Comparison of the Use of Immune Checkpoint Inhibitor/Tyrosine Kinase Inhibitor and Tyrosine Kinase Inhibitor Alone for Patients With Low Risk Metastatic Renal Cell Carcinoma

Abstract

Background/Aim

Currently, a combination of an immune checkpoint inhibitor (ICI) and a tyrosine kinase inhibitor (TKI) is the most widely used first-line treatment for metastatic renal cell carcinoma (mRCC). However, patients in the IMDC favourable risk group have been reported to have a relatively good prognosis, even when they undergo TKI monotherapy. The aim of this study was to evaluate whether ICI/TKI combination therapy or TKI monotherapy is more effective in patients with favourable IMDC risk.

Patients and Methods

We retrospectively reviewed 11 patients with favourable IMDC risk who underwent ICI/TKI combination therapy and 12 who underwent TKI monotherapy as first-line treatment for mRCC at our institution between April 2008 and September 2024 and compared their characteristics and treatment outcomes. The endpoints were overall survival (OS), progression-free survival (PFS) and treatment response, which was assessed using the overall response rate (ORR) and disease control rate (DCR). The safety of the regimens was evaluated using the incidences of grade ≥3 adverse events (AEs) and treatment discontinuation.

Results

There was a significant difference between the groups regarding the duration of follow-up (24.4 months for the ICI/TKI group vs. 65.9 months for the TKI group, p=0.01), but no other differences were noted in the characteristics of the patients. The PFS and OS of the groups did not significantly differ following initial treatment. The ORR did not significantly differ, but tended to be better in the ICI/TKI group. The incidence of grade ≥3 AEs and the discontinuation of treatment owing to AEs did not significantly differ but tended to be higher in the TKI group. Conclusion: Based on its superiority with respect to ORR and AE at our Institution, ICI/TKI therapy should be considered whenever possible, even in patients in the IMDC favourable risk group.

Introduction

Approximately 30% of patients who are newly diagnosed with renal cell carcinoma (RCC) have metastases, and 20%-50% of those treated for localized RCC eventually relapse and progress to metastatic RCC (mRCC). The 5-year overall survival rate for RCC is 76%, but only 12% for patients with stage IV disease (1). Several prognostic risk models for mRCC have been developed, of which the International Metastatic RCC Database Consortium (IMDC) risk classification is most commonly used (2). In recent years, most patients with mRCC have undergone systemic therapy, and international guidelines have recommended the use of a combination of two immune checkpoint inhibitors (ICIs) or an ICI and a tyrosine kinase inhibitor (TKI), according to the IMDC risk classification of the patient (favourable, intermediate or poor) as the treatment for mRCC (3,4). In clinical practice, it has been reported that ICI/TKI combination therapy has better outcomes than TKI monotherapy (5).

TKI monotherapy has been reported to yield relatively good outcomes in patients with a favourable risk profile, compared with those with intermediate or poor risk profiles, and although the ICI/TKI combinations that have been approved for use in Japan (pembrolizumab plus axitinib, nivolumab plus cabozantinib, pembrolizumab plus lenvatinib and avelumab plus axitinib) have been shown to be superior to sunitinib with respect to the primary endpoints in clinical trials, subgroup analyses based on risk category have not demonstrated clear superiority with respect to overall survival (OS) or progression-free survival (PFS) for the favourable risk group (6-9). Furthermore, serious adverse events (AEs) are also a concern when ICIs are added (10). Considering the toxicity and cost of ICI/TKI combination therapy, it is important to determine whether ICI/TKI combination therapy or TKI monotherapy would be optimal for patients in this risk group. Therefore, the purpose of the present study was to evaluate the benefits of TKI monotherapy for patients in the favourable risk group.

Patients and Methods

We performed a retrospective analysis of 23 patients who had been diagnosed with mRCC at the Nagasaki University Hospital between April 2008 and September 2024 but were in the IMDC favourable risk group. All the patients underwent systemic therapy, and they were allocated to one of two groups: an ICI/TKI group (n=11) that underwent combination therapy with an ICI and a TKI as first-line treatment and a TKI group (n=12) that underwent TKI monotherapy. Data regarding the age, sex, history of nephrectomy, pathological tissue type, metastatic sites and the follow-up period were collected.

