Comparison of IO-IO and IO-TKI Treatment Outcomes in Metastatic Renal Cell Carcinoma: Influence of Metastatic Site Count

Abstract

Background/Aim

The therapeutic efficacy of Immuno-Oncology combination therapy based on the number of metastatic organs in renal cancer has yet to be examined. Therefore, we herein compared the efficacy of dual immune checkpoint blockade (IO-IO) and combination of immunotherapy with tyrosine kinase inhibitors (IO-TKI) strategies in metastatic renal cell carcinoma (mRCC), with a focus on how the number of metastatic organs affects clinical outcomes.

Patients and Methods

This retrospective study included 147 patients with mRCC treated with systemic therapies between August 2015 and July 2023. A multivariable Cox proportional hazards model was used to examine the relationships between clinical parameters and survival. To examine whether the effects of the number of metastatic organs on survival varied between treatment regimens, interaction terms were evaluated.

Results

In the multivariate Cox regression analysis, IMDC poor risk [hazard ratio (HR)=1.95; 95% confidence interval (CI)=1.19-3.18] and the presence of three or more metastatic organs in the IO-TKI group (HR=3.72; 95% CI=1.35-10.23) were identified as independent predictors of progression-free survival (PFS). In the IO-TKI group, patients with <3 metastatic organs had longer PFS than those with ≥3 metastatic organs. No significant difference in PFS was observed between <3 and ≥3 metastatic organs in the IO-IO group. This differential effect of the metastatic burden was confirmed by a significant interaction between the treatment group and number of metastatic organs (p for interaction=0.001).

Conclusion

The number of metastatic organs affects the efficacy of IO-TKI but has no effect on the efficacy of IO-IO treatment. We recommend considering the number of metastatic organs as an additional prognostic factor to optimize treatment selection for patients with mRCC.

Keywords: Renal cell carcinoma, dual immune checkpoint blockade, immune-oncology combination therapy, systemic treatment, tyrosine kinase inhibitors, metastasis

Introduction

In the last decade, the treatment landscape for advanced renal cell carcinoma (RCC) has been revolutionized by recent advances in immunotherapy. Dual immune checkpoint blockade (IO-IO) and the combination of immunotherapy with tyrosine kinase inhibitors (IO-TKI) have emerged as two promising approaches in the management of metastatic RCC (mRCC) (1-4). IO-IO regimens, which typically include agents targeting complementary immune pathways, aim to synergistically enhance the anti-tumor immune response, while IO-TKI combinations not only modulate immune activity, but also target tumor angiogenesis and other oncogenic pathways that are critical for tumor growth and dissemination (5,6).

Clinical trials showed that survival outcomes were significantly better with the IO-IO and IO-TKI combinations than with conventional therapies; however, the degree of benefit appeared to vary with the metastatic burden and disease distribution (7,8). In IO-IO, the tumor burden has been reported to correlate with prognosis, with a higher tumor burden being associated with a poorer prognosis (7,9). Nevertheless, the impact of the number of metastatic organs, a simple and clinically accessible variable, on the efficacy of these therapeutic strategies has not yet been characterized in detail. A deeper understanding of how metastatic patterns affect treatment responses may lead to more personalized treatment strategies.

Therefore, the present study aimed to investigate differences in treatment efficacy between IO-IO and IO-TKI combinations in mRCC patients, with a focus on the impact of the number of metastatic organs on treatment outcomes.

Patients and Methods

Study design. This was a retrospective study conducted by three institutions (Akita University Hospital, Hokkaido University Hospital, and Yamagata University Hospital). The Ethics Committee of Hokkaido University approved the present study (Approval no. 023-0105). Informed consent was waived though the use of an opt-out method.

Study population. The present study included 176 mRCC patients who were treated with IO combination therapy as the first-line treatment at three institutions between August 2015 and July 2023. Of 176 patients, International Metastatic RCC Database Consortium (IMDC) favorable risk cases (n=24) were excluded. Furthermore, after the exclusion of five patients [without a pathology (n=1), less than four weeks of treatment (n=3), and missing detailed data (n=1)], 147 were ultimately included in the present study. Data collected included age, sex, histology, the IMDC risk status, treatment regimen and outcomes, previous nephrectomy, and the number of metastatic organs.

Evaluation. Initially, we estimated overall survival (OS) and progression-free survival (PFS) for the entire cohort. The best overall response (BOR) in the first-line treatment, PFS with the first-line treatment, and OS in the IO-IO and IO-TKI groups were the primary endpoints assessed. Subsequently, a comparative analysis was conducted between the PFS and OS of the IO-IO and IO-TKI groups, with the metrics evaluated based on the number of metastatic organs. The percentage of patients exhibiting a complete or partial response was determined to be the best response, and this response was designated as BOR.

