Skip to main content
SpringerLink
Log in

Targeted therapies for renal cell carcinoma: understanding their impact on survival

  • Review
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

Within the past 5 years, the United States Food and Drug Administration have approved six targeted agents for the treatment of metastatic renal cell carcinoma (mRCC). While this offers great potential to patients afflicted with this disease, oncologists are faced with the challenge of applying each agent in the appropriate clinical setting. Doing so requires an intricate understanding of the pivotal trials evaluating these agents. Herein, we have provided a detailed analysis of the study design employed in these trials. Use of appropriate comparator arms for targeted therapies (i.e., interferon-α or placebo) is addressed. Furthermore, we discuss the relative merits of using progression-free survival (PFS) or overall survival (OS) as a primary endpoint—importantly, the two endpoints may not be precisely correlated. Strategies to appropriately interpret OS in the context of post-study therapies and crossover designs are described. Ultimately, head-to-head trials comparing targeted therapies are necessary to resolve clinical equipoise. Several ongoing efforts juxtaposing the approved agents for mRCC are discussed.

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. Paget S (1889) The distribution of secondary growth in cancer of the breast. Lancet 133(3421):571–573

    Article  Google Scholar 

  2. Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M (2002) Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 20(1):289–296. doi:10.1200/jco.20.1.289

    Article  CAS  PubMed  Google Scholar 

  3. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA (2009) Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 27(22):3584–3590. doi:10.1200/jco.2008.20.1293

    Article  CAS  PubMed  Google Scholar 

  4. Escudier BJ, Bellmunt J, Negrier S, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, on behalf of the AVOREN Investigators (2009) Final results of the phase iii, randomized, double-blind AVOREN trial of first-line bevacizumab (bev) + interferon-{alpha}2a (IFN) in metastatic renal cell carcinoma (mRCC). J Clin Oncol (Meeting Abstracts) 27(15S):5020

    Google Scholar 

  5. Rini BI, Halabi S, Rosenberg J, Stadler WM, Vaena DA, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ (2009) Bevacizumab plus interferon-alpha versus interferon-alpha monotherapy in patients with metastatic renal cell carcinoma: Results of overall survival for calgb 90206. J Clin Oncol (Meeting Abstracts) 27(18S):LBA5019-

    Google Scholar 

  6. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IGH, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ, the Global ARCC Trial (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356(22):2271–2281. doi:10.1056/NEJMoa066838

    Article  CAS  PubMed  Google Scholar 

  7. Medical research council renal cancer collaborators (1999) Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet 353(9146):14–17. doi:S0140673698035442

    Article  Google Scholar 

  8. Sternberg CN, Szczylik C, Lee E, Salman PV, Mardiak J, Davis ID, Pandite L, Chen M, McCann L, Hawkins R (2009) A randomized, double-blind phase iii study of pazopanib in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). J Clin Oncol (Meeting Abstracts) 27(15S):5021-

    Google Scholar 

  9. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarba JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE. Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomized phase iii trial. J Clin Oncol 28(6):1061–1068. doi:10.1200/jco.2009.23.9764

  10. Van Gool AR, Verkerk R, Fekkes D, Sleijfer S, Bannink M, Kruit WHJ, van der Holt B, Scharpé S, Eggermont AMM, Stoter G, Hengeveld MW (2008) Plasma activity of prolyl endopeptidase in relation to psychopathology during immunotherapy with ifn-î± in patients with renal cell carcinoma. J Interferon Cytokine Res 28(5):283–286. doi:10.1089/jir.2007.0058

    Article  PubMed  Google Scholar 

  11. Beckman M (2007) More clinical cancer treatments judged by progression-free rather than overall survival. J Natl Cancer Inst 99(14):1068–1069. doi:10.1093/jnci/djm073

    Article  PubMed  Google Scholar 

  12. Trask PC, Bushmakin AG, Cappelleri JC, Bycott P, Liau K, Kim S (2008) Health-related quality of life during treatment for renal cell carcinoma: results from a phase II study of axitinib. Acta Oncol 47(5):843–851. doi:10.1080/02841860802047395

