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Midterm outcomes of combination therapy with immune checkpoint inhibitors and VEGFR-TKIs in real-world patients with advanced renal cell carcinoma1,2Hiroki Ishihara, 3Nanaka Katsurayama, 4Yuki Nemoto, 5Shinsuke Mizoguchi, 2Takayuki Nakayama, 2Hironori Fukuda, 4Hiroaki Shimmura, 1Yasunobu Hashimoto, 2Kazuhiko Yoshida, 2Junpei Iizuka, 3Tsunenori Kondo, 2Toshio Takagi
1Department of Urology, Saiseikai Kawaguchi General Hospital
5-11-5 Nishikawaguchi, Kawaguchi, Saitama, Japan
2Department of Urology, Tokyo Women’s Medical University
8 − 1 Kawada-cho, Shinjuku-ku, Tokyo, Japan
3Department of Urology, Tokyo Women’s Medical University Adachi Medical Center
4-33-1 Kouhoku, Adachi-ku, Tokyo, Japan
4Department of Urology, Jyoban Hospital
Uenodai 57, Joban Kamiyunagayamachi, Iwaki, Fukushima, Japan
5Department of Urology, Saiseikai Kazo Hospital
1680 Kamitakayanagi, Kazo, Saitama, Japan
*Corresponding author
Hiroki Ishihara, M.D., Ph.D.
Department of Urology, Saiseikai Kawaguchi General Hospital
5-11-5 Nishikawaguchi, Kawaguchi, Saitama, Japan
Phone: +81-570-08-1551
Fax: +81-48-256-5703
Email: ishihara.hiroki@twmu.ac.jp
Word counts
Abstract: 244 words
Main text: 1,989 words (excluding the abstract)
Number of Figures
5
Number of Tables
3
Number of Supplementary Tables
1
Running title
Midterm outcomes of IO-TKI for RCC
Abstract
Background
Limited data are available on the midterm outcomes of combination therapy with immune checkpoint inhibitors and VEGFR-TKIs (IO-TKI therapy) for advanced renal cell carcinoma (RCC) in real-world settings.
Methods
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We retrospectively evaluated clinical data from 68 patients who received lenvatinib plus pembrolizumab (n = 14), cabozantinib plus nivolumab (n = 20), pembrolizumab plus axitinib (n = 23), or avelumab plus axitinib (n = 11) as first-line therapy for advanced RCC. All patients had a minimum follow-up of 3 years after treatment initiation. Effectiveness and safety profiles were assessed.Results
During a median follow-up of 32.7 months, the median progression-free survival (PFS) and overall survival (OS) were 19.9 and 46.7 months, respectively. The objective response rate was 57%. In subgroup analysis, histology was associated with survival outcomes; median PFS (23.0 vs. 8.97 months, p = 0.0362) and OS (not reached vs. 32.1 months, p = 0.0005) were longer in patients with clear-cell RCC than in those with non-clear cell RCC. Regarding safety, grade ≥ 3 adverse events occurred in 44 patients (65%). Treatment discontinuation of both drugs was required in 14 patients (21%), and discontinuation of one drug in 21 patients (31%). High-dose corticosteroids (≥ 40 mg prednisone/day) were required in 10 patients (15%).
Conclusion
With a minimum of 3 years of follow-up, IO-TKI therapy demonstrated feasible effectiveness and manageable safety in patients with advanced RCC in real-world. More effective treatment strategies and novel therapeutic targets are needed for patients with non-clear cell RCC.
Key words
Immuno-oncology
immunotherapy
PD-1
PD-L1
targeted therapy
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1. Introduction
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Combination therapy with immune checkpoint inhibitors (ICIs) and VEGFR-TKIs (IO-TKI therapy) has been approved as a standard first-line systemic treatment for advanced renal cell carcinoma (RCC). To date, three regimens—lenvatinib plus pembrolizumab, nivolumab plus cabozantinib, and pembrolizumab plus axitinib—have demonstrated improved overall survival (OS) compared with sunitinib in patients with previously untreated advanced RCC in randomized phase III clinical trials [1–3].In these pivotal trials, extended follow-up has consistently shown sustained efficacy and manageable safety of IO-TKI therapy [4–7]. Long-term follow-up provides stronger evidence for outcomes, particularly OS and treatment-related toxicities. However, real-world reports remain limited, with most studies assessing outcomes only up to 2 years [8–14]. In real-world practice, some patients are considered trial-ineligible due to characteristics such as non-clear cell histology, severe organ dysfunction, or brain metastases [15]. Since these patients are generally excluded from randomized phase III trials, evidence regarding IO-TKI outcomes in this population is lacking. Importantly, their prognosis after systemic therapy, including ICIs, may be worse than that reported in clinical trials [15]. Therefore, extended real-world follow-up data are needed to clarify the outcomes of IO-TKI therapy.
