Evaluation and analysis of renal injury in patients with advanced renal cell carcinoma receiving first-line benmelstobart plus anlotinib: results from the ETER100 study

Abstract

Background

Combination treatment with anti-angiogenic agents and immune checkpoint inhibitors has demonstrated significant efficacy in advanced renal cell carcinoma (RCC). However, data on treatment-emergent renal injury during combination therapy and its prognostic implications remain limited. This study analyzed renal injury and its association with survival outcomes in patients with advanced RCC receiving first-line benmelstobart combined with anlotinib in the ETER100 trial.

Methods

All randomized patients in the ETER100 (NCT04523272) trial treated with at least one dose of study treatment were included in this analysis. Baseline characteristics, laboratory test results, and information on objective responses, disease progression, and death events were collected. The primary outcomes of this study included renal function changes during therapy, risk factors for renal function abnormalities, clinical outcomes of patients with renal function abnormalities, and the association between renal function abnormalities and survival outcomes.

Results

Compared with sunitinib monotherapy, patients receiving benmelstobart combined with anlotinib showed no significant differences in the incidence of serum creatinine elevation (p = 0.0538), percentage decrease in creatinine clearance (p = 0.2546), absolute decrease in creatinine clearance (p = 0.7343), or proteinuria (p = 0.0728). Multivariate analysis identified a history of nephrectomy and estimated glomerular filtration rate <90 mL/min/1.73 m² as independent predictors of serum creatinine elevation in patients receiving combination therapy. As of January 2024, 64.00% of patients (64/100) who developed serum creatinine elevation during combination therapy had recovered to normal levels, and 6.00% (6/100) showed improvement. Besides, 45.56% of patients (77/169) who had proteinuria recovered to normal, and 22.49% (38/169) experienced improvement. Multivariate Cox regression analysis showed that both serum creatinine elevation (progression-free survival [PFS]: p = 0.3526; overall survival [OS]: p = 0.0521) and proteinuria (PFS: p = 0.5831; OS: p = 0.1224) were not independent risk factors for progression-free survival or overall survival in patients receiving combination therapy.

Conclusions

For patients with advanced RCC in the ETER100 trial, combination therapy with anti-angiogenic agents and immune checkpoint inhibitors did not increase the risk of renal injury, and in this treatment context, renal function abnormalities occurring during treatment were not significantly associated with survival outcomes.

Trial registration

ClinicalTrials.gov identifier: NCT04523272.

Background

Renal cell carcinoma (RCC) is one of the most common malignancies of the urinary system, accounting for approximately 90% of renal cancer cases [1]. In recent years, multiple phase III clinical trials, including IMmotion151, KEYNOTE-426, CLEAR, and RENOTORCH, have demonstrated that combination regimens of anti-angiogenic agents and immune checkpoint inhibitors significantly prolong progression-free survival (PFS) and overall survival (OS) as first-line treatments for advanced RCC [2–5], ushering in a new era of first-line treatment dominated by targeted therapy combined with immunotherapy [6]. Despite these efficacy breakthroughs, combination therapies are associated with cumulative renal toxicities, such as proteinuria, serum creatinine elevation, and hypertension [7–9]. The mechanisms underlying the renal toxicities of combination therapy remain incompletely understood. Mechanistic studies suggest tyrosine kinase inhibitors impair the glomerular filtration barrier by inhibiting vascular endothelial growth factor receptor activity in podocytes, leading to proteinuria and reduced glomerular filtration rate [10–14]. Immune checkpoint inhibitors may disrupt tolerance to endogenous kidney antigens through T-cell activation, causing autoimmune-mediated renal injury [15–18]. When used in combination, the resulting nephrotoxicity may not be purely additive but may reflect a synergistic effect [19]. Thus, it is necessary to comprehensively analyze the nephrotoxicity of targeted combined immunotherapy in RCC patients.

Besides, emerging evidence indicates that renal injury occurring during treatment may have prognostic implications [20–25]. However, subgroup analysis related to renal injury was limited in current phase III trials (e.g., KEYNOTE-426 and CLEAR); consequently, a comprehensive evaluation of renal injury in the context of targeted therapy combined with immunotherapy remains lacking. In the era of advancing personalized medicine, understanding the efficacy of combining targeted therapy with immunotherapy in patients with or without renal injury is of significant clinical importance. This study aims to fill this gap by systematically evaluating renal injury in patients who received targeted therapy combined with immunotherapy in the ETER100 trial.

