:925–933. https://doi.org/10.1002/cncr.31154

    Article  PubMed  Google Scholar 

  23. Fallara G, Bandini M, Larcher A, Pederzoli F, Karakiewicz P, Tian Z et al (2021) High-risk surgically resected renal cell carcinoma: Is there a role for adjuvant VEGF-TKI inhibitors? Curr Prob Cancer. https://doi.org/10.1016/j.currproblcancer.2021.100759

    Article  Google Scholar 

Download references

Funding

None.

Author information

Authors and Affiliations

  1. Division of Experimental Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy

    Giuseppe Fallara, Alessandro Larcher, Giuseppe Rosiello, Giuseppe Basile, Gianmarco Colandrea, Daniele Cignoli, Federico Belladelli, Chiara Re, Giacomo Musso, Francesco Cei, Roberto Bertini, Alberto Briganti, Andrea Salonia, Francesco Montorsi & Umberto Capitanio

  2. University Vita-Salute San Raffaele, Milan, Italy

    Giuseppe Fallara, Alessandro Larcher, Giuseppe Rosiello, Daniele Raggi, Laura Marandino, Giuseppe Basile, Gianmarco Colandrea, Daniele Cignoli, Federico Belladelli, Chiara Re, Giacomo Musso, Francesco Cei, Roberto Bertini, Alberto Briganti, Andrea Salonia, Francesco Montorsi, Andrea Necchi & Umberto Capitanio

  3. Division of Experimental Oncology/Unit of Oncology, IRCCS Ospedale San Raffaele, Milan, Italy

    Daniele Raggi, Laura Marandino & Andrea Necchi

  4. Department of Urology, La Croix du Sud Hospital, Toulouse, France

    Alberto Martini

  5. Department of Urology, Institut Universitaire du Cancer Toulouse-Oncopôle, Toulouse, France

    Alberto Martini

Authors
  1. Giuseppe Fallara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alessandro Larcher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giuseppe Rosiello
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniele Raggi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Laura Marandino
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alberto Martini
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Giuseppe Basile
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gianmarco Colandrea
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Daniele Cignoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Federico Belladelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Chiara Re
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Giacomo Musso
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Francesco Cei
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Roberto Bertini
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Alberto Briganti
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Andrea Salonia
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Francesco Montorsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Andrea Necchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Umberto Capitanio
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

GF: project development; data collection or management; data analysis; manuscript writing/editing. AL: data collection or management; manuscript writing/editing. GR: data collection or management; manuscript writing/editing. DR: data collection or management; manuscript writing/editing. LM: data collection or management; manuscript writing/editing. AM: data collection or management; manuscript writing/editing. GB: data collection or management; manuscript writing/editing. GC: data collection or management; manuscript writing/editing. DC: data collection or management; manuscript writing/editing. FB: data collection or management; manuscript writing/editing. CR: data collection or management; manuscript writing/editing. GM: data collection or management; manuscript writing/editing. FC: data collection or management; manuscript writing/editing. RB: data collection or management; manuscript writing/editing. AB: data collection or management; manuscript writing/editing. AS: data collection or management; manuscript writing/editing. FM: data collection or management; manuscript writing/editing. AN: data collection or management; manuscript writing/editing. UC: data collection or management; manuscript writing/editing.

Corresponding author

Correspondence to Giuseppe Fallara.

Ethics declarations

Conflict of interest

Necchi reports honoraria from Roche, Merck Sharp & Dohme, AstraZeneca, Janssen Pharmaceuticals and Foundation Medicine; has served as a consultant or advisor for Merck Sharp & Dohme, Bristol-Myers Squibb, Rainier Therapeutics, Roche, Bayer, AstraZeneca, Clovis Oncology, Janssen Pharmaceuticals, Incyte, Seattle Genetics, Astellas Pharma and Rainier Therapeutics; has received research funding from Incyte, Merck Sharp & Dohme (institution), and AstraZeneca (institution); and has received travel funding from Roche, Merck Sharp & Dohme, Astra Zeneca, and Janssen Pharmaceuticals outside the submitted work.

Ethical approval and informed consent

The study has been conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from all individual participants included in the study. The study was approved by the IRCCS San Raffaele Hospital Ethical Committee (protocollo RENE-versione 29/08/2007-Ospedale San Raffaele di Milano).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 9409 KB)

Supplementary file2 (DOCX 15 KB)

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fallara, G., Larcher, A., Rosiello, G. et al. How to optimize the use of adjuvant pembrolizumab in renal cell carcinoma: which patients benefit the most?. World J Urol 40, 2667–2673 (2022). https://doi.org/10.1007/s00345-022-04153-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00345-022-04153-6

Keywords

Search

Navigation