In this context, we retrospectively evaluated the midterm outcomes of IO-TKI therapy for previously untreated advanced RCC using a minimum 3-year follow-up dataset collected from multiple institutions in Japan.
2. Patients and methods
2.1. Patient selection and study design
At Tokyo Women’s Medical University and four affiliated institutions (Tokyo Women’s Medical University Adachi Medical Center, Saiseikai Kawaguchi General Hospital, Saiseikai Kazo Hospital, and Jyoban Hospital), a total of 71 patients received IO-TKI therapy (lenvatinib plus pembrolizumab, nivolumab plus cabozantinib, pembrolizumab plus axitinib, or avelumab plus axitinib) initiated on or before September 2022, ensuring a minimum follow-up of 3 years. Three patients were excluded due to incomplete baseline data, leaving 68 patients for evaluation in this retrospective observational study.
Treatment was continued until radiographic disease progression or the occurrence of intolerable adverse events (AEs). ICI doses could not be modified; however, administration intervals could be adjusted based on toxicity or patient condition. For TKIs, both dose and administration interval could be modified as needed.
Effectiveness was assessed by progression-free survival (PFS), OS, and objective response rate (ORR). PFS was defined as the time from treatment initiation to disease progression or death, whichever occurred first. OS was defined as the time from treatment initiation to death. The cutoff date for outcome assessment was September 2025. Patients lost to follow-up were censored at the date of last contact. Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1 [16]. Computed tomography of the chest, abdomen, and pelvis was performed at 4–12 week intervals after treatment initiation, depending on the patient's condition. Magnetic resonance imaging, positron emission tomography/computed tomography, and brain imaging were performed when clinically indicated. Safety was assessed by evaluating the incidence of AEs, treatment discontinuation, and corticosteroid use. AEs were graded using the Common Terminology Criteria for Adverse Events version 5.0 [17].
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The study protocol was approved by the Institutional Ethics Review Board of Tokyo Women’s Medical University (ID: 2020-0009). A
The study was conducted in accordance with the principles of the Declaration of Helsinki (1964) and its later amendments. Clinical and laboratory data were obtained from electronic databases and patient medical records.2.2. Protocol for IO-TKI combination therapy
The protocol for IO-TKI therapy as first-line treatment has been described previously [18, 19]. In practice, lenvatinib plus pembrolizumab or nivolumab plus cabozantinib are preferentially selected for patients who require rapid and/or substantial tumor shrinkage due to disease-related symptoms, for use as presurgical therapy (for example, deferred cytoreductive nephrectomy), or for those with non-clear cell histology. Pembrolizumab plus axitinib or avelumab plus axitinib may be considered for patients with a favorable International Metastatic RCC Database Consortium (IMDC) risk, older patients, those with multiple or severe comorbidities, or individuals intolerant to corticosteroids because of AEs.
Due to the timing of approval under the Japanese insurance system, pembrolizumab plus axitinib and avelumab plus axitinib were primarily used in the early period. However, lenvatinib plus pembrolizumab and nivolumab plus cabozantinib have since become the main IO-TKI regimens. Despite these trends, no consensus-based criteria for treatment selection have been established across our affiliated institutions.
2.3. Statistical analysis
Baseline characteristics were summarized as numbers (%) for categorical variables and as medians with interquartile ranges for continuous variables. Categorical variables were compared using Fisher’s exact test. Survival was estimated using the Kaplan–Meier method and compared with the log-rank test. Risks were reported as hazard ratios (HRs) with 95% confidence intervals (CIs). All analyses were performed using JMP software, version 17 (SAS Institute Inc., Cary, NC, USA). Statistical significance was defined as p < 0.05.
