Augmenting the Randomized Controlled Trial with Real-World Data to Aid Clinical Decision Making in Metastatic Renal Cell Carcinoma: A Systematic Review and Meta-Analysis

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Table 1. Inclusion and exclusion criteria based on the Population, Intervention, Comparator, Outcomes Study Designs framework.

PICOS element	Inclusion	Exclusion
Patient population	Men and women; aged >18 years; mRCC population; first-line treatment; January 2000–December 2017; cohorts ≥50 patients	Pediatric patients; mixed-disease population; cohorts <50 patients
Intervention	Medical treatment for mRCC TKI	Non-TKI treatment; prior therapy
Comparator	Research study outcomes from RCTs and retrospective studies
Outcomes	Efficacy: PFS, OS, ORR	Non-efficacy based
Study design	Phase II and III RCTs; RWD; health records; cohort studies; case-controlled studies; cross-sectional studies	Phase I RCT; case reports; animal and preclinical trials; opinion papers and letters; systematic reviews and meta-analyses

mRCC: Metastatic renal cell carcinoma; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival; RCT: Randomized controlled trial; RWD: Real-world data; TKI: Tyrosine kinase inhibitor.

Figure 1. PRISMA flow diagram of the literature search process.

PRISMA: Preferred reporting items for systematic reviews and meta-analyses; RCT: Randomized controlled trial; RWD: Real-world data; TKI: Tyrosine kinase inhibitor.

Table 2. Number of studies, treatment arms and patients by end point and group.

End point	Group	Number of studies	Cumulative treatment arms	Patients, n^†	TKI agent (n) ^†
mPFS	RWD-TKI	18	20	4771	Pazopanib (636) Sorafenib (1037) Sunitinib (3098)
	RCT-TKI	13	18	3427	Axitinib (248) Cabozantinib (79) Lapatinib (209) Pazopanib (557) Sorafenib (436) Sunitinib (1717) Tivozanib (181)
	RCT-control	8	8	1295	NA
mOS	RWD-TKI	20	23	5622	Pazopanib (729) Sorafenib (921) Sunitinib (3972)
	RCT-TKI	8	11	2312	Axitinib (56) Cabozantinib (79) Lapatinib (209) Pazopanib (557) Sorafenib (62) Sunitinib (1349)
	RCT-control	6	6	965	NA
ORR	RWD-TKI	15	17	3925	Pazopanib (406) Sorafenib (825) Sunitinib (2694)
	RCT-TKI	10	14	2820	Axitinib (248) Cabozantinib (76) Lapatinib (209) Pazopanib (551) Sorafenib (247) Sunitinib (1489)
	RCT-control	6	6	966	NA

† Patient numbers as represented by the aggregate data.

mOS: Median overall survival; mPFS: Median progression-free survival; NA: Not applicable; ORR: Objective response rate; RCT: Randomized controlled trial; RCT-control: Matching control, non-TKI treatments in RCT; RWD: Real-world data; TKI: Tyrosine kinase inhibitor.

Table 3. Number of studies by publication year and study type for median progression-free survival.

Publication year	RCT	RWD
2008	1	0
2009	2	0
2010	0	1
2011	1	0
2012	1	0
2013	3	0
2014	1	3
2015	0	6
2016	3	5
2017	1	3

RCT: Randomized controlled trial; RWD: Real-world data.

Figure 2. Observed median progression-free survival data.

*1 or 2 denotes TKI treatment group, 0 denotes non-TKI treatment group.

mPFS: Median progression-free survival; RCT-control: Matching control, non-TKI treatments in randomized controlled trial; RCT-TKI: TKI as a single agent in the first-line setting in randomized controlled trials; RWD-TKI: TKI as a single agent in the first-line setting in real-world data study; TKI: Tyrosine kinase inhibitor; Tx: Treatment group.

Figure 3. Observed median overall survival data.

*1 or 2 denotes TKI treatment group, 0 denotes non-TKI treatment group.

**mOS data were not mature at the time of publication and were extracted from a later analysis [33].

mOS: Median overall survival; RCT-control: Matching control, non-TKI treatments in randomized controlled trial; RCT-TKI: TKI agent in randomized controlled trial; RWD-TKI: TKI as a single agent in the first-line setting in real-world data study; TKI: Tyrosine kinase inhibitor; Tx: Treatment group.

Figure 4. Observed objective response rate data.

*1 or 2 denotes TKI treatment group, 0 denotes non-TKI treatment group.

ORR: Objective response rate; RCT-control: Matching control, non-TKI treatments in randomized controlled trial; RCT-TKI: TKI agent in randomized controlled trial; RWD-TKI: TKI as a single agent in the first-line setting in real-world data study; TKI: Tyrosine kinase inhibitor; Tx: Treatment group.

Figure 5. Meta-analysis efficacy estimates.

Forest plot of (A) mPFS, (B) mOS and (C) ORR for patients with mRCC treated with first-line TKIs.

mOS: Median overall survival; mPFS: Median progression-free survival; mRCC: Metastatic renal cell carcinoma; ORR: Objective response rate; RCT: Randomized controlled trial; RCT-control: Matching control, non-TKI in randomized controlled trial; RCT-TKI: TKI agent in randomized controlled trial; RWD: Real-world data; RWD-TKI: TKI agent in RWD study; TKI: Tyrosine kinase inhibitor.

Procopio G , VerzoniE, BracardaSet al. Overall survival for sorafenib plus interleukin-2 compared with sorafenib alone in metastatic renal cell carcinoma (mRCC): final results of the ROSORC trial. Ann. Oncol.24(12), 2967–2971 (2013).

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