Immunotherapeutic Approaches
IMA901

IMA901 is a therapeutic anticancer vaccine that was administered in a Phase 2 trial to 68 patients with tumor associated peptides HLA-A*02-positive clear cell RCC who had progression of disease during or after a cytokine or TKI. The disease control rate was 31% in the post-cytokine group and 12% in the post-TKI group, with a sturdy trend toward better outcome in patients with multiple T-cell responses to the vaccine.42 A randomized Phase 3 trial, with a planned enrollment of 330 patients with the same HLA-type as in the Phase 2 trial, is evaluating the combination of IMA901 plus granulocyte macrophage colony-stimulating factor (GM-CSF) and sunitinib in comparison to sunitinib alone as first-line therapy of RCC.43 The final data-collection date for the primary end point of OS is set for mid-2014.

AGS-003
AGS-003 is an autologous immunotherapeutic agent prepared from monocyte-derived dendritic cells co-electroporated with the patient’s tumor. A Phase 2 trial presented at ASCO in 2010, combined this agent with sunitinib for treatment of patients with newly diagnosed clear cell RCC. There were minimal AEs other than those typically associated with sunitinib.44 According to a June 2011 press release from the manufacturer, the superior median PFS compared to historical control of sunitinib alone (11.9 months vs. 8 months) has stimulated plans for a global Phase 3 study, although this has not been listed in the clinicaltrials.gov website at this time.45


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Conclusion
Although some of the most recent clinical trials in advanced RCC are showing relatively small incremental differences between treatments, the overall effect of sequencing targeted drugs over time has almost doubled the survival time compared with two decades ago. The next two to three years are set to be an exciting time for those patients with RCC, as clinical trial results for a number of unique compounds become available.

References

1. American Cancer Society. Cancer Facts and Figures 2011. Atlanta, GA: American Cancer Society; 2011.

2. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Kidney Cancer Version 1.2012. www.nccn.org. Accessed January 22, 2012.

3. Pantuck AJ, Zisman A, Belldegrun AS. The changing natural history of renal cell carcinoma. J Urol. 2001;166(5):1611-1623.

4. Waxman J, Thomas H. Metastatic renal cell cancer–is the outlook really improving? Postgrad Med J. 1990;66(776):435-440.

5. George S, Pili R, Carducci MA, et al. Role of immunotherapy for renal cell cancer in 2011. J Natl Compr Canc Netw. 2011;9(9):1011-1018.

6. McDermott DF, Ghebremichael MS, Signoretti S, et al. The high-dose aldesleukin (HD IL-2)‘SELECT’ trial in patients with metastatic renal cell carcinoma (mRCC) [abstract 4514]. J Clin Oncol. 2010;28(suppl):15s.

7. Coppin C, Porzsolt F, Kumpf J, et al. Immunotherapy for advanced renal cell cancer [published online ahead of print April 24, 2000]. Cochrane Database Syst Rev. 2005;(1):CD001425. doi:10.1002/14651858.CD001425.

8. Coppin C, Kollmannsberger C, Le L, et al. Targeted therapy for advanced renal cell cancer (RCC): a Cochrane systematic review of published randomised trials [published online ahead of print September 27, 2011]. BJU Int. 2011;108(10):1556-1563. doi:10.1111/j.1464-410X.2011.10629.X.

9. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349(5):427-434.

10. Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206 [published online ahead of print October 20, 2008].  J Clin Oncol. 2008;26(33):5422-5428.

11. Escudier B, Bellmunt J, Negrier S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival [published online ahead of print April, 5 2010]. J Clin Oncol. 2010;28(13):2144-2150.

12. Bracarda S, Porta C, Boni C, et al. Randomized prospective phase II trial of two schedules of sorafenib daily and interferon-a2a in metastatic renal cell carcinoma (RAPSODY): GOIRC study 0681 [abstract 357]. In: Genitourinary Cancer Symposium, American Society of Clinical Oncology, 2008.

13. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma [published online ahead of print June 1, 2009]. J Clin Oncol. 2009;27(22):3584-3590.

14. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial [published online ahead of print January 15, 2010]. J Clin Oncol. 2010;28(6):1061-1068.

15. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271-2281.

16. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial [published online ahead of print July 22, 2008]. Lancet. 2008;372(9637):449-456.

17. Clark PE. The role of VHL in clear-cell renal cell carcinoma and its relation to targeted therapy [published online ahead of print August 5, 2009]. Kidney Int. 2009;76(9):939-945. doi:10.1038/ki.2009.296.

18. Tamaskar I, Garcia JA, Elson P, et al. Antitumor effects of sunitinib or sorafenib in patients with metastatic renal cell carcinoma who received prior antiangiogenic therapy [published online ahead of print November 12, 2007]. J Urol. 2008;179(1):81-86.

19. Gupta S, Fishman M. Progress and contrasts of the development of tivozanib for therapy of kidney cancer. Expert Opin Pharmacother. 2011;12(18):2915-2922.

20. Nosov D, Bhargava P, Esteves WB, et al. Final analysis of the phase II randomized discontinuation trial (RDT) of tivozanib (AV-951) versus placebo in patients with renal cell carcinoma (RCC) [abstract 4550]. J Clin Oncol. 2011;29(suppl).

21. A study to compare tivozanib (AV-951) to sorafenib in subjects with advanced renal cell carcinoma (TIVO-1). Bethesda, MD: National Institutes of Health. Dept. of Health and Human Services. www.clinicaltrials.gov/ct2/show/NCT01030783. Updated June 8, 2011. Accessed January 22, 2012.

22. AVEO and Astellas Announce Tivozanib Successfully Demonstrated Progression-Free Survival Superiority over Sorafenib in Patients with Advanced Renal Cell Cancer in Phase 3 TIVO-1 Trial [news release].Cambridge, MA: Aveo Pharmaceuticals, Inc. Tokyo, Japan: Astellas Pharma, Inc. January 3, 2012. http://investor.aveopharma.com/phoenix.zhtml?c=219651&p=irol-newsArticle&ID=1643913&highlight. Accessed January 22, 2012.

23. Angevin E, Grunwald V, Ravaud A, et al. A phase II study of dovitinib (TKI258), an FGFR- and VEGFR-inhibitor, in patients with advanced or metastatic renal cell cancer (mRCC) [abstract 4551]. J Clin Oncol. 2011;29(suppl).

24. Study of dovitinib versus sorafenib in patients with metastatic renal cell carcinoma. Bethesda, MD: National Institutes of Health. Dept. of Health and Human Services. www.clinicaltrials.gov/ct2/show/NCT01223027. Updated November 18, 2011. Accessed January 22, 2012.

25. Yamada K, Yamamoto N, Yamada Y, et al. Phase I dose-escalation study and biomarker analysis of E7080 in patients with advanced solid tumors [published online ahead of print March 3, 2011]. Clin Cancer Res. 2011;17(8):2528-2537. doi:10.1158/1078-0432.CCR-10-2638.

26. A study of E7080 alone, and in combination with everolimus in subjects with unresectable advanced or metastatic renal cell carcinoma following one prior vascular endothelial growth factor (VEGF)-targeted treatment. Bethesda, MD: National Institutes of Health. Dept. of Health and Human Services. www.clinicaltrials.gov/ct2/show/NCT01136733. Updated November 18, 2011. Accessed January 25, 2012.

27. Huang H, Bhat A, Woodnutt G, et al. Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer. 2010;10(8):575-585.

28. Mendelson DS, Rosen LS, Gordon MS, et al. First-in-human dose-escalation safety and PK trial of a novel humanized monoclonal CovX body dual inhibitor of angiopoietin 2 and vascular endothelial growth factor [abstract 3055]. J Clin Oncol. 2011;29(suppl).

29. PF-04856884 (CVX-060) in combination with axitinib in patients with previously treated metastatic renal cell carcinoma. Bethesda, MD: National Institutes of Health. Dept. of Health and Human Services. www.clinicaltrials.gov/ct2/show/NCT01441414. Updated January 4, 2012. Accessed January 26, 2012.

30. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124(3):471-484.

31. Robb VA, Karbowniczek M, Klein-Szanto AJ, et al. Activation of the mTOR signaling pathway in renal clear cell carcinoma. J Urol. 2007;177(1):346-352.

