VEGF(r)-TKI & mTOR inhibitor vs placebo
|
NCT00019539 (1616. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, et al. A randomized trial of bevacizumab, na anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349:427-34.) |
4.8/2.5 |
0.43 (0.26-0.72) |
<0.0001 |
10 vs 0 |
ns |
nr |
0.84(0.58-1.22) |
ns |
NCT00079612 (1717. Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Kaye SB, Rosner GL, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:2505-12.) |
5.5/1.4 |
0.42 (0.20-0.91) |
0.009 |
nr |
nr |
nr |
nr |
nr |
TARGET (1818. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125-34. Erratum in: N Engl J Med. 2007;357:203., 1919. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, et al. Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009;27:3312-8.) |
5.5/2.8 |
0.51 (0.43-0.60) |
<0.0001 |
2 vs 0 |
ns |
17.8/15.2 |
0.88(0.74-1.04) |
0.146 |
VEG 105192 (2020. Nieto M, Borregaard J, Ersbøll J, ten Bosch GJ, van Zwieten-Boot B, Abadie E, et al. The European Medicines Agency review of pazopanib for the treatment of advanced renal cell carcinoma: summary of the scientific assessment of the Committee for Medicinal Products for Human Use. Clin Cancer Res. 2011;17:6608-14.
21. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28:1061-8.-2222. Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, et al. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013;49:1287-96.) |
9.2 (7.4-12.9)/4.2 (2.8-4.2) |
0.46 (0.34-0.62) |
<0.0001 |
30 vs 3 |
<0.0001 |
22.9 (19.9-25.4)/20.5 (15.6-27.6) |
0.91 (0.71-1.16) |
0.224 |
NCT00502307 (2323. Nosov DA, Esteves B, Lipatov ON, Lyulko AA, Anischenko AA, Chacko RT, et al. Antitumor activity and safety of tivozanib (AV-951) in a phase II randomized discontinuation trial in patients with renal cell carcinoma. J Clin Oncol. 2012;30:1678-85.) |
10.3 (8.1-21.2)/3.3 (1.8-8.0) |
0.55 (0.33-0.91) |
0.01 |
nr |
nr, |
nr |
nr |
nr |
NCT00423332 (2424. Mulders P, Hawkins R, Nathan P, de Jong I, Osanto S, Porfiri E, et al. Cediranib monotherapy in patients with advanced renal cell carcinoma: results of a randomised phase II study. Eur J Cancer. 2012;48:527-37.) |
12.1/2.76 |
0.45 (0.26-0.78) |
0.017 |
34 vs 5.56 |
nr |
nr |
nr |
nr |
RECORD-1 (2525. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a doubleblind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449-56.) |
4.0 (3.7-5.5)/1.9 (1.8-1.9) |
0.30 (0.22-0.40) |
<0.0001 |
1 vs 0 |
ns |
NA/8.8 (7.9-NA) |
0.83(0.50-1.37) |
0.23 |
VEGF(r)-TKI & mTOR inhibitor vs IFN-α |
CALGB 90206 (2626. Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008;26:5422-8.) |
8.5 (7.5-9.7)/5.2 (3.1-5.6) |
0.71 (0.61-0.83) |
<0.0001 |
25.5 vs 13.1 |
<0.0001 |
nr |
nr |
nr |
AVOREN (2727. Melichar B, Bracarda S, Matveev V, Alekseev B, Ivanov S, Zyryanov A, et al. A multinational phase II trial of bevacizumab with low-dose interferon-α2a as first-line treatment of metastatic renal cell carcinoma: BEVLiN. Ann Oncol. 2013;24:2396-402.-2828. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370:2103-11.) |