The ETER100 trial, published in our previous work, assessed the efficacy and safety of the PD-L1 inhibitor benmelstobart in combination with anlotinib as a first-line therapy for advanced RCC, yielding an objective response rate (ORR) of 72% and a median PFS of 19.0 months with this regimen, indicating substantial clinical antitumor activity [26]. This post-hoc analysis of the ETER100 trial systematically evaluated the incidence and risk factors of renal injury during combination therapy and explored the association between renal injury and patient survival outcomes.

Methods

Study design and participants

The ETER100 trial was a multicenter, randomized, open-label phase III trial conducted at 37 medical sites in China comparing the efficacy of benmelstobart plus anlotinib versus sunitinib in previously untreated patients with advanced clear-cell RCC. The trial design and primary results of the ETER100 trial have been reported previously [26]. In brief, patients enrolled in the ETER100 trial were aged 18-80 years with advanced renal cell carcinoma with a clear-cell component who had not received systemic therapy for locally progressed or metastatic disease, although prior cytokine therapy was allowed. Eligible patients were randomly assigned in a 1:1 ratio to receive benmelstobart plus anlotinib or sunitinib monotherapy. Benmelstobart was administered intravenously at a dose of 1200 mg on day 1 of each 3-week cycle, and anlotinib was administered orally at a dose of 12 mg daily for the first 2 weeks of each 3-week cycle. Sunitinib was administered orally at a dose of 50 mg daily for the first 4 weeks of each 6-week cycle. This study was a post-hoc analysis of the ETER100 trial, focusing on renal injury during treatment and its association with survival outcomes. All patients in the ETER100 trial who were randomized and received at least one dose of the study treatment were included in this analysis. This post-hoc analysis was approved by the Medical Ethics Committee of Peking University Cancer Hospital (approval number: 2026KT96). This post-hoc analysis used de-identified data collected from the ETER100 trial, for which all participants had provided written informed consent before enrolment; therefore, additional informed consent was not required.

Data collection and outcomes

For patients included in this post-hoc analysis, baseline data, laboratory results (including proteinuria, serum creatinine, creatinine clearance, and estimated glomerular filtration rate (eGFR), as well as information on objective responses, disease progression, and death were collected.

The primary outcomes of this study included changes in renal function during therapy (serum creatinine elevation, creatinine clearance decline, and proteinuria), risk factors for renal function abnormalities (serum creatinine elevation and proteinuria), clinical outcomes of patients with renal function abnormalities, and the association between renal function abnormalities and survival outcomes. In addition, this study evaluated chronic kidney disease (CKD) and its association with survival outcomes during combination therapy.

In this study, serum creatinine and proteinuria were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, with abnormalities defined as values reaching or exceeding grade 1 (G1). The detailed grading criteria are provided in Additional file 1: Table S1. Creatinine clearance was calculated using the Cockcroft-Gault formula. CKD stratification was based on the eGFR classification method recommended by the Kidney Disease: Improving Global Outcomes guidelines, with eGFR ≥ 60 mL/min/1.73 m² defined as mild CKD and eGFR < 60 mL/min/1.73 m²defined as moderate or more severe CKD.

Statistical analysis

All statistical analyses were performed using SAS version 9.4, with a two-sided significance level of 0.05. Hazard ratios (HRs) and odds ratios (ORs) are presented with 95% confidence intervals (CIs). Categorical variables were summarized as frequencies (percentage [%]), and continuous variables were presented as mean ± standard deviation or median with interquartile range (IQR). Between-group comparisons of serum creatinine elevation, creatinine clearance decline, and proteinuria were performed using the Wilcoxon rank-sum test. Univariate logistic regression was used to identify potential risk factors for renal function abnormalities. Variables with P < 0.05 in the univariate analysis, along with demographic factors (age and sex), were included in the multivariate logistic regression model to determine independent predictors of renal function abnormalities. PFS and OS were estimated using the Kaplan-Meier method, with between-group comparisons performed using the log-rank test, and multivariate survival analysis conducted using the Cox proportional hazards model.

