The Cochrane Collaboration conducted a systematic review of randomized controlled trials in advanced RCC published through June 2011 that included a targeted agent in at least one study arm and reported efficacy outcome by allocation.8 Published manuscripts as well as meeting abstracts were included. The primary outcome of the systematic review was progression free survival (PFS). In all, 28 eligible trials were identified, with 8 being available only in abstract form. Those that included FDA-approved targeted agents demonstrating statistically significant improvement in PFS are shown in Table 1

Table 1. Outcomes for trials of FDA-approved targeted agents for RCC reporting statistically significant improvement in PFS8


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Reference

Phase

Trial Name

Agent

Control

PFS, mo

HR

OS, mo

HR

Yang (9)

R2

NCT19539

BEV

Placebo

4.8 vs. 2.5*

0.39

NR

NR

Rini (10)

3

CALGB 90206

BEV/IFN

IFN

8.5 vs. 5.2*

0.71

18.3 vs. 17.4

0.86

Escudier (11)

3

AVOREN

BEV/IFN

Placebo/IFN

10.2 vs. 5.4*

0.61

23.2 vs. 21.3

0.86

Bracarda (12)

R2

RAPSODY

SOR/IFN 5x

SOR/IFN 3x

8.6 vs. 7.9*

NR

NR

NR

Motzer (13)

3

NCT 83889

SUN

IFN

11 vs. 5*

0.54

26.4 vs. 21.8*

0.82

Sternberg (14)

3

VEG 10192

PAZ

Placebo

9.2 vs. 4.2*

0.46

22.9 vs. 20.5

0.91

Hudes (15)

3

Global ARCC

TEM

IFN

3.8 vs. 1.9*

NR

10.9 vs. 7.3*

0.73

Motzer (16)

3

RECORD-1

EVE

Placebo

4.9 vs. 1.9*

0.33

14.8 vs. 14.4

0.8

* P<0.05; BEV=bevacizumab; EVE=everolimus; IFN=interferon-alfa; mo=months; PAZ=pazopanib; R2=randomized Phase 2; RDT=randomized discontinuation trial; SOR=sorafenib; SUN=sunitinib; TEM=temsirolimus; 3=Phase 3 trial; 3x=3 times weekly; 5x=5 times weekly.

Consensus guidelines from the National Comprehensive Cancer Network (NCCN) recommend sunitinib, pazopanib or bevacizumab with IFN-α as acceptable regimens based on the strength of available evidence.2 Differences in side effects and convenience are relevant factors in the prescribing decision. For poor-prognosis patients, temsirolimus is another recommended option. When the disease progresses after one of these approaches, everolimus is recommended for use based on available evidence, although any of the other available agents are considered acceptable options.2

Despite the impressive improvements these targeted agents bring to the natural course of RCC, none reliably produce complete responses, and patients eventually have progressive disease. Improvements are obviously needed to improve the outcome of these patients, and this article will discuss agents currently in Phase 2 and 3 trials, organized by mechanism of action.