Statistical analysis. Continuous variables are presented as median (interquartile range; IQR), while categorical variables are as counts and percentages. The differences in patient characteristics were analyzed utilizing the chi-square test or Fisher’s exact test (for categorical variables) or with Student’s t-test, for continuous variables. PFS was calculated from the initiation of the immunotherapy combination to the date of first progression or death, whichever occurred first. OS was calculated from the initiation of the immunotherapy combination to death. Patients without an event were censored at the date of last follow-up. OS and PFS curves were estimated using the Kaplan-Meier method and comparisons between the groups were performed using the Log-rank test. A multivariable Cox proportional hazards model was used to investigate associations between patient characteristics and OS or PFS. We evaluated whether the effect of treatment (IO-IO vs. IO-TKI) on survival differed by IMDC risk group and the number of metastatic organs (<3 vs. ≥3) by including interaction terms in a Cox proportional hazards model. The statistical significance of these differences was set at a p-value of less than 0.05. The analysis of the data was conducted using JMP version 17 (SAS Institute).

Results

Patient characteristics. Patient characteristics are shown in Table I. A total of 103 patients received IO-IO and 44 received IO-TKI. The median observation time from the initiation of drug treatment was 16.0 months (IQR=6.3−31.4). The median age of the entire group was 68 years (IQR=63-73). In total, 81.0% of patients had a clear cell pathology and 45.6% underwent nephrectomy prior to the drug treatment. Overall, 67.4% of patients had less than three metastatic organs at baseline (63.1 and 77.7% in the IO-IO and IO-TKI groups, respectively). No significant difference was observed in the frequency of metastasis by organ between the IO-IO and IO-TKI groups.

Treatment outcomes in IO-IO and IO-TKI groups. BOR in the IO-IO and IO-TKI groups are shown in Table II. Objective response rates were 44.7% for IO-IO and 63.6% for IO-TKI. Median OS and PFS in the entire cohort were not reached (NR) (95% CI=40.1-NR) and 12.9 months (95% CI=8.7-17.1), respectively (Figure 1). Median OS did not differ between the IO-IO and IO-TKI groups (NR and 43.4, respectively; p=0.1497), while median PFS was lower in the IO-IO group compared to the IO-TKI group (10.1 vs. 24.2, p=0.0215) (Supplementary Figure 1). The clinical course from the first- to second-line treatment is shown in Figure 2. Progressive disease was observed after the first-line treatment in 67.0% and 36.3% of patients in the IO-IO and IO-TKI groups, respectively. Eighteen (17.4%) and 22 (50.0%) patients in the IO-IO and IO-TKI groups, respectively, continued the first-line treatment. Forty-five (43.7%) and 13 (29.5%) patients in the IO-IO and IO-TKI groups, respectively, moved to the second-line treatment. Cabozantinib was the most frequently used drug in the second-line treatment (Supplementary Table I).

Comparison of treatment outcomes between IO-IO and IO-TKI groups according to the number of metastatic organs. Patients were further classified according to the number of metastatic organs (<3 or ≥3). Among patients with <3 or ≥3 metastatic organs, there was no significant difference in the pattern of metastatic organ involvement between the IO-IO and IO-TKI groups (Supplementary Table II and III). Kaplan-Meier curves for PFS and OS were also calculated for each treatment group stratified by the number of metastatic organs (Figure 3A, Supplementary Figure 2A). PFS was longer in patients who were treated with IO-TKI and had <3 metastatic organs than in those who were treated with IO-TKI and had ≥3 metastatic organs (median PFS=NR, 95% CI=11.5-NR vs. median PFS=7.0, 95% CI=2.8-13.8, p=0.0032). On the other hand, no significant difference was noted between patients with <3 and ≥3 metastatic organs in the IO-IO group. In the multivariate Cox regression for PFS, IMDC poor risk was associated with shorter PFS compared to intermediate risk (HR=1.95, 95% CI=1.19-3.18) (Table III). Among patients with <3 metastatic organs, those treated with IO-TKI had longer PFS compared to those treated with IO-IO (HR=0.38, 95% CI=0.18-0.81), based on multivariable Cox proportional hazards regression model analysis, adjusted for age, sex, histology, nephrectomy, and IMDC risk (Figure 3B). Interactions between treatment group (IO-IO vs. IO-TKI) and IMDC risk status, as well as between treatment group and the number of metastatic organs (<3 vs. ≥3), were tested to determine whether the survival benefit differed across these subgroups (Table IV). We found a statistically significant interaction only between treatment group and number of metastatic organs (p for interaction=0.001). Specifically, although treatment had no significant effect on PFS in patients with ≥3 metastatic organs, IO-TKI treatment was associated with significantly longer PFS compared to IO-IO, among patients with <3 metastatic organs.

Discussion

We herein investigated how the number of metastatic organs affected the efficacy of IO combination therapy in patients with mRCC. Patients under treatment with IO-TKI and with fewer than three metastatic organs had significantly longer PFS, whereas in patients treated with IO-IO, the number of metastatic organs was not associated with PFS.