Results

Renal function abnormalities: characteristics and clinical outcomes

Among patients receiving benmelstobart plus anlotinib (N = 264), 100 (37.88%) experienced serum creatinine elevation, compared with 120 (45.63%) in the sunitinib group (N = 263), with no significant difference between the two groups (p = 0.0538, Additional file 1: Fig. S1). Similarly, there were no significant differences between the two groups in the decline of creatinine clearance, either in percentage (p = 0.2546) or absolute values (p = 0.7343). Of the 100 patients who developed serum creatinine elevation while receiving combination therapy, 47 (47.00%) had hypertension, 20 (20.00%) had diabetes, 79 (79.00%) had undergone prior nephrectomy, and 86 (86.00%) had an eGFR <90 mL/min/1.73 m²; most patients (75.00%, 75/100) had a Karnofsky performance status (KPS) of 90–100 (Table 1).

Table 1.

Baseline characteristics of patients with serum creatinine elevation and proteinuria while receiving benmelstobart plus anlotinib

Characteristics	Serum creatinine elevation (N = 100)	Proteinuria (N = 169)
Age (years), < 65	65 (65.00)	103 (60.95)
Male sex	78 (78.00)	135 (79.88)
BMI, < 25	53 (53.00)	101 (59.76)
Hypertension	47 (47.00)	79 (46.75)
Diabetes	20 (20.00)	29 (17.16)
ECOG performance status
0	25 (25.00)	42 (24.85)
1	75 (75.00)	127 (75.15)
KPS
90-100	75 (75.00)	36 (21.30)
70-80	25 (25.00)	133 (78.70)
IMDC prognostic risk
Favourable	18 (18.00)	26 (15.38)
Intermediate	73 (73.00)	120 (71.01)
Poor	9 (9.00)	23 (13.61)
History of nephrectomy	79 (79.00)	109 (64.50)
eGFR, < 90 mL/min/1.73 m²	86 (86.00)	127 (75.15)

Data are n (%). Abbreviations: BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; KPS, Karnofsky performance status; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; eGFR, estimated glomerular filtration rate

Regarding proteinuria, 64.02% of patients (169/264) receiving benmelstobart plus anlotinib developed proteinuria, compared with 59.32% (156/263) receiving sunitinib, with no statistically significant difference (p = 0.0728, Additional file 1: Fig. S1). Of the 169 patients treated with the combination therapy who experienced proteinuria, 46.75% (79/169) had hypertension and 17.16% (29/169) had diabetes (Table 1). A total of 64.50% of patients (109/169) had undergone prior nephrectomy, 75.15% (127/169) had an eGFR <90 mL/min/1.73 m², and 78.70% (133/169) had a KPS of 70-80. Given the considerable incidence of renal function abnormalities, we next sought to identify potential risk factors associated with their development during combination therapy.

We analyzed risk factors for serum creatinine elevation (Table 2) and proteinuria (Additional file 1: Table S2) in the combination group. Univariate analysis indicated that patients with a history of diabetes had a 103% higher risk of serum creatinine elevation than those without diabetes (OR = 2.03, p = 0.0455), and patients with a history of nephrectomy had a 225% higher risk than those without nephrectomy (OR = 3.25, p < 0.0001). In addition, International Metastatic RCC Database Consortium (IMDC) poor-risk status (OR = 0.32, p = 0.0240) and baseline eGFR ≥ 90 mL/min/1.73 m² (OR = 0.28, p = 0.0001) were protective factors against serum creatinine elevation. Multivariate analysis showed that a history of nephrectomy (OR = 2.22, p = 0.0177) remained an independent risk factor for serum creatinine elevation during treatment, whereas an eGFR ≥90 mL/min/1.73 m² (OR = 0.41, p = 0.0158) was an independent protective factor. With respect to proteinuria, patient age, sex, BMI, comorbidities, and baseline performance status were not significantly associated. Similarly, a history of nephrectomy and baseline eGFR showed no significant correlation with proteinuria.

Table 2.