5.5/2.8 |
0.51 (0.43-0.60) |
<0.0001 |
31 vs 13 |
<0.0001 |
17.8/15.2 |
0.88(0.74-1.04) |
0.146 |
NCT00117637 (2929. Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda 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. J Clin Oncol. 2010;28:2144-50.) |
5.7 (5.0-7.4)/5.6 (3.7-7.4) |
0.88 (0.61-1.27) |
0.504 |
5.2 vs 8.6 |
ns |
nr |
nr |
nr |
NCT00083889 (3030. Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, et al. Randomized phase II trial of firstline treatment with sorafenib versus interferon Alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:1280-9. Erratum in: J Clin Oncol. 2009; 27:2305.) |
11 (10-12)/5 (4-6) |
0.42 (0.32-0.54) |
<0.0001 |
11 vs 5 |
0.54 |
114.6 (100.1-142.9)/94.9 (77.7-117) |
0.65(0.45-0.94) |
0.02 |
Global ARCC (3131. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-24.) |
3.8 (3.6-5.2)/1.9 (1.9-2.2) |
0.76 (0.62-0.92) |
<0.0001 |
8.6 vs 4.8 |
ns |
10.9 (8.6-12.7)/7.3 (6.1-8.8) |
0.73(0.58-0.92) |
0.008 |
VEGF(r)-TKI & mTOR inhibitor combination vs monotherapy
|
NCT00126594 (3232. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271-81.) |
7.56 (5.19-11.07)/7.39 (5.5-9.2) |
0.85 (0.51-1.42) |
0.53 |
30 vs 25 |
ns |
27.04 (22.31- NA)/NA |
1.95(0.84-4.52) |
0.122 |
ROSORC (3333. Jonasch E, Corn P, Pagliaro LC, Warneke CL, Johnson MM, Tamboli P, et al. Upfront, randomized, phase 2 trial of sorafenib versus sorafenib and low-dose interferon alfa in patients with advanced renal cell carcinoma: clinical and biomarker analysis. Cancer. 2010;116:57-65.) |
33/20 |
0.75 (0.34-1.65) |
0.11 |
27.3 vs 14.5 |
ns |
nr |
nr |
nr |
NCT00467025 (3434. Procopio G, Verzoni E, Bracarda S, Ricci S, Sacco C, Ridolfi L, et al. Sorafenib with interleukin-2 vs sorafenib alone in metastatic renal cell carcinoma: the ROSORC trial. Br J Cancer. 2011;104:1256-61.) |
9.0 (5.6-13.1)/9.0 (5.5-10.9) |
0.8 (0.5-1.28) |
0.35 |
38 vs 25 |
ns |
nr |
nr |
nr |
Global ARCC (3131. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-24.) |
3.7 (2.9-4.4)/3.8 (3.6-5.2) |
1.08 (0.89-1.3) |
ns |
8.1 vs 8.6 |
ns |
8.4 (6.6-10.3)/10.9 (8.6-12.7) |
1.19(0.94-1.50) |
ns |
Single VEGF(r)-TKI & mTOR inhibitor comparison
|
AXIS (3535. Rini B, Szczylik C, Tannir NM, Koralewski P, Tomczak P, Deptala A, et al. AMG 386 in combination with sorafenib in patients with metastatic clear cell carcinoma of the kidney: a randomized, double-blind, placebo-controlled, phase 2 study. Cancer. 2012;118:6152-61.) |
12.1 (8.6-NA)/4.9 (2.8-6.6) |
0.39 (0.13-1.17) |
0.04 |
52 vs 3.4 |
0.0001 |
nr |
nr |
nr |
AXIS (3636. Ueda T, Uemura H, Tomita Y, Tsukamoto T, Kanayama H, Shinohara N, et al. Efficacy and safety of axitinib versus sorafenib in metastatic renal cell carcinoma: subgroup analysis of Japanese patients from the global randomized Phase 3 AXIS trial. Jpn J Clin Oncol. 2013;43:616-28., 3737. Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013;14:552-62. Erratum in: Lancet Oncol. 2013;14:e254.) |
