2.1

Search strategy

In addition to 4 high-impact general medical journals including The Lancet, The New England Journal of Medicine (NEJM), The British Medical Journal (BMJ), and The Journal of the American Medical Association (JAMA), we used InCites Journal Citation Reports to identify the top 25 highest impact urological journals. RCTs related to a/mRCC published in the above journals were systematically searched in PubMed using the MeSH terms for “randomized controlled trials” and “renal/kidney cell cancer/carcinoma” along with synonymous keywords from January 1, 2000, to December 31, 2023, publishing language set to English.

2.2

Eligibility criteria

The following inclusion criteria was included: (1) 2 parallel arms or two-by-two factorial design RCTs (randomized 1:1) related to a/mRCC, (2) at least one of the primary or secondary endpoints with a statistically significant outcome in the dichotomous trials ( P < 0.05 or a 95% confidence interval that excluded the null value), (3) involved human participants. The exclusion criteria covered case reports, meta-analyses, systematic reviews, cadaveric studies, animal studies, in vitro studies, and nondichotomous data.

2.3

Study selection and data extraction

The titles and abstracts of each article were screened by 2 independent reviewers to confirm that the literature for initial inclusion met the eligibility criteria. We have excluded studies on the diagnostic, cost-effective, non-a/mRCC, without specific numbers of patients in the 2 arms and investigation of baseline factors for outcomes. All included studies were on the comparison of treatments. The full text of the initially included studies was subsequently reviewed for final inclusion. Any disagreements between the 2 reviewers were resolved by a third reviewer.

We gathered the following variables for each trial that ultimately met the inclusion criteria: authors, publication year, journal name, sample size of patients enrolled, arms and number of patients per arm, number of patients lost to follow-up, P -value recalculated, efficacy outcomes and whether outcomes were primary or secondary.

2.4

Application of the fragility index

In case of more than one outcome variable was reported to be eligible for the calculation of FI in the studies, we gave priority to the primary outcome. If the primary outcome was not eligible, we then considered the most significant secondary outcome according to the Grading of Recommendations Assessment, Development and Evaluation guideline (GRADE) [ ]. We described trials in which the number of patients lost to follow-up was greater than or equal to FI as statistical fragility group, while vice versa as statistical robustness group. We calculated the FI for each trial utilizing a two-by-two contingency table based on the methodology presented by Walsh et al. [ ]. The P -value for each outcome was firstly recalculated by using a 2-sided Fisher’s exact test. We then repeatedly added the number of events in the arm with the lower number of events while simultaneously subtracting the number of nonevents to maintain the total number of patients unchanged. The number of additional events that when the P -value exactly changed from< 0.05 to ≥ 0.05 by Fisher’s exact test represented the FI. If the recalculated P -value was greater than or equal to 0.05 without change in the event, the FI was reported as zero.

2.5

Statistical analysis

SPSS software (version 23; IBM, Armonk, NY, USA) and Microsoft Excel 2016 (Redmond, WA, USA) were used for data analysis. Agreement amongst reviewers was determined using the Cohen kappa coefficient. The interpretation of kappa values was performed according to the guidelines previously published by Landis and Koch [ ]: kappa values of 0.00 to 0.20, 0.21 to 0.40, 0.41 to 0.60, 0.61 to 0.80, 0.81 to 1.00 are considered to be slightly, fairly, moderately, substantially, and almost perfectly consistent, respectively. We utilized descriptive statistics to conclude the FI of the RCTs and determined interquartile ranges (IQRs) to contribute to the overall understanding and explanation of the reported variability and dispersion. Spearman correlation analyses were conducted to investigate the relationship between the FI and trial characteristics variables including trial sample size, number of patients lost to follow-up, and P -value. All significance tests were 2-tailed, with a P -value less than 0.05 considered significant.

3.1

Study selection

The literature search identified 1158 potentially eligible studies. After excluding duplicate articles and screening titles, abstracts, and journals, 73 articles were eligible for full-text review. Finally, 16 RCTs related to a/mRCC were included after a review of full texts ( Fig. 2 ). The agreement between the 2 reviewers for eligibility was substantially consistent (kappa = 0.67).

PRISMA flow chart and search strategy.

3.2

Trial characteristics and outcomes

The characteristics of all included studies were summarized in Table 1 ( Supplementary Table 1 in details). The median total number of patients in the samples was 654.5 (IQR, 461–847). All included RCTs unequivocally reported patients lost to follow-up, with a median of 14 (IQR, 3–23). Among all the outcomes reported in the confirmed studies, 13 were primary outcomes (81%) [ ], and 3 were secondary outcomes (19%) [ ]. Reported P -values (a total of 19 P -values, including co-primary endpoints in 2 studies) for each outcome were less than 0.05 but greater than or equal to 0.01 for 5 (26%) [ , , , , ], less than 0.01 but greater than or equal to 0.001 for 4 (21%) [ , , , ], and less than 0.001 for ten (53%) [ , , , , , , ]. The treatment management could be categorized into comparisons between single agents of the same category (12.5%) (including mTOR inhibitors and tyrosine kinase inhibitors [TKI]), single agents of different categories (43.75%) (3 of which were comparisons with placebo), and 2-drug combinations vs. single agents (43.75%) (4 comparisons of immune checkpoint inhibitors (ICI)+TKI vs. TKI and 3 comparisons of ICI+ICI vs. TKI). The outcomes (a total of 19 outcomes, including co-primary endpoints with co-outcomes in 2 studies) reported in the trials were as follows: overall survival (OS), objective response rate (ORR), progression-free survival (PFS), disease-free survival (DFS), and the proportion of patients achieving an objective response.

Table 1

Characteristics and fragility analysis of included trials.

Authors	Year	Journal	Patients enrolled	Efficacy outcomes	Lost to follow-up	P -value	FI
Bernard et al. [ ]	2007	N Engl J Med	903	PFS	17	<0.001	20
Bernard et al. [ ]	2007	The Lacent	649	PFS	21	<0.001	34
Robert et al. [ ]	2007	N Engl J Med	750	PFS	35	<0.001	54
Powles et al. [ ]	2016	Eur Urol	49	PFS	2	<0.001	8
Toni et al. [ ]	2016	The Lacent Oncology	658	PFS	25	0.005	11
Robert et al. [ ]	2017	N Engl J Med.	821	OS	18	0.011	9
Robert et al. [ ]	2018	N Engl J Med	847	OS	3	<0.001	38
				ORR		<0.001	36
				PFS		NA	NA
Robert et al. [ ]	2019	N Engl J Med	560	PFS	13	0.022	4
Robert et al. [ ]	2019	Lancet Oncol	847	OS	3	0.002	18
				PFS		0.022	5
				The proportion achieving objective response		<0.001	25
Brian et al. [ ]	2019	The Lacent	362	PFS	4	0.044	1
Brian et al.	2019	The Lacent	915			P > 0.05
Thomas et al. [ ]	2020	Lancet Oncol	861	OS	34	0.009	10
Brian et al. [ ]	2020	Lancet Oncol	350	PFS	2	<0.001	10
T.K. et al. [ ]	2021	N Engl J Med	651	PFS	12	<0.001	20
T.K. et al. [ ]	2021	N Engl J Med	994	DFS	31	0.003	14
Robert et al. [ ]	2022	Lancet Oncol	651	PFS	15	<0.001	37
Gr¨¹nwald et al. [ ]	2023	Eur Urol	49	ORR	1	0.038	1

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