    Article  CAS  PubMed  Google Scholar 

  13. Johnson JR, Williams G, Pazdur R (2003) End points and united states food and drug administration approval of oncology drugs. J Clin Oncol 21(7):1404–1411. doi:10.1200/jco.2003.08.072

    Article  PubMed  Google Scholar 

  14. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D (2005) Vegfr1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438(7069):820–827

    Article  CAS  PubMed  Google Scholar 

  15. Lebwohl DMD, Kay AMD, Berg WMD, Baladi JF, Zheng J (2009) Progression-free survival: gaining on overall survival as a gold standard and accelerating drug development. Cancer J September/October 15(5):386–394

    CAS  Google Scholar 

  16. Chia SK, Speers CH, D'yachkova Y, Kang A, Malfair-Taylor S, Barnett J, Coldman A, Gelmon KA, O'Reilly SE, Olivotto IA (2007) The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with metastatic breast cancer. Cancer 110(5):973–979

    Article  PubMed  Google Scholar 

  17. Grothey A, Sargent D, Goldberg RM, Schmoll H-J (2004) Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 22(7):1209–1214. doi:10.1200/jco.2004.11.037

    Article  CAS  PubMed  Google Scholar 

  18. Thiesse P, Ollivier L, Di Stefano-Louineau D, Negrier S, Savary J, Pignard K, Lasset C, Escudier B (1997) Response rate accuracy in oncology trials: reasons for interobserver variability. Groupe francais d'immunotherapie of the federation nationale des centres de lutte contre le cancer. J Clin Oncol 15(12):3507–3514

    CAS  PubMed  Google Scholar 

  19. Ford R, Schwartz L, Dancey J, Dodd LE, Eisenhauer EA, Gwyther S, Rubinstein L, Sargent D, Shankar L, Therasse P, Verweij J (2009) Lessons learned from independent central review. Eur J Cancer 45(2):268–274

    Article  CAS  PubMed  Google Scholar 

  20. Bast RC, Thigpen JT, Arbuck SG, Basen-Engquist K, Burke LB, Freedman R, Horning SJ, Ozols R, Rustin GJ, Spriggs D, Wenzel LB, Pazdur R (2007) Clinical trial endpoints in ovarian cancer: Report of an fda/asco/aacr public workshop. Gynecol Oncol 107(2):173–176

    Article  PubMed  Google Scholar 

  21. de Gramont A, Hubbard J, Shi Q, O'Connell MJ, Buyse M, Benedetti J, Bot B, O'Callaghan C, Yothers G, Goldberg RM, Blanke CD, Benson A, Deng Q, Alberts SR, Andre T, Wolmark N, Grothey A, Sargent D. Association between disease-free survival and overall survival when survival is prolonged after recurrence in patients receiving cytotoxic adjuvant therapy for colon cancer: Simulations based on the 20,800 patient accent data set. J Clin Oncol 28(3):460–465. doi:10.1200/jco.2009.23.1407

  22. Tang PA, Bentzen SM, Chen EX, Siu LL (2007) Surrogate end points for median overall survival in metastatic colorectal cancer: Literature-based analysis from 39 randomized controlled trials of first-line chemotherapy. J Clin Oncol 25(29):4562–4568. doi:10.1200/jco.2006.08.1935

    Article  PubMed  Google Scholar 

  23. Delea TE, Khuu A, Kay A, Zheng J, Baladi JF (2009) Association between treatment effects on disease progression (dp) endpoints and overall survival (os) in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol (Meeting Abstracts) 27(15S):5105-

    Google Scholar 

  24. Halabi S, Rini BI, Stadler WM, Small EJ (2010) Use of progression-free survival (pfs) to predict overall survival (os) in patients with metastatic renal cell carcinoma (mrcc). J Clin Oncol 28:7s, suppl; abstr 4525