32. Roulin D, Waselle L, Dormond-Meuwly A, et al. Targeting renal cell carcinoma with NVP-BEZ235, a dual PI3K/mTOR inhibitor, in combination with sorafenib. Mol Cancer. 2011;10:90.

33. BEZ235 in patients with advanced renal cell carcinoma (RCC). Bethesda, MD: National Institutes of Health. Dept. of Health and Human Services. www.clinicaltrials.gov/ct2/show/NCT01453595. Updated January 10, 2012. Accessed January 22, 2012.

34. Yap TA, Patnaik A, Fearen I, et al. First-in-class phase I trial of a selective Akt inhibitor, MK2206 (MK), evaluating alternate day (QOD) and once weekly (QW) doses in advanced cancer patients (pts) with evidence of target modulation and antitumor activity [abstract 3009]. J Clin Oncol. 2010;28(suppl):15s.

35. MK2206 or everolimus in treating patients with refractory kidney cancer. Bethesda, MD: National Institutes of Health. Dept. of Health and Human Services. www.clinicaltrials.gov/ct2/show/NCT01239342. Updated September 13, 2011. Accessed January 22, 2012.

36. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates [published online ahead of print June 1, 2010]. J Clin Oncol. 2010;28(19):3167-3175. doi:10.1200/JCO.2009.26.7609.

37. BMS-936558 (MDX-1106) in subjects with advanced/metastatic clear-cell renal cell carcinoma (RCC). Bethesda, MD: National Institutes of Health. Dept. of Health and Human Services. www.clinicaltrials.gov/ct2/show/NCT01354431. Updated January 13, 2012. Accessed January 22, 2012.

38. BMS-936558 (MDX-1106) in combination with sunitinib or pazopanib in subjects with renal cell carcinoma (RCC). Bethesda, MD: National Institutes of Health. Dept. of Health and Human Services. www.clinicaltrials.gov/ct2/show/NCT01472081. Updated January 13, 2012. Accessed January 22, 2012.

39. Sethi N, Kang Y. Notch signalling in cancer progression and bone metastasis [published online ahead of print November 10, 2011]. Br J Cancer. 2011;105(12):1805-1810. doi:10.1038/bjc.2011.497.

40. Tolcher AW, Mikulski SM, Messersmith WA, et al. A phase I study of RO4929097, a novel gamma secretase inhibitor, in patients with advanced solid tumors [abstract 2502]. J Clin Oncol. 2010;28(suppl):15s.

41. A Study of RO4929097 in patients with advanced renal cell carcinoma that have failed vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) therapy. Bethesda, MD: National Institutes of Health. Dept. of Health and Human Services. www.clinicaltrials.gov/ct2/show/NCT01141569. Updated August 9, 2010. Accessed January 25, 2012.

42. Reinhardt C, Zdrojowy R, Szczylik C, et al. Results of a randomized phase II study investigating multipeptide vaccination with IMA901 in advanced renal cell carcinoma (RCC) [abstract 4529]. J Clin Oncol. 2010;28(suppl):15s.

43. IMA901 in patients receiving sunitinib for advanced/metastatic renal cell carcinoma. Bethesda, MD: National Institutes of Health. Dept. of Health and Human Services. www.clinicaltrials.gov/ct2/show/NCT01265901. Updated January 18, 2012. Accessed January 22, 2012.

44. Amin A, Dudek A, Logan T, et al. A phase II study testing the safety and activity of AGS-003 as an immunotherapeutic in subjects with newly diagnosed advanced stage renal cell carcinoma (RCC) in combination with sunitinib [abstract 4588]. J Clin Oncol. 2010;28(suppl):15s.

45. Argos Therapeutics Presents New Phase 2 Data Showing its Arcelis Immunotherapy AGS-003 in Combination with Sunitinib Improves Progression-free Survival (PFS) in Patients with Advanced Renal Cell Carcinoma (RCC) [news release]. Durham, NC: Argos Therapeutics. June 5, 2011. www.argostherapeutics.com/news/news_release_posterASCO2011_final.html. Accessed January 22, 2012.