Five-year overall survival of metastatic renal cell carcinoma patients treated with everolimus after progression on bevacizumab: a prospective multicenter study CRAD001LRU02T

Background. In a CRAD001LRU02T study of everolimus for metastatic renal cell carcinoma patients previously treated with bevacizumab ±  interferon, median overall survival (OS) was 17.4 months (95 % confidence interval 13.5–21.3 month).

Objective of final analysis was to evaluate 5-year OS and long-term toxicity in this study.

Materials and methods. Survival data were collected from 37 patients with bevacizumab-refractory metastatic renal cell carcinoma who received everolimus in a completed prospective multicenter study. Patients were predominantly male, 89 % had ECOG performance status of 0/1, 51 % received previous bevacizumab in combination with interferon, and 38/62% had MSKCC favorable/intermediate risk disease.

Results. The 5-year survival rate was 16.2% (95 % confidence interval 14.1–18.3 %), with a median follow-up of 5 years. The 1-, and 3-year OS rates were 81.0 and 43.0 %, respectively. The median duration of second-line of everolimus was 315 (range 61–569) days. 11 (29.7 %) patients received third-line therapy with a median duration of 3.6 months. Confirmed objective tumor responses were seen in 5 (14.0 %) patients. 70.0 % (n = 26) patients had a stable disease. 1 (2.7 %) patient achieved complete response after 4 years of therapy. One (2.7 %) patient  discontinued everolimus therapy on their own accord due to relapse of systemic lupus erythematosus and one (2.7 %)  patient had 14-days interruption of an everolimus therapy due to grade 3 hyperglycemia. No grade 4 treatment-related toxicity was found.

Conclusions. Everolimus provided an estimated 5-year survival rate of 16.2 % for bevacizumab-resistant metastatic renal cell carcinoma. Prolonged everolimus was not associated with new types or increased severity of adverse events.

1. Носов Д.А., Волкова М.И., Гладков О.А., Харкевич Г.Ю. Практические рекомендации по лекарственному лечению почечноклеточного рака. Злокачественные опухоли: Практические рекомендации RUSSCO 2017;(7): 404–10. [Nosov D.A., Volkova M.I., Gladkov O.A., Kharkevich G.Yu. Practical guidelines on drug treatment of renal cell carcinoma. Malignant tumors: RUSSCO practical guidelines 2017;(7):404–10. (In Russ.)]. DOI: 10.18027/2224-50572017-7-3s2-404-410.

2. Tsimafeyeu I., Zart J.S., Chung B. Cytoreductive radiofrequency ablation in patients with metastatic renal cell carcinoma (RCC) with small primary tumours treated with sunitinib or interferon-a. BJU Int 2013;112(1):32–8. DOI: 10.1111/bju.12107. PMID: 23746142.

3. Rini B.I., Escudier B., Tomczak P. et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011;378(9807):1931–9. DOI: 10.1016/S0140-6736(11)61613-9. PMID: 22056247.

4. Motzer R.J., Hutson T.E., Glen H. et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol 2015;16(15):1473–82. DOI: 10.1016/S1470-2045(15)00290-9. PMID: 26482279.

5. McDermott D.F., Motzer R.J., Atkins M.B. et al. Long-term overall survival (OS) with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I and II studies. J Clin Oncol 2016;34(suppl; abstr 4507).

6. Tsimafeyeu I., Snegovoy A., Varlamov S. et al. Everolimus in patients with metastatic renal cell carcinoma previously treated with bevacizumab: a prospective multicenter study CRAD001LRU02T. Target Oncol 2015;10(3):423–7. DOI: 10.1007/s11523-014-0347-4. PMID: 25466382.

7. Тимофеев И., Снеговой А., Варламов С. и др. Применение эверолимуса у больных метастатическим раком почки, ранее получавших бевацизумаб: проспективное многоцентровое исследование CRAD001LRU02T. Онкоурология 2015;11(2):34–9. [I. Tsimafeyeu, A. Snegovoy, S. Varlamov et al. Everolimus in patients with metastatic renal cell carcinoma previously treated with bevacizumab: a prospective multicenter study CRAD001LRU02T. Onkourolo- giya = Cancerurology 2015;11(2):34–9. (In Russ.)].

8. Motzer R.J., Escudier B., Oudard S. et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372(9637):449–56. DOI: 10.1016/S0140-6736(08)61039-9. PMID: 18653228.

9. Tsimafeyeu I., Zolotareva T., Varlamov S. et al. Five-year overall survival among patients with metastatic renal cell carcinoma: results of Russian populationbased study RENSUR5. J Clin Oncol 2017;35(suppl 5S; abstr 20).

10. Goss P.E., Strasser-Weippl K., Lee-Bychkovsky B.L. et al. Challenges to effective cancer control in China, India, and Russia. Lancet Oncol 2014;15(5):489–538. DOI: 10.1016/S1470-2045(14)70029-4. PMID: 24731404.

11. Tsimafeyeu I., Zolotareva T., Varlamov S. et al. Five-year survival of patients with metastatic renal cell carcinoma in the Russian Federation: results from the RENSUR5 Registry. Clin Genitourin Cancer 2017;15(6):e1069–72. DOI: 10.1016/j.clgc.2017.07.017. PMID: 28882737.

12. Rini B.I., Halabi S., Rosenberg J.E. et al. 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 2010;28(13):2137–43. DOI: 10.1200/JCO.2009.26.5561. PMID: 20368558.

13. Escudier B., Pluzanska A., Koralewski P. et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007;370(9605):2103–11. DOI: 10.1016/S0140-6736(07)61904-7. PMID: 18156031.

14. Escudier B., Sharma P., McDermott D.F. 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. DOI: 10.1016/j.eururo.2017.02.010. PMID: 28262413.

15. Choueiri T.K., Escudier B., Powles T. et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 2016;17(7):917–27. DOI: 10.1016/S1470-2045(16)30107-3. PMID: 27279544.

16. Knox J.J., Barrios C.H., Kim T.M. et al. Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC. Ann Oncol 2017;28(6):1339–45. DOI: 10.1093/annonc/mdx075. PMID: 28327953.