Univariate and multivariate analysis of serum creatinine elevation in patients treated with benmelstobart plus anlotinib (N = 264)

	N1	Characteristics	N2	Univariate analysis		Multivariate analysis
				OR (95% CI)	P	OR (95% CI)	P
Age (years)	95	≥ 65 vs. < 65	169	0.93 (0.56–1.57)	0.7951	0.75 (0.43–1.33)	0.3228
Sex	204	Male vs. Female	60	1.07 (0.59–1.94)	0.8265	1.19 (0.62–2.25)	0.6047
BMI	107	≥ 25 vs. < 25	157	1.54 (0.93–2.55)	0.0953
Hypertension	116	Yes vs. No	148	1.22 (0.74–2.01)	0.4342
Diabetes	38	Yes vs. No	226	2.03 (1.01–4.05)	0.0455	2.01 (0.96–4.22)	0.0634
IMDC prognostic risk	188	Intermediate vs. Favourable	37	0.67 (0.33–1.36)	0.5507	0.81 (0.38–1.73)	0.7967
	39	Poor vs. Favourable	37	0.32 (0.12–0.85)	0.0240	0.56 (0.19–1.65)	0.3025
KPS	62	70-80 vs. 90-100	202	1.14 (0.64–2.05)	0.6503
ECOG performance status	192	1 vs. 0	72	1.21 (0.68–2.12)	0.5176
History of nephrectomy	167	Yes vs. No	97	3.25 (1.84–5.75)	< 0.0001	2.22 (1.15–4.29)	0.0177
eGFR (mL/min/1.73 m²)	74	≥ 90 vs. < 90	190	0.28 (0.15–0.54)	0.0001	0.41 (0.20–0.85)	0.0158

Abbreviations: BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; KPS, Karnofsky performance status; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; IQR, interquartile range; eGFR, estimated glomerular filtration rate; OR, odds ratio; CI, confidence interval

We further analyzed the clinical outcomes of the 100 patients who developed serum creatinine elevation and the 169 patients who developed proteinuria during treatment with benmelstobart plus anlotinib (Table 3). Among patients with serum creatinine elevation, 78 patients (78.00%) had G1 serum creatinine elevation, with a median time to first occurrence of 24.00 weeks (IQR, 6.14–41.86); 17 patients (17.00%) had G2 serum creatinine elevation, with a median time to first occurrence of 21.29 weeks (IQR, 9.00–28.00); and 5 patients (5.00%) had G3 serum creatinine elevation, with a median time to first occurrence of 72.29 weeks (IQR, 63.29–74.86). Due to serum creatinine elevation, 2 (2.00%) and 3 (3.00%) of 100 patients experienced treatment interruption of benmelstobart and anlotinib, respectively, with no related permanent discontinuations observed (Additional file 1: Table S3). By the end of follow-up in January 2024, 64 patients (64.00%) had recovered to normal serum creatinine, including 58, 4, and 2 patients from G1, G2, and G3, respectively (Table 3). The median time to recovery was 12.00 weeks (IQR, 3.71–21.29) for G1, 5.57 weeks (IQR, 4.36–12.14) for G2, and 75.07 weeks (IQR, 25.29–124.86) for G3 patients. Additionally, 5 patients with G2 and 1 patient with G3 experienced a reduction in the severity of serum creatinine elevation. Of the patients with proteinuria, 66 patients (39.05%) had G1 proteinuria, with a median time to first occurrence of 13.86 weeks (IQR, 2.14–28.71); 80 patients (47.34%) had G2 proteinuria, with a median time to first occurrence of 27.64 weeks (IQR, 9.21–48.50); and 23 patients (13.61%) had G3 proteinuria, with a median time to first occurrence of 21.29 weeks (IQR, 12.29–53.86; Table 3). Due to proteinuria, 17 (10.06%) and 3 (1.78%) of 169 patients experienced treatment interruption and permanent discontinuation of benmelstobart, respectively, while the corresponding numbers for anlotinib were 23 (13.61%) and 4 (2.37%), respectively (Additional file 1: Table S3). By the end of follow-up in January 2024, 77 patients (45.56%) had recovered to normal (43 from G1, 32 from G2, and 2 from G3), with a median time to recovery of 6.71 weeks (IQR, 3.00–15.29) for G1, 15.36 weeks (IQR, 4.50–29.50) for G2, and 12.86 weeks (IQR, 12.71–13.00) for G3 patients (Table 3). In addition, 38 patients (22.49%) experienced a reduction in proteinuria severity (27 from G2 and 11 from G3).

Table 3.