We aimed to compare the outcomes of patients in the two groups, and thereby to evaluate the efficacy of TKI monotherapy for patients in the favourable risk group. The endpoints were overall survival (OS), progression-free survival (PFS) and treatment response, which was assessed using the overall response rate (ORR) and disease control rate (DCR). The safety of the regimens was evaluated using the incidences of grade≥3 adverse events (AEs) and treatment discontinuation. OS was defined as the period between the start of first-line therapy and death, regardless of its cause. PFS was defined as the period between the start of first-line therapy and disease progression or death from any cause. ORR was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) ver.1.1 and defined as the proportion of patients who achieved a complete response (CR) or partial response (PR). DCR was defined as the proportion of patients who did not show disease progression, which included those with stable disease (SD). AEs were evaluated according to the Common Terminology Criteria for AEs ver.5.0 and the Response Evaluation Criteria in Solid Tumors.

Categorical datasets were compared using the Chi-square test and continuous datasets were compared using the Mann-Whitney U test. OS and PFS were plotted using the Kaplan-Meier method and the log-rank test was used to identify significant differences. Cox proportional hazards regression models were constructed, and hazard ratios (HRs) were calculated. All the statistical analyses were conducted using EZR (Easy R, ver.1.68; Jichi Medical University, Saitama, Japan), and statistical significance was defined as p<0.05.

The study was approved by the Ethical Review Committee of our hospital (permit no: 25013008). Informed consent for patients was waived because of the retrospective and observational nature of this study.

Results

The demographic characteristics of patients are shown in Table I. The median age of the patients at the initiation of treatment was 70 years (range=23-81 years). There were 19 male and 4 female patients. All the patients underwent tumour resection (22 underwent nephrectomy and 1 underwent partial nephrectomy). The pathological findings were clear cell RCC in 19 patients (83%), papillary RCC in 2 (9%), TFE3 in 1 (4%) and unclassified in 1 (4%). When treatment was initiated, the sites of metastasis were as follows: lung in 11 patients (48%), lymph node in 7 (30%), bone in 5 (22%) and liver in 4 (17%). The median durations of follow-up were 24.4 months (range=3.7-60.0 months) for the ICI/TKI group and 65.9 months (range=10.5-146.5 months) for the TKI group. There were significant differences between the groups during the follow-up period, but none with respect to the other characteristics of the patients.

Table I. Comparison of the characteristics of ICI/TKI combination therapy group and TKI monotherapy group.

Analyzed with Mann-Whitney U test. ICI, Immune checkpoint inhibitor; TKI, tyrosine kinase inhibitor; RCC, renal cell carcinoma.

The therapeutic agents used are listed in Table II. In the ICI/TKI group, the first-line treatment was pembrolizumab plus lenvatinib for four patients, avelumab plus axitinib for four patients, pembrolizumab plus axitinib for two patients and nivolumab plus cabozantinib for one patient. In the TKI group, sunitinib was administered to nine patients and sorafenib to three patients.

Table II. Rounds of treatment for the immune checkpoint inhibitor plus tyrosine kinase inhibitor and tyrosine kinase inhibitor groups.

ICI, Immune checkpoint inhibitor; TKI, tyrosine kinase inhibitor; BSC, best supportive care; RAPN, robot-assisted partial nephrectomy.

The median OS time was not reached in the ICI/TKI group and was 68 months in the TKI group, but this did not significantly differ (p=0.71, HR=0.71; 95% confidence interval=0.11-4.37) (Figure 1). The median PFS was 25 months for the ICI/TKI group and 32 months for the TKI group, but this also did not significantly differ (p=0.85, HR=0.89; 95% confidence interval=0.28-2.83). The ORR was 82% (CR 0, PR 9) for the ICI/TKI group and 50% (CR 1, PR 5) for the TKI group; and the DCR was 100% (CR 0, PR 9, SD 2) for the ICI/TKI group and 83% (CR 1, PR 5, SD 4) for the TKI group (Figure 2). Although not statistically significant, there was a trend toward higher response rates for the ICI/TKI group (p=0.11 and p=0.16, respectively).