    Article  Google Scholar 

  25. Robins JM, Tsiatis AA (1991) Correcting for non-compliance in randomized trials using rank preserving structural failure time models. Commun Stat, Theory Methods 20(8):2609–2631

    Article  Google Scholar 

  26. Demetri GD, Huang X, Garrett CR, Schoffski P, Blackstein ME, Shah MH, Verweij J, Tassell V, Baum CM, Casali PG (2008) Novel statistical analysis of long-term survival to account for crossover in a phase III trial of sunitinib (su) vs. placebo (pl) in advanced gist after imatinib (im) failure. J Clin Oncol (Meeting Abstracts) 26(15_suppl):10524-

    Google Scholar 

  27. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM, the TARGET Study Group (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356(2):125–134. doi:10.1056/NEJMoa060655

    Article  Google Scholar 

  28. Tanaka C, O'Reilly T, Kovarik JM, Shand N, Hazell K, Judson I, Raymond E, Zumstein-Mecker S, Stephan C, Boulay A, Hattenberger M, Thomas G, Lane HA (2008) Identifying optimal biologic doses of everolimus (rad001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol 26(10):1596–1602. doi:10.1200/jco.2007.14.1127

    CAS  PubMed  Google Scholar 

  29. Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: Final results of calgb 90206. J Clin Oncol doi:10.1200/jco.2009.26.5561

  30. Escudier B, Bellmunt J, Negrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, Sneller V. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): Final analysis of overall survival. J Clin Oncol doi:10.1200/jco.2009.26.7849

  31. Wilmes LJ, Pallavicini MG, Fleming LM, Gibbs J, Wang D, Li K-L, Partridge SC, Henry RG, Shalinsky DR, Hu-Lowe D, Park JW, McShane TM, Lu Y, Brasch RC, Hylton NM (2007) Ag-013736, a novel inhibitor of VEGF receptor tyrosine kinases, inhibits breast cancer growth and decreases vascular permeability as detected by dynamic contrast-enhanced magnetic resonance imaging. Magn Reson Imaging 25(3):319–327

    Article  CAS  PubMed  Google Scholar 

  32. Dham A, Dudek AZ (2007) Sequential therapy with sorafenib and sunitinib in renal cell carcinoma. J Clin Oncol (2007 ASCO Annual Meeting Proceedings Part I) 25(18S):5106-

    Google Scholar 

  33. Vickers MM, Choueiri TK, Zama I, Cheng T, North S, Knox JJ, Kollmannsberger C, McDermott DF, Rini BI, Heng DY (2009) Failure of initial VEGF-targeted therapy in metastatic renal cell carcinoma (mRCC): What next? J Clin Oncol (Meeting Abstracts) 27(15S):5098-

    Google Scholar 

  34. Gez E, Rubinov R, Gaitini D, Meretyk S, Best LA, Mashiach T, Native O, Stein A, Kuten A (2007) Immuno-chemotherapy in metastatic renal cell carcinoma: Long-term results from the rambam and linn medical centers, haifa, israel. J Chemother 19(1):79–84

    CAS  PubMed  Google Scholar 

  35. Rini BI, Wilding G, Hudes G, Stadler WM, Kim S, Tarazi J, Rosbrook B, Trask PC, Wood L, Dutcher JP (2009) Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol 27(27):4462–4468. doi:10.1200/jco.2008.21.7034

    Article  CAS  PubMed  Google Scholar 

  36. Gigante M, Mandic M, Wesa AK, Cavalcanti E, Dambrosio M, Mancini V, Battaglia M, Gesualdo L, Storkus WJ, Ranieri E (2008) Interferon-alpha (IFN-[alpha])-conditioned dc preferentially stimulate type-1 and limit treg-type in vitro t-cell responses from RCC patients. J Immunother 31(3):254–262, 210.1097/CJI.1090b1013e318167b318023

