The Role of Immune Checkpoint Inhibitors (ICI) as Adjuvant Treatment in Renal Cell Carcinoma (RCC): A Systematic Review and Meta-Analysis

The standard treatment for localized renal cell carcinoma is partial or radical nephrectomy. However, 40-80% of patients with localized disease will present disease relapse after surgery. Since 2017 sunitinib is an adjuvant treatment option for patients with nonmetastatic high-risk disease, but the toxicity associated with the treatment is a critical issue and a limiting factor to its use in daily clinical practice. In this context, considering the efficacy and survival benefit of immunotherapy in the treatment of metastatic RCC, four phase three randomized clinical trials (RCT) evaluating ICI in adjuvant setting were recently published and or presented (The details of each trial are summarized in table 1). Despite the benefit in disease-free-survival (DFS) with adjuvant pembrolizumab demonstrated in the KEYNOTE-564 trial, the lack of overall survival benefit and the negative results of other trials put into question the real benefit of ICI in adjuvant treatment setting.

Table 1. Characteristics of the Selected Trials

	KEYNOTE-564	IMmotion 010	PROSPER	CheckMate 914
N	994	778	819	816
Population	pT2 G4, pT 3 G_any_,pT 1 G_any pN1 or pT 1 G_any pN_any M1 NED	pT2 G4, pT 3a G 3, pT 3b G_any_,pT 1 G_any pN1 or pT 1 G_any pN_any M1 NED	pT 2 G_any_,pT 1 G_any N1 or pT 1 G_any pN_any M1 NED	pT2a G 3, pT 2b G_any or pT_any G_any pN1
Experimental Arm	Pembrolizumab	Atezolizumab	Nivolumab (neo-adjuvant and adjuvant)	Nivolumab + Ipilimumab
Control Arm	Placebo	Placebo	Observation	Placebo
Duration of Treatment (mo)	12 (17 cycles)	12 (16 cycles)	12 (1+9 cycles)	6 (4 cycles of Ipi + 12 cycles of Nivo)
UISS¹ intermediate-high risk (%)	86	62	NI²	43
UISS high risk (%)	8	24	NI	56
N+ (%)	6	11	17	NI
M1 Ressected (NED³) (%)	6	14	3	None
Non-Clear Cell RCC (%)	None	7	17	NI
Sarcomatoid Component (%)	10	9	NI	5
PD-L1 positive (%)	74	59	NI	NI

1UISS = UCLA Integrated Staging System; 2NI = Not Informed; 3NED = No evidence of disease

Therefore, we perform a systematic review and study-level meta-analysis including the four RCT addressing ICI in adjuvant settings totalizing 3,405 patients with localized renal cell carcinoma. In resume, for ITT population there was no DFS benefit with adjuvant ICI therapy (Figure 1). Considering the high heterogeneity associated with this analysis, subgroup analyses were performed. Thus, there were DFS benefits for PD-L1 positive and intermediate-high risk patients and patients with sarcomatoid component (Figure 2, 3 and 4, respectively).

Figure 1. Adjuvant immunotherapy versus placebo / observation in the ITT population; the outcome (Effect Size) was Hazard Ratio (HR) of Disease-Free Survival (DFS). Abbreviations: CI: confidence interval; ES: Effect Size; N: total number of patients; N1: number of patients in the experimental arm; N2: number of patients in the control arm; W: weight.

table 2.png
Figure 2. Adjuvant immunotherapy versus placebo/observation in PD-L1 positive population; the outcome (Effect Size) was Hazard Ratio (HR) of Disease-Free Survival (DFS). Abbreviations: CI: confidence interval; ES: Effect Size; N: total number of patients; N1: number of patients in the experimental arm; N2: number of patients in the control arm; W: weight

Figure 3. Adjuvant immunotherapy versus placebo/observation in intermediate-high risk RCC patients; the outcome (Effect Size) was Hazard Ratio (HR) of Disease-Free Survival (DFS). Abbreviations: CI: confidence interval; ES: Effect Size; N: total number of patients; N1: number of patients in the experimental arm; N2: number of patients in the control arm; W: weight.

Figure 4. Adjuvant immunotherapy versus placebo in (A) patients with sarcomatoid component; the outcome (Effect Size) was Hazard Ratio (HR) of Disease-Free Survival (DFS). Abbreviations: CI: confidence interval; ES: Effect Size; N: total number of patients; N1: number of patients in the experimental arm; N2: number of patients in the control arm; W: weight.

In conclusion, considering the heterogeneity between the trials such as different populations and ICI used as well as the design of the trials and duration of ICI treatment, our meta-analysis was unable to demonstrate DFS benefit in overall population, therefore the decision to use adjuvant ICI should be individualized.

Written by: Fernando Sabino Marques Monteiro, Latin American Oncology Group (LACOG) – Genito-Urinary Tumors Section. Hospital Santa Lucia – Oncology and Hematology Department, Brazil

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