Figure 1.

Kaplan-Meier curve for (A) OS, and (B) PFS compared by treatment groups. No significant differences were observed in either OS or PFS. OS: Overall survival; PFS: progression-free survival.

Figure 2.

Comparison for (A) ORR, (B) DCR, (C) AE ≥ grade 3 and (D) treatment discontinuation rate by AE. ORR: Overall response rate; DCR: disease control rate; AE: adverse event.

Grade≥3 AEs occurred in 6 patients (55%) in the ICI/TKI group and 10 (83%) in the TKI group. AEs led to the discontinuation of first-line therapy in one patient (9%) in the ICI/TKI group and five (42%) in the TKI group. Although not statistically significant, there were higher incidences for the TKI group (p=0.13 and p=0.08, respectively). AEs other than immune-related AEs (AEs caused by the TKI) occurred in four patients (36%) in the ICI/TKI group, which was a significantly larger number than in the TKI group (p=0.02).

Discussion

To the best of our knowledge, no previous real-world studies have compared the treatment outcomes of ICI plus TKI and TKI monotherapy in patients in the IMDC favourable risk group. According to Motzer et al. (11), patients in this risk group show higher expression of genes associated with the VEGF pathway than those in the intermediate or poor risk groups, and this may explain why TKI monotherapy as the initial treatment could be associated with a good long-term prognosis for patients in the favourable risk group. However, Gao and Yang reported that VEGF can alter the tumour micro-environment and reduce the activity of tumour-infiltrating lymphocytes by increasing the number and function of immunosuppressive cells, such as regulatory T lymphocytes, bone marrow-derived suppressor cells and M2 macrophages (12); and VEGF has been reported to reduce the expression of PD-L1, PD-1 and CTLA-4 (13,14). Thus, some previous studies have indicated that there would be benefits of administering a TKI alongside an ICI.

Subgroup analyses of the results of four clinical trials [JAVELIN Renal 101 (6), KEYNOTE-426 (7), KEYNOTE-581 (8) and CheckMate-9ER (9)] that compared the treatment outcomes of patients undergoing ICI/TKI or TKI therapy have been performed to evaluate outcomes in the favourable risk subgroup, and the findings are shown in Table III. All of these demonstrated a significant prolongation of PFS in the ICI/TKI group vs. the TKI group. According to a meta-analysis of these clinical trials performed by Ciccarase et al., the risk of progression was reduced by 39% (HR=0.63; p<0.00001) (15). However, there was no significant difference in the OS of the ICI/TKI and TKI groups in any of the clinical trials, and no superiority with respect to OS was identified in the meta-analysis (HR=0.99; p=0.95). Three of the four clinical trials (not JAVERIN Renal 101) used a protocol in which ICI administration was discontinued after 2 years. Therefore, if patients who underwent longer-term treatment had been included, the OS might have been extended. In the present study, there was no significant difference between the groups with respect to either OS or PFS (p=0.71 and p=0.85, respectively). However, there was a significant difference in the duration of follow-up between the ICI/TKI and TKI groups. Therefore, if the follow-up period were extended to include subsequent interventions, OS and PFS might have been prolonged. Thus, caution is required when interpreting OS and PFS data for application in real-world clinical practice.

Table III. Summary of results of previous clinical trials and the present study.

ICI, Immune checkpoint inhibitor; TKI, tyrosine kinase inhibitor; OS, overall survival; ORR, overall response rate; AE, adverse event; Ave, avelumab; Axi, axitinib; Pem, pembrolizumab; Len, lenvatinib; Nivo, nivolumab; Cabo, cabozantinib; Suni, sunitinib; HR, hazard ratio; NR, not reach; M, months.