3. Results
3.1. Patient characteristics
Table 1 summarizes patient characteristics. Forty-two patients (62%) were ≥ 65 years old, and 50 (74%) were male. Prior nephrectomy was performed in 47 patients (69%), and 45 (66%) had clear-cell RCC. Lenvatinib plus pembrolizumab, nivolumab plus cabozantinib, pembrolizumab plus axitinib, and avelumab plus axitinib were administered in 14 (21%), 20 (29%), 23 (34%), and 11 (16%) patients, respectively. Based on IMDC risk classification, 12 (18%), 42 (62%), and 14 (21%) patients were categorized as favorable, intermediate, and poor risk, respectively. The median follow-up period was 32.7 months (interquartile range: 18.5–39.4 months).
Variables | All (n = 68) |
|---|---|
Age >65 years (ref. ≤ 65 years) | 42 (62%) |
Sex Male (ref. female) | 50 (74%) |
Prior Nephrectomy Presence (ref. absence) | 47 (69%) |
Histology Clear-cell renal cell carcinoma Non-clear cell renal cell carcinoma Unknown | 45 (66%) 15 (22%) 8 (12%) |
Regimen Lenvatinib plus pembrolizumab Nivolumab plus cabozantinib Pembrolizumab plus axitinib Avelumab plus axitinib | 14 (21%) 20 (29%) 23 (34%) 11 (16%) |
cM status cM1 (ref. cM0) | 31 (46%) |
IMDC risk Favorable Intermediate Poor | 12 (18%) 42 (62%) 14 (21%) |
Karnofsky performance status score ≤ 80 (ref. >80) | 11 (16%) |
Serum CRP levels >1 mg/dL (ref. ≤ 1 mg/dL) | 20 (29%) |
Serum neutrophil-to-lymphocyte ratio >3 (ref. ≤ 3) | 38 (56%) |
Chronic kidney disease Presence (ref. absence) | 51 (75%) |
Lung metastasis Presence (ref. absence) | 44 (65%) |
Bone metastasis Presence (ref. absence) | 14 (21%) |
Liver metastasis Presence (ref. absence) | 11 (16%) |
Lymph node metastasis Presence (ref. absence) | 17 (25%) |
Follow-up period, months* | 32.7 (18.5–39.4) |
| *median (interquartile range) | |
| IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; CRP, C-reactive protein | |
3.2. Effectiveness
During follow-up, 51 patients (75%) experienced disease progression, and 24 (35%) died. The median PFS was 19.9 months (95% CI: 13.8–26.0), and the median OS was 46.7 months (95% CI: 38.8–not reached) (Fig. 1). Univariate analysis of PFS and OS showed that histology was the only factor significantly associated with survival. Clear-cell histology was associated with improved PFS (HR: 0.54, 95% CI: 0.30–0.97, p = 0.0393) and OS (HR: 0.25, 95% CI: 0.11–0.58, p = 0.0011) (Figs. 2 and 3, Supplementary Table 1). Patients with clear-cell RCC had longer PFS (median: 23.0 months, 95% CI: 18.3–32.6 vs. 8.97 months, 95% CI: 4.31–18.1, p = 0.0362) and OS (median: not reached, 95% CI: 46.7–not reached vs. 32.1 months, 95% CI: 17.8–40.6, p = 0.0005) compared with those with non-clear cell RCC or unknown histology (Fig. 4).
Fig. 1
Survival after IO-TKI therapy initiation
Progression-free survival. (b) Overall survival.