Clinical outcomes in patients with serum creatinine elevation and proteinuria

	Events (n, %)	First occurrence time (median week, IQR)	Recovery events (n)	Recovery time (median, IQR)	No recovery events (n)	Reduction events (n)
Serum creatinine elevation* (N = 100)
G1	78 (78.00)	24.00 (6.14–41.86)	58	12.00 (3.71–21.29)	20	/
G2	17 (17.00)	21.29 (9.00–28.00)	4	5.57 (4.36–12.14)	13	5
G3	5 (5.00)	72.29 (63.29–74.86)	2	75.07 (25.29–124.86)	3	1
Proteinuria# (N = 169)
G1	66 (39.05)	13.86 (2.14–28.71)	43	6.71 (3.00–15.29)	23	/
G2	80 (47.34)	27.64 (9.21–48.50)	32	15.36 (4.50–29.50)	48	27
G3	23 (13.61)	21.29 (12.29–53.86)	2	12.86 (12.71–13.00)	21	11

^*G1/G2/G3 = serum creatinine elevation grade 1/grade 2/grade3

^#G1/G2/G3 = proteinuria grade 1/grade 2/grade3

Abbreviations: IQR, interquartile range

Renal function abnormalities and survival outcomes

Patients receiving benmelstobart plus anlotinib were grouped according to the occurrence of serum creatinine elevation to assess their association with clinical outcomes. The ORR was 72.00% (95% CI, 62.13–80.52) in patients with serum creatinine elevation (N = 100) and 71.34% (95% CI, 63.77–78.12) in those without (N = 164), with no statistically significant difference (p = 0.9084, Additional file 1: Table S4). Median PFS was 22.37 months (95% CI, 15.34–27.66) for patients with serum creatinine elevation and 16.66 months (95% CI, 13.73–20.53) for those without (HR = 0.81, 95% CI, 0.57–1.16; p = 0.2568; Fig. 1A). Multivariate Cox regression indicated that patients with IMDC poor-risk status had a 201% higher risk of disease progression or death compared with favourable-risk patients (p = 0.0016), and serum creatinine elevation was not independently associated with PFS (HR = 0.84; 95% CI, 0.58–1.22; p = 0.3526; Fig. 2A). Median OS was not reached in either group (p = 0.0262; Fig. 1B), and multivariate Cox regression analysis showed that patients with IMDC poor-risk status had a 224% higher risk of death compared with favourable-risk patients (p = 0.0134), whereas serum creatinine elevation was not an independent predictor of OS (HR = 0.57; 95% CI, 0.33–1.00; p = 0.0521; Fig. 2B).

Fig. 1.

Kaplan-Meier survival curve for progression-free survival and overall survival for patients with serum creatinine elevation or proteinuria. (A) Progression-free survival for patients with or without serum creatinine elevation; (B) Overall survival for patients with or without serum creatinine elevation; (C) Progression-free survival for patients with or without proteinuria; (D) Overall survival for patients with or without proteinuria. Between-group difference was analysed using the log-rank test, and p-values were two-sided. Abbreviations: NE, not estimable; NR, not reached; CI, confidence interval

Fig. 2.

Forest plots of the association between serum creatinine elevation or proteinuria and survival outcomes. (A) Multivariable Cox regression analysis of the association between serum creatinine elevation and progression-free survival; (B) Multivariable Cox regression analysis of the association between serum creatinine elevation and overall survival. (C) Multivariable Cox regression analysis of the association between proteinuria and progression-free survival; (D) Multivariable Cox regression analysis of the association between proteinuria and overall survival. Abbreviations: HR, hazard ratio; CI, confidence interval; BMI, body mass index; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; KPS, Karnofsky performance status

For patients with proteinuria, the median PFS was 19.38 months (95% CI, 15.34–25.46), compared with 16.72 months (95% CI, 11.14–30.16) in those without, with a risk of disease progression or death of 0.86 (95% CI, 0.60–1.24; p = 0.4273; Fig. 1C). Multivariate Cox regression analysis indicated that patients with IMDC poor-risk status had a 206% higher risk of disease progression or death compared with favourable-risk patients (p = 0.0014). Proteinuria was not independently associated with PFS (HR = 0.90; 95% CI, 0.62–1.31; p = 0.5831; Fig. 2C). Regarding OS, neither group had reached the median OS (p = 0.0995; Fig. 1D). Multivariate Cox regression analysis again identified that patients with IMDC poor-risk status had a 258% higher risk of death compared with favourable-risk patients (p = 0.0070). Conversely, proteinuria was not an independent predictor of OS (HR = 0.67; 95% CI, 0.40–1.11; p = 0.1224; Fig. 2D).