The ORR of the ICI/TKI group tended to be higher than that of the TKI group in all of the clinical trials, and the present results were consistent with this. The DCR also tended to be higher in the ICI/TKI group. These results suggest that ICI combination therapy should be considered even for patients in the favourable risk group who require tumour volume reduction or who have clinical symptoms. A meta-analysis of phase III trials performed by Bolek et al. showed that OS was no longer for the ICI/TKI group than for the TKI group, but that there was a superior ORR, which was associated with a 33% lower risk of disease progression (16). We consider that one of the reasons for the difference in survival rate is that ICIs are typically used as a subsequent therapy in patients who are initially administered a TKI alone.

In the present study, grade ≥3 AEs were more frequent in the TKI group than in the ICI/TKI group (55% vs. 83%; p=0.13), and AEs other than immune-related AEs (TKI-related AEs) were significantly more frequent in the TKI group (36% vs. 83%; p=0.02). Primary treatment discontinuation owing to an AE was also more frequent in the TKI group (9% vs. 42%; p=0.08). Clinical trials (6-9) have shown that the incidences of grade≥3 AEs and primary treatment discontinuation owing to an AE were higher for patients undergoing ICI/TKI therapy. However, in the present study, the incidences were higher in the TKI group (Table III). This disparity may have been caused by differences in the specific TKI used and/or the accumulation of clinical experience. Fogli et al. (17) reported the concentration of each drug required to inhibit 50% of tyrosine kinase activity for various TKIs, and found that compared with the first-generation TKIs, such as sunitinib and sorafenib, the new-generation TKIs administered alongside ICIs, such as axitinib, lenvatinib and cabozantinib, tended to have lower concentrations required to inhibit 50% of tyrosine kinase activity. Therefore, the higher incidences of grade ≥3 AEs and AE-related discontinuation of primary therapy in the ICI/TKI group in the present study may be attributed to the induction of therapeutic effects at lower doses, an increase in clinical experience, leading to improvements in the prediction and management of AEs in the real world, and the shorter follow-up period for the ICI/TKI group.

Based on the results of the present study, even for patients in the favourable risk group, it may be better to consider administering ICI/TKI combination therapy whenever possible, given its superiority with respect to ORR and the incidence of AE. However, because no clear superiority has been demonstrated with respect to OS or PFS, and because the patient’s overall condition and cost must be taken into account, the treatment strategy used should be chosen on the basis of a shared decision-making process. Of note, studies by Wang et al. regarding the cost-effectiveness of ICI/TKI, albeit not in Japan, showed that nivolumab plus cabozantinib and pembrolizumab plus lenvatinib were not more cost-effective than sunitinib treatment (18,19).

Finally, further stratification of the favourable risk group and reanalysis showed that being in a very favourable risk group, defined using the period between the initial diagnosis and systemic therapy, a Karnofsky performance status >80 and the presence or absence of brain, liver or bone metastases, significantly predicts OS (HR=1.4-1.5; p<0.05) (20). Thus, in the future, further stratification of the favourable risk group may permit the standardization of treatment according to whether ICI/TKI combination therapy or TKI monotherapy is more appropriate for the patient in question.

The present study had several limitations. These included the small number of patients at a single centre, the retrospective nature of the analysis, which may have introduced information or selection bias, and the difference between the duration of the follow-up period between the groups. However, the results of this real-world comparison of the use of ICI/TKI vs. TKI alone in patients in the favourable IMDC risk group should help inform future discussion regarding their treatment. Therefore, we believe that our research can be positioned as meaningful exploratory research.

Conclusion

The superiority of ICI/TKI with respect to ORR and AE, even for patients with mRCC in the favourable risk group, implies that the use of this combination therapy should be considered whenever possible.

Conflicts of Interest

The Authors declare that they have no conflicts of interest in relation to this study.

Authors’ Contributions

Conceptualization: MO and KO; Data curation: Tsuyoshi Matsuda; Formal analysis: Yuta Mukae; Investigation: HN; Methodology: MO; Project administration: KO; Supervision: RI; Validation: KM, Tomohiro Matsuo and Yasushi Mochizuki; Visualization; Roles/Writing - original draft: MO and KO; Writing - review & editing: MO and KO.

Acknowledgements

We thank Mark Cleasby, Ph.D. from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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.