PFS, progression-free survival; OS, overall survival; N.R., not reached
Fig. 2
Subgroup analysis of progression-free survival
HR, hazard ratio; CI, confidence interval; Nx, nephrectomy; ccRCC, clear-cell renal cell carcinoma; nccRCC, non-clear cell renal cell carcinoma; unk, unknown; LP, lenvatinib plus pembrolizumab; NC, nivolumab plus cabozantinib; PA, pembrolizumab plus axitinib; AA, avelumab plus axitinib; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; KPS, Karnofsky Performance Status; CRP, C-reactive protein; NLR, neutrophil-to-lymphocyte ratio; CKD, chronic kidney disease; LN, lymph node
Fig. 3
Subgroup analysis of overall survival
HR, hazard ratio; CI, confidence interval; Nx, nephrectomy; ccRCC, clear-cell renal cell carcinoma; nccRCC, non-clear cell renal cell carcinoma; unk, unknown; LP, lenvatinib plus pembrolizumab; NC, nivolumab plus cabozantinib; PA, pembrolizumab plus axitinib; AA, avelumab plus axitinib; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; KPS, Karnofsky Performance Status; CRP, C-reactive protein; NLR, neutrophil-to-lymphocyte ratio; CKD, chronic kidney disease; LN, lymph node
Fig. 4
Survival after IO-TKI therapy initiation according to histology
Progression-free survival. (b) Overall survival.
PFS, progression-free survival; OS, overall survival; N.R., not reached; ccRCC, clear-cell renal cell carcinoma; nccRCC, non-clear cell renal cell carcinoma; unk, unknown
Regarding tumor response, the ORR was 57%, including 5 patients (7%) with complete response and 34 (50%) with partial response (Fig. 5, Table 2). ORRs by regimen were 70% for nivolumab plus cabozantinib, 57% for lenvatinib plus pembrolizumab, 52% for pembrolizumab plus axitinib, and 45% for avelumab plus axitinib. The median best tumor response among 66 evaluable patients was − 35.0% (interquartile range: -56.7% to -13.6%). When stratified by histology, ORR tended to be higher in patients with clear-cell RCC than in those with non-clear cell RCC or unknown histology (64% vs. 43%, p = 0.124). The median best tumor response was also greater in patients with clear-cell RCC (-42.3%, 95% CI: -60.7% to -20.5%) than in those with non-clear cell or unknown histology (-24.3%, 95% CI: -43.7 to -11.0%, p = 0.0329).
Fig. 5
Waterfall plot showing the magnitude of best tumor shrinkage
Overall. (b) By treatment regimens.
Variables | All (n = 68) |
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Best overall response Complete response Partial response Stable disease Progressive disease Not applicable | 5 (7%) 34 (50%) 26 (38%) 2 (3%) 1 (1%) |
Objective response rate | 57% |
Magnitude of best tumor response* | -35.0 (-56.7 to -13.6) |
| *66 patients were analyzed | |
3.3. Safety
At least one AE of any grade occurred in all patients (100%); in contrast, grade ≥ 3 AEs developed in 44 patients (65%) (Table 3). Treatment discontinuation of both drugs was required in 14 patients (21%), and discontinuation of one drug in 21 patients (31%). Corticosteroids were administered to 23 patients (34%), including 10 (15%) who required high-dose treatment (≥ 40 mg prednisone per day).
Variables | All (n = 68) |
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Any grade adverse events | 68 (100%) |
Grade 3 or higher adverse events | 44 (65%) |
Treatment discontinuation Both drugs Either drug | 14 (21%) 21 (31%) |
Corticosteroid need Presence High-dose corticosteroid | 23 (34%) 10 (15%) |
4. Discussion
This retrospective, multi-institutional study with a minimum follow-up of 3 years demonstrated that IO-TKI therapy provides feasible effectiveness and manageable safety for patients with previously untreated advanced RCC. A midterm survival benefit was observed regardless of baseline characteristics, except for histological subtype. To our knowledge, this is the first study to report midterm, real-world outcomes of first-line IO-TKI therapy for RCC.
The effectiveness observed in this cohort is broadly comparable to results from phase III randomized clinical trials. For example, in the CLEAR trial, lenvatinib plus pembrolizumab achieved a median OS of 53.7 months, a median PFS of 23.9 months, and an ORR of 71.3% with approximately 4 years of follow-up [20]. The CheckMate 9ER trial reported median OS and PFS of 49.5 and 16.6 months, respectively, and an ORR of 56% for nivolumab plus cabozantinib at a median follow-up of 44.0 months [5]. In the KEYNOTE-426 trial, median OS and PFS for pembrolizumab plus axitinib were 46 and 16 months, respectively, with an ORR of 60% at 43 months of follow-up [6]. Similarly, the JAVELIN Renal 101 trial reported median OS and PFS of 44.8 and 13.9 months, respectively, and an ORR of 59.7% during a median follow-up of 73 months for avelumab plus axitinib [7].