Previous studies have examined the relationship between the tumor burden and the efficacy of IO-based therapies (7,9); however, data specifically addressing the number of metastatic organs remain limited. In the era of TKI monotherapy, the number of metastatic organs and the tumor burden have been associated with the prognosis of patients. Basappa et al. showed that in a group of patients treated with sunitinib, patients with a single metastatic organ had a better prognosis than those with multiple metastatic organs (10). Roviello et al. also reported similar findings in a group of favorable-risk patients treated with TKI (sunitinib or pazopanib) (11). In the IO era, a post hoc analysis of the CLEAR trial demonstrated that fewer metastatic sites were associated with longer survival in patients receiving lenvatinib plus pembrolizumab (8). The present results are consistent with these findings, supporting the prognostic relevance of the number of metastatic organs in mRCC.

The number of metastatic organs may not only reflect the extent of tumor dissemination but also suggests underlying differences in cancer biology. While previous studies reported aggressive pathological features in metastatic lesions, such as sarcomatoid differentiation and high PD-L1 expression (12-14), patients with multiple metastatic organs may be more likely to harbor such biologically aggressive tumors. Although this relationship has not been directly demonstrated, it is plausible that the accumulation of metastatic lesions reflects the selective expansion of clones with an enhanced metastatic potential and immune evasion capabilities. Notably, tumors with multiple metastatic lesions have been associated with the increased expression of aggressive-featured genes, such as PD-L1, and were historically linked to a poor prognosis in the era of TKI monotherapy. However, the introduction of IO-based therapy has significantly improved clinical outcomes in this group.

Conversely, limited metastatic spread may reflect tumors with less aggressive clonal evolution. Indeed, patients in whom complete resection of metastatic lesions is feasible tend to have favorable outcomes (15), suggesting that such tumors progress more slowly. Genomic analyses have shown that early driver mutations, such as VHL and PBRM1, are associated with more indolent disease trajectories (12). These tumors may remain more dependent on angiogenic signaling pathways, which could explain their higher sensitivity to TKI-containing regimens. Notably, the prognosis of patients with IMDC favorable risk does not differ significantly between the IO and TKI eras (16). This may reflect the fact that favorable-risk cases often present with a limited metastatic burden, which may confer greater responsiveness to TKIs. This hypothesis warrants further investigation and may contribute to future biomarker development for treatment stratification in mRCC.

Study limitations. It was a retrospective analysis with a relatively small cohort and short observation period. In particular, the small sample size and short follow-up period in the IO-TKI group may have introduced bias. Although a large-scale analysis is necessary, the ability to predict the efficacy of IO combination therapy, particularly IO-TKI, based on the number of metastatic organs, may be a useful tool for guiding treatment in clinical practice. The number of metastatic organs does not require much effort and may be used immediately in clinical practice.

Conclusion

The efficacy of IO-TKI therapy was affected significantly more than that of IO-IO by the number of metastatic organs. The present results suggest the potential of the number of metastatic organs as an additional prognostic variable to optimize treatment selection for patients with mRCC.

Supplementary Material

Available at: https://github.com/hiroshikikuchi16/Manuscript-No-233-K/tree/f84460971ab681f8d7d80b7cf358234ebe54260c

Conflicts of Interest

Takahiro Osawa has received honoraria from MSD and Eisai. Tomonori Habuchi has received honoraria from Ono Pharmaceutical Co., Merck Biopharma Co., MSD and research fundings from Novartis Pharmaceuticals Co, LTD., Chugai Pharm. Nobuo Shinohara has received honoraria from Pfizer, MSD, ONO, Bristol-Meyers Squibb, Eisai, Bayer, Takeda. Norihiko Tsuchiya has received honoraria from Pfizer, Astellas Pharma Inc. None of the other authors have any conflicts of interest.

Authors’ Contributions

Hiroshi Kikuchi: Data curation, Formal analysis, Investigation, Methodology, Writing - original draft. Takahiro Osawa: Conceptualization, Formal analysis, Methodology, Project administration, Supervision, Validation, Writing - review & editing. Sei Naito: Investigation, Project administration. Kazuyuki Numakura: Investigation, Project administration. Ojiro Tokairin: Investigation. Yuki Takai: Investigation. Yuya Sekine: Investigation. Haruka Miyata: Investigation. Ryuji Matsumoto: Investigation. Takashige Abe: Supervision, Writing - review & editing; Yoichi Ito: Formal analysis. Tomonori Habuchi: Conceptualization, Supervision. Norihiko Tsuchiya: Conceptualization, Supervision. Nobuo Shinohara: Supervision.

Acknowledgements

We express our gratitude to Editage (www.editage.com) for their assistance with English language editing.

Artificial Intelligence (AI) Disclosure

No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.