    Article  CAS  PubMed  Google Scholar 

  37. Heymach J, Tran HT, Fritsche HA, Gornet TG, Liu Y, Rajagopalan D, Figlin RA, Amado RG, Pandite L (2009) Lower baseline levels of plasma hepatocyte growth factor (HGF), il-6 and il-8 are correlated with tumor shrinkage in renal cell carcinoma patients treated with pazopanib. Presented at the AACR-NCI-EORTC International Conference on Molecular Targets adn Cancer Therapeutics; November 15–17, 2009; Boston, MA [Abstr A11]

  38. Gordan JD, Lal P, Dondeti VR, Letrero R, Parekh KN, Oquendo CE, Greenberg RA, Flaherty KT, Rathmell WK, Keith B, Simon MC, Nathanson KL (2008) HIF-alpha effects on c-myc distinguish two subtypes of sporadic vhl-deficient clear cell renal carcinoma. Cancer Cell 14(6):435–446. doi:S1535-6108(08)00366-8016/j.ccr.2008.10.016

    Article  CAS  PubMed  Google Scholar 

  39. Rini BI, Zhou M, Aydin H, Elson P, Maddala T, Knezevic D, Parodi L, Bukowski RM, Novotny WF, Cowens JW (2010) Identification of prognostic genomic markers in patients with localized clear cell renal cell carcinoma (ccRCC). J Clin Oncol 28:7s, suppl; abstr 4501

    Article  Google Scholar 

  40. Rini BI, Cohen DP, Lu D, Chen I, Hariharan S, Gore ME, Figlin RA, Baum MS, Motzer RJ. Hypertension (HTN) as a biomarker of efficacy in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with sunitinib. Presented at the 2010 Genitourinary Cancers Symposium [Abstr 312]

  41. Harzstark AL, Halabi S, Stadler WM, Vaena DA, Atkins JN, Picus J, Czaykowski P, Dutcher JP, Rini BI, Small EJ (2010) Hypertension is associated with clinical outcome for patients (pts) with metastatic renal cell carcinoma (rcc) treated with interferon and bevacizumab on calgb 90206. Presented at the 2010 Genitourinary Cancers Symposium [Abstr 351]

  42. Schneider BP, Wang M, Radovich M, Sledge GW, Badve S, Thor A, Flockhart DA, Hancock B, Davidson N, Gralow J, Dickler M, Perez EA, Cobleigh M, Shenkier T, Edgerton S, Miller KD (2008) Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: Ecog 2100. J Clin Oncol 26(28):4672–4678. doi:10.1200/jco.2008.16.1612

    Article  CAS  PubMed  Google Scholar 

  43. Gouttefangeas C, Stenzl A, Stevanović S, Rammensee H-G (2007) Immunotherapy of renal cell carcinoma. Cancer Immunol Immunother 56(1):117–128

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Dr. Pal’s efforts are supported by the NIH Loan Repayment Plan (LRP), the CBCRP 15IB-0140 (California Breast Cancer Research Program Junior IDEA Award) and NIH K12 2K12CA001727-16A1. We would also like to acknowledge the support of Kure It, The Hoeven Family Foundation, and the Richard and Nancy Bloch Kidney Cancer Research Fund.

Conflict of interest statement

Dr. Pal receives honoraria from Novartis and Pfizer. Dr. Figlin receives consulting fees from Pfizer, Genentech and Novartis, and receives research support from GlaxoSmithKline, Pfizer, Wyeth, Novartis, Argos Therapeutics, and Antisoma.

Author information

Authors and Affiliations

  1. Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA

    Sumanta Kumar Pal & Robert A. Figlin

Authors
  1. Sumanta Kumar Pal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert A. Figlin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sumanta Kumar Pal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pal, S.K., Figlin, R.A. Targeted therapies for renal cell carcinoma: understanding their impact on survival. Targ Oncol 5, 131–138 (2010). https://doi.org/10.1007/s11523-010-0145-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-010-0145-6

Keywords

Search

Navigation