The association between serum creatinine elevation recovery and treatment efficacy was further evaluated by categorizing patients with serum creatinine elevation into the recovery group (N = 64) and the non-recovery group (N = 36). The ORR was 75.00% (95% CI, 62.60–84.98) and 66.67% (95% CI, 49.03–81.44) in the recovery and non-recovery groups, respectively (Additional file 1: Table S4). Median PFS was 22.83 months (95% CI, 16.95–not estimable) in the recovery group and 16.89 months (95% CI, 11.20–27.20) in the non-recovery group (Fig. 3A), with a 32% lower risk of disease progression or death in the recovery group. Median OS was not reached in either group, but the recovery group demonstrated a 40% lower risk of death (Fig. 3B); however, these differences were not statistically significant. Similarly, no significant differences were observed in PFS (p = 0.8221; Fig. 3C) or OS (p = 0.6812; Fig. 3D) between patients who recovered from proteinuria and those who did not.

Fig. 3.

Progression-free survival and overall survival for patients with serum creatinine elevation or proteinuria according to recovery status. (A) Progression-free survival for patients with serum creatinine elevation according to recovery status; (B) Overall survival for patients with serum creatinine elevation according to recovery status; (C) Progression-free survival for patients with proteinuria according to recovery status; (D) Overall survival for patients with proteinuria according to recovery status. Between-group difference was analysed using the log-rank test, and p-values were two-sided. Abbreviations: NE, not estimable; NR, not reached; CI, confidence interval

CKD and survival outcomes

For patients with CKD, we evaluated changes in the severity of CKD during treatment. Among patients receiving benmelstobart plus anlotinib, 62 patients (23.48%) had moderate or more severe CKD at baseline, of whom 15 recovered to mild CKD after treatment; among the 202 patients (76.51%) with mild CKD at baseline, 16 developed moderate or more severe CKD after treatment (Additional file 1: Table S5). The clinical course of CKD was generally comparable between patients receiving benmelstobart plus anlotinib and those receiving sunitinib.

We further stratified patients based on post-combined treatment CKD severity into a mild CKD group (N = 201) and a moderate or more severe CKD group (N = 63). The results showed no significant differences in ORR or median PFS between the two groups, whereas the median OS was significantly longer in the moderate or more severe CKD group compared with the mild CKD group (p = 0.0352, Additional file 1: Table S6). Additionally, patients were grouped according to changes in CKD severity before and after treatment. The results showed that, regardless of changes in CKD severity, there was no significant difference in median OS between the combination therapy group and the sunitinib group (Additional file 1: Table S7).

Discussion

For patients with advanced RCC, changes in renal function during treatment are critical for assessing the feasibility of therapeutic regimens. This post-hoc analysis of the ETER100 trial systematically evaluated the incidence and risk factors of serum creatinine elevation and proteinuria during treatment with benmelstobart plus anlotinib. It further explored the association between renal function abnormalities and survival outcomes, providing valuable insights for clinical monitoring and risk management of this anti-angiogenic agent and immune checkpoint inhibitor combination.

A previous meta-analysis found that compared with targeted monotherapy, immune-based combination therapy did not result in a significant difference in serum creatinine elevation, but the risk of proteinuria was significantly higher with combination treatment [27]. Recognizing that serum creatinine elevation is not an ideal, comprehensive, or exclusive marker of renal injury, we employed a multidimensional assessment incorporating a comprehensive panel of renal injury parameters. Our study found no significant differences between patients receiving targeted monotherapy and those receiving combination therapy regarding the incidence of serum creatinine elevation, decline in creatinine clearance, occurrence of proteinuria, or CKD severity. Overall, the combination of benmelstobart and anlotinib did not increase the risk of renal injury in our patient population.