Several real-world studies have also evaluated IO-TKI outcomes with meaningful follow-up durations. The ARON-1 study, using multi-center retrospective data with a median follow-up of 15.1 months, showed that 202 patients receiving lenvatinib plus pembrolizumab had a 2-year OS rate of 67%, median PFS of 15.1 months, and ORR of 59% [8]. The same group reported that among 333 patients receiving nivolumab plus cabozantinib, the 2-year OS rate was 75%, median PFS was 33.7 months, and ORR was 58% with a 15.9-month median follow-up [10]. In Italy, a prospective study of pembrolizumab plus axitinib in 170 patients showed a 2-year OS rate of 62%, a median PFS of 19.2 months, and a disease control rate of 84.6% at 19.3 months [12]. The J-DART2 study from Japan reported that avelumab plus axitinib achieved a 2-year OS rate of 84.7%, median PFS of 17.1 months, and ORR of 53.3% with 18.7 months of follow-up [13]. Collectively, the results of our study are consistent with these prior findings, suggesting that IO-TKI therapy maintains clinical activity even in real-world patients. In this study, treatment effectiveness was not influenced by baseline patient characteristics, supporting the broad feasibility of IO-TKI therapy. However, patients with non-clear cell RCC had worse survival outcomes compared with those with clear-cell histology, consistent with previous reports in patients treated with pembrolizumab plus axitinib [12]. We previously reported similar findings with nivolumab plus ipilimumab, where patients with non-clear cell RCC experienced poorer outcomes than those with clear-cell RCC at a minimum of 3 years of follow-up [21]. A recent network meta-analysis using clinical trial data indicated notable activity of IO-TKI therapy in patients with non-clear cell RCC [22]. However, given the persistent survival disadvantage in this subgroup, more effective treatment strategies and novel therapeutic targets are urgently needed [23, 24].
Regarding safety, the CLEAR trial reported grade ≥ 3 AEs in 82.4% of patients receiving lenvatinib plus pembrolizumab, with treatment discontinuation in 37.2% [1]. In the CheckMate 9ER trial, 66.9% of patients experienced grade ≥ 3 treatment-related AEs, 27.5% discontinued at least one agent [5], and 21.9% required prolonged corticosteroid therapy (≥ 40 mg prednisone daily) [5]. In the KEYNOTE-426 trial, 68% of patients receiving pembrolizumab plus axitinib developed grade ≥ 3 AEs [6], and 7% discontinued both drugs [25]. Similarly, in the JAVELIN Renal 101 trial, 66.8% of patients treated with avelumab plus axitinib developed grade ≥ 3 AEs, and 15.4% required high-dose corticosteroids [7]. The safety outcomes in our study align with these clinical trial data, which is noteworthy given that real-world patients may have comorbidities or organ dysfunction (for example, renal impairment) that increase vulnerability to treatment-related toxicity [15, 26].
This study has some limitations. First, its retrospective design and small sample size inevitably introduce selection bias, which may affect the findings. Second, the follow-up duration may still be insufficient to fully assess OS, potentially limiting interpretation. Third, subgroup analyses were based on univariate analysis, which are susceptible to confounding factors.
5. Conclusion
This multi-institutional, real-world study with midterm follow-up demonstrated that first-line IO-TKI combination therapy provides feasible effectiveness and a manageable safety profile for patients with previously untreated advanced RCC. The outcomes were generally comparable to those reported in clinical trials, supporting the use of IO-TKI therapy in real-world. Further studies with longer follow-up and larger sample sizes are needed to evaluate the long-term OS benefit of this treatment in real-world settings.
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Acknowledgements
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Funding
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Conflicts of interestToshio Takagi received honorariums from Bristol Myers Squibb, Ono Pharmaceutical Co., Ltd., Merck KGaA, and Takeda Pharmaceutical Co., Ltd. Tsunenori Kondo received honoraria from Pfizer, Novartis, Bristol-Myers Squibb, and Ono Pharmaceutical Co., Ltd.
Electronic Supplementary Material
Below is the link to the electronic supplementary material
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Supplementary Table legends
Supplementary Table 1. Univariate analysis of survival