8.3 (6.7-9.2)/5.7 (4.7-6.5) |
0.66 (0.55-0.78) |
<0.0001 |
19.4 vs 9.4 |
0.0001 |
20.1 (16.7-23.4)/19.2 (17.5-22.3) |
0.97(0.80-1.17) |
0.37 |
INTORSECT (3838. Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378:1931-9. Erratum in: Lancet. 2012;380:1818.) |
4.28 (4.01-5.43)/3.91 (2.80-4.21) |
0.87 (0.71-1.07) |
0.19 |
7.7 vs 7.9 |
ns |
(17.5-22.3) 12.27 (10.13-14.8)/16.64(13.55-18.72) |
1.31(1.05-1.63) |
0.014 |
COMPARZ (3939. Xiao W, Wang J, Li H, Guan W, Xia D, Yu G, et al. Fibulin-1 is down-regulated through promoter hypermethylation and suppresses renal cell carcinoma progression. J Urol. 2013;190:291-301.) |
8.4 (8.3-10.9)/9.5 (8.3-11.1) |
1.05 (0.90-1.22) |
ns |
30.7 vs 24.8 |
28.4 (26.2-35.6)/29.3 (25.3-32.5) |
nr |
nr |
NCT01147822 (4040. Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013;31:3791-9.) |
8.4 (8.3-11.1)/11.1 (8.2-14.3) |
1.02 (0.77-1.35) |
ns |
35.6 vs 20.7 |
NA (23.7-NA)/31.5(29.5-NA) |
nr |
nr |
VEGF(r)-TKI & mTOR inhibitor combined treatment
|
AVOREN (2727. Melichar B, Bracarda S, Matveev V, Alekseev B, Ivanov S, Zyryanov A, et al. A multinational phase II trial of bevacizumab with low-dose interferon-α2a as first-line treatment of metastatic renal cell carcinoma: BEVLiN. Ann Oncol. 2013;24:2396-402.) |
23.3/26 |
0.92 (0.69-1.23) |
ns |
nr |
nr |
nr |
nr |
nr |
RAPSODY (4242. Bracarda S, Porta C, Boni C, Santoro A, Mucciarini C, Pazzola A, et al. Could interferon still play a role in metastatic renal cell carcinoma? A randomized study of two schedules of sorafenib plus interferon-alpha 2a (RAPSODY). Eur Urol. 2013;63:254-61.) |
7.9 (5.1-10.9)/8.6 (2.2-15.1) |
1.35 (1.01-1.59) |
0.049 |
17.6 vs 34 |
0.058 |
20.3 (20.5-32.4)/19.4 (23.4-36.8) |
1.17(0.69-2.00) |
0.412 |
Bukowski, 2007 (4343. Bukowski RM, Kabbinavar FF, Figlin RA, Flaherty K, Srinivas S, Vaishampayan U, et al. Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol. 2007;25:4536-41.) |
9.9/8.5 |
0.86 (0.50-1.49) |
0.58 |
14 vs 13 |
0.99 |
20/NA |
1.57(0.84-2.94) |
0.16 |
INTORACT (4444. Wheler JJ, Moulder SL, Naing A, Janku F, Piha-Paul SA, Falchook GS, et al. Anastrozole and everolimus in advanced gynecologic and breast malignancies: activity and molecular alterations in the PI3K/AKT/mTOR pathway. Oncotarget. 2014;5:3029-38.) |
9.1 (8.1-10.2)/9.3 (9.0-11.2) |
1.1 (0.9-1.3) |
ns |
27 vs 27.4 |
1.0 |
25.8 (21.1-30.7)/25.5 (20.4-30.8) |
1.0(0.9-1.3) |
0.6 |
TORAVA (4545. Négrier S, Gravis G, Pérol D, Chevreau C, Delva R, Bay JO, et al. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol. 2011;12:673-80.) |
8.2 (7.0-9.6)/16.8 (6.0-26.0) |
1.21 (0.7-2.09) |
ns |
27 vs 43 |
nr |
nr |
nr |
nr |
TORAVA (4545. Négrier S, Gravis G, Pérol D, Chevreau C, Delva R, Bay JO, et al. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol. 2011;12:673-80.) |
8.2 (5.5-11.7)/16.8 (6.0-26.0) |
1.62 (0.84-3.16) |
ns |
29 vs 43 |
nr |
nr |
nr |
nr |