In our study, the onset of all-grade serum creatinine elevation and proteinuria was generally late. The median time to the first onset of a grade 3 serum creatinine elevation was as long as 72.29 weeks, while the median time for a grade 2 proteinuria was 27.64 weeks. This indicated that patients receiving combination therapy exhibited good renal tolerability in the early stages of treatment. Importantly, renal function abnormalities in patients receiving the combination therapy were largely reversible: 64.00% of serum creatinine elevation returned to normal and 6.00% improved; 45.56% of proteinuria returned to normal and 22.49% improved. This finding was consistent with previous studies on renal function abnormalities associated with immune checkpoint inhibitors or anti-angiogenic agents used alone [28, 29]. Guided by protocol-specified timely interventions, no corticosteroid therapy was administered for either serum creatinine elevation or proteinuria in our population. Furthermore, no treatment discontinuations were attributable to serum creatinine elevation, and permanent discontinuation of either agent due to proteinuria was infrequent (benmelstobart, 1.78%; anlotinib, 2.37%).

Although most renal function abnormalities were reversible, prolonged or more severe events can still disrupt treatment continuity and adversely affect the patient’s overall health. Therefore, identifying high-risk factors for renal function abnormalities and strengthening monitoring during treatment to prevent severe renal injury is crucial. Multivariate analysis showed that a history of nephrectomy and an eGFR <90 mL/min/1.73 m² were independent risk factors for serum creatinine elevation during the combination therapy, suggesting that a comprehensive nephrologic evaluation at baseline is warranted for patients scheduled to receive potentially nephrotoxic agents. Where feasible, involvement of nephrologists in patient assessment and management will likely help optimize treatment decisions and improve clinical outcomes [30]. Based on these findings, we proposed a simple risk-stratified monitoring algorithm as a hypothesis-generating suggestion for clinical practice. Patients without risk factors may follow routine monitoring per the trial protocol (e.g., each cycle or as clinically indicated), whereas those with one or both risk factors may benefit from more frequent monitoring during the first two treatment cycles (e.g., every 2–3 weeks) to enable early detection of renal function abnormalities and timely intervention. This pragmatic framework aims to concentrate monitoring resources by focusing on high-risk patients, thereby enhancing patient safety without imposing an undue burden on the healthcare system or compromising treatment continuity for the majority. Prospective validation is still required before this risk-stratified monitoring algorithm can be formally implemented in routine clinical practice.

Several studies have suggested that renal function abnormalities occurring during anti-angiogenic and/or immune checkpoint inhibitor therapy in patients with RCC may be associated with survival outcomes [20–25]. In our analysis stratified by CKD severity, a similar pattern was observed, with patients having moderate or more severe CKD showing significantly longer OS (p = 0.0352). Renal injury in cancer patients is typically multifactorial, arising not only from treatment-related toxicity but also from tumor-related factors and underlying disease burden [31]; therefore, this positive association may more likely reflect differences in baseline characteristics or treatment-related factors rather than a direct protective effect of CKD itself. In addition, the limited sample size, follow-up duration, and data maturity may also have influenced the robustness of the findings. Given these considerations, one possible hypothesis is that the severity of CKD may potentially be associated with differences in adequate drug exposure and treatment efficacy, which requires further validation through pharmacokinetic and translational studies.

When analyzing based on serum creatinine elevation and proteinuria, patients with these abnormalities showed a trend toward improved survival compared with those without these abnormalities in the Kaplan-Meier analysis, particularly with a significantly longer OS observed in patients with serum creatinine elevation (p = 0.026). Nevertheless, this association was not confirmed in the multivariate Cox regression model, possibly due to limited statistical power from the small sample size, the potential heterogeneity in the study population, and the relatively short follow-up duration. Furthermore, for patients who develop renal function abnormalities, the recovery of renal function remains crucial for ensuring the effectiveness of combination therapy. In our study, we observed that patients whose renal function recovered had a lower risk of disease progression or death compared to those whose renal function did not recover. This indicates that timely intervention and management of renal function abnormalities may have potential benefits for improving clinical outcomes.

Clinically, our findings carry significant implications for managing patients who develop renal function abnormalities during combination therapy. Previous studies have also suggested that renal injury should not be regarded as a reason to withhold or discontinue anti-RCC therapy [32, 33]. Our results may further provide clinicians with increased confidence to continue an effective treatment regimen, particularly in patients who develop low-grade serum creatinine elevation or proteinuria, while otherwise continuing to derive clinical benefit from benmelstobart plus anlotinib therapy. This is pivotal, as it could help avert unnecessary dose reductions or premature treatment discontinuations that might compromise antitumor efficacy. Our data thus provide a rationale for a more nuanced approach: rather than a reflexive modification of therapy for isolated renal parameter changes, management should be individualized, weighing the severity of the renal abnormality against the magnitude of the ongoing oncological benefit. This strategy aims to optimize the risk-benefit balance, ensuring patients maintain access to potentially life-prolonging treatment while implementing appropriate monitoring and supportive care for renal adverse events. Beyond its immediate implications for RCC, our study raises a provocative question regarding the broader oncological context: Is the dissociation between treatment-emergent renal injury and survival outcomes a phenomenon unique to this specific RCC regimen, or might it reflect a more general principle applicable to other malignancies treated with analogous anti-angiogenic and immune checkpoint inhibitor combinations? For instance, in hepatocellular carcinoma treated with atezolizumab plus bevacizumab or in endometrial cancer with lenvatinib plus pembrolizumab, similar patterns could theoretically exist. If validated, this would suggest that the management paradigm we observed—prioritizing anticancer efficacy while vigilantly managing reversible organ toxicity—could be extrapolated, thereby optimizing therapeutic strategies across multiple cancer types.

This study had several limitations. First, serum creatinine elevation and proteinuria were used as the primary indicators of renal injury, which may not fully capture immune-related or subclinical renal injury and could therefore underestimate the true incidence. Second, although this study preliminarily explored the relationship between CKD during treatment and survival outcomes, the impact of long-term renal injury (e.g., CKD persisting beyond one year post-treatment) on prognosis was not assessed. Third, as a post-hoc analysis based on a single clinical trial (ETER100), the findings should be interpreted with inherent limitations of such analyses, including unavoidable risks of selection and interpretation bias. In addition, whether these findings can be generalized to other combination treatment regimens remains to be further investigated. Finally, this study did not analyze potential renal injury biomarkers such as KIM-1, NGAL, and cystatin C, which may allow earlier detection of subclinical tubular and glomerular injury and serve as complementary indicators to traditional measures [34–36]. Future studies incorporating these biomarkers may enable a more comprehensive assessment of renal safety.

Conclusions

In summary, this post-hoc analysis of the ETER100 trial showed that, compared with targeted monotherapy, combination therapy with anti-angiogenic agents and immune checkpoint inhibitors did not increase the risk of renal injury, and no significant association was observed between treatment-emergent renal injury and survival outcomes.

Abbreviations

RCC

Renal cell carcinoma

PFS

Progression-free survival

OS

Overall survival

ORR

Objective response rate

eGFR

Estimated glomerular filtration rate

CKD

Chronic kidney disease

G1

Grade 1

HRs

Hazard ratios

ORs

Odds ratios

CIs

Confidence intervals

IQR

Interquartile range

KPS

Karnofsky performance status

IMDC

International Metastatic RCC Database Consortium

Author contributions

JL: Conceptualization, Funding acquisition, Project administration, Validation, Visualization, Writing – original draft; HCT: Investigation, Writing – original draft; HYX: Data curation; XQY: Formal analysis, Methodology, Software, Validation; BXT: Data curation, Methodology; SML: Investigation; LZ: Data curation, Formal analysis, Software; XWW: Resources; ZHC: Resources; CLC: Validation; LS: Supervision, Validation, Writing – review & editing; JG: Conceptualization, Funding acquisition; XNS: Conceptualization, Project administration, Supervision, Visualization, Writing – review & editing. All authors read and approved the final manuscript.

Funding

This work was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2026ZD0553706), the CAPTRA-STAR Research Grant Program 2025, Beijing Cancer Prevention and Research Association (KY202502055), and the Beijing High-level Innovation and Entrepreneurship Talent Support Program leading talent projects (G202512054).

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request after completion of the trial (doctor_sheng@126.com).

Declarations

Ethical approval and consent to participate

This post-hoc analysis was approved by the Medical Ethics Committee of Peking University Cancer Hospital (approval number: 2026KT96). This post-hoc analysis used de-identified data collected from the ETER100 trial, for which all participants had provided written informed consent before enrolment; therefore, additional informed consent was not required.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Supplementary information

The online version contains supplementary material available at https://doi.org/10.1186/s12916-026-05026-0.