Introduction
Renal cell carcinoma (RCC), a malignant tumor originating from renal tubular epithelial cells, is characterized by high heterogeneity and variable pathological types; its global incidence has been increasing annually, particularly among males aged 50 to 70, although in recent years, the affected population has gradually become younger (1,2). The notable pathological features of RCC include its high invasiveness and propensity for metastasis. Notably, ~30% of patients present with distant metastases at initial diagnosis, and even after surgical treatment for localized RCC, there is still a 20–50% risk of RCC progressing to metastatic RCC (mRCC), which has a poor prognosis (3,4). At this stage, surgery is no longer the primary treatment and medication becomes crucial.
In recent years, with the in-depth study of the pathogenesis of RCC, targeted therapy and immunotherapy have made notable progress in the treatment of advanced RCC, becoming important means of precision medicine. Particularly, the roles of the vascular endothelial growth factor (VEGF) and mTOR) pathways in RCC have been elucidated: VEGF signaling promotes tumor angiogenesis to support tumor growth and metastasis, while mTOR regulates cell proliferation and amplifies VEGF expression, making targeted therapy a crucial strategy for advanced renal cancer (5). Pazopanib, a VEGF receptor tyrosine kinase inhibitor (TKI), can inhibit multiple receptors closely related to tumor angiogenesis, cell proliferation and migration, effectively suppressing tumor angiogenesis and achieving antitumor effects (6). Multiple clinical studies have confirmed that pazopanib demonstrates significant efficacy in prolonging progression-free survival (PFS) and overall survival (OS) in patients with mRCC, and is feasible and safe as a first-line treatment option (7–9). Although pazopanib has shown notable effects in RCC treatment, the efficacy of single targeted therapy is still limited for some patients with refractory mRCC.
With the development of immunotherapy, the combined application of immunotherapy and targeted therapy has become a research hotspot (10,11). Rallis et al (12) comprehensively reviewed the potential application value of combining targeted therapy with immunotherapy for the treatment of mRCC in the future. Toripalimab, a programmed death 1 (PD-1) inhibitor, has demonstrated good safety and efficacy; it exerts antitumor effects by relieving the immunosuppression in the tumor microenvironment and activating T cell immune responses against tumors (13). Studies have shown that the combination of PD-1 inhibitors with targeted drugs has achieved positive results in the treatment of mRCC (14–16). However, at present, there are few studies on the treatment of Chinese patients with mRCC using pazopanib combined with toripalimab, and there is a lack of real-world data. Therefore, there is an urgent need to further investigate the therapeutic effects, clinical adverse events (AEs) and the impact on survival of this combination therapy.
The aim of the present study was to retrospectively analyze the clinical data of patients with mRCC who received the treatment regimen of pazopanib combined with toripalimab at Shanxi Province Cancer Hospital (Taiyuan, China). Efficacy indicators such as objective response rate (ORR), disease control rate (DCR), PFS and OS, as well as the occurrence of AEs were assessed. The results of the present study may offer preliminary real-world data that could help generate hypotheses and inform the design of future prospective trials, rather than serving as a direct reference for clinical decision-making.
Discussion
In recent years, the incidence of RCC has continued to rise globally, with a 5-year mortality rate reaching 30–40% (1,2). According to statistics, factors such as sex, obesity, chronic kidney disease, smoking and hypertension are known risk factors for RCC (17). When RCC progresses to the advanced stage and metastasizes, it is referred to as mRCC. The common sites of metastasis include the liver, lungs, adrenal glands, bones, skin and even the brain (2). The progression to mRCC often indicates a poor prognosis for patients, with a potentially significant reduction in survival time (2). The underlying mechanism of mRCC development involves inactivation of the von Hippel-Lindau tumor suppressor gene, which promotes the upregulation of crucial proteins such as VEGF, platelet-derived growth factor, transforming growth factor and other proteins related to neovascularization (18). These factors play pivotal roles in the development and metastasis of tumors (19).
Immunotherapy, which activates the immune system to inhibit tumor growth and dissemination, has emerged as a new hope in the treatment of mRCC (20). PD-1/PD-L1 and CTLA-4 inhibitors are commonly used ICIs. ICIs targeting PD-1/PD-L1 have made significant breakthroughs in the field of oncology. Toripalimab, which targets PD-1, has been approved for first-line clinical treatment of multiple malignancies (21,22), and significantly prolongs PFS without introducing new safety concerns compared with existing treatment regimens. In a Phase I clinical study of toripalimab for advanced melanoma and urological tumors, 5 patients with advanced renal cancer who had progressed after previous conventional treatments were enrolled. Among them, 2 patients achieved confirmed PR and 1 patient had SD, resulting in an overall ORR of 33% and a DCR of 50%. These findings initially demonstrated the antitumor activity of toripalimab in advanced renal cancer (23).
Targeted therapy, characterized by its high specificity and relatively milder side effects, has become a cornerstone in the treatment of renal cancer. Commonly used targeted drugs in renal cancer primarily inhibit tumor growth by affecting tumor angiogenesis. Representative drugs in this category include sorafenib, sunitinib, everolimus and pazopanib, which exert their tumor-suppressing effects through different pathways (24–30). In particular, pazopanib targets tyrosine kinases to block the formation of new blood vessels in tumors, thereby inhibiting the further proliferation and migration of tumor cells, ultimately suppressing tumor growth and dissemination (31,32). Multiple studies have shown evidence of pazopanib's positive response as a first-line treatment for mRCC. For instance, Park et al (33) reported that pazopanib treatment resulted in a PFS time of 8 months compared with placebo, and a PFS of 11 months compared with sunitinib. Joshi et al (34) reported that, in a continuous treatment study of 28 patients with mRCC in India, the overall clinical benefit rate (PR + SD) was 76%, with a median PFS time of 5.9 months. In a single-center retrospective study of 40 patients with mRCC treated with three different TKIs (sunitinib, pazopanib and sorafenib), Rudresha et al (35) reported that the median PFS and OS times for patients treated with pazopanib were 11.2 and 20.1 months, respectively.
In recent years, the combination of targeted therapy and immunotherapy has achieved certain efficacy in the field of oncology. For instance, a study by Hedegaard et al (36) reported the results of a Phase III clinical trial where the combination of axitinib and pembrolizumab was used to treat advanced renal cancer, showing significant improvements in OS and PFS compared with axitinib alone. The KEYNOTE-426 study (37) focused on the combined application of pembrolizumab with axitinib, using sunitinib as a comparator, for first-line treatment of advanced ccRCC. This long-term follow-up study demonstrated that the immune-targeted combination therapy significantly improved the PFS and OS times of patients, with the median OS time in the combination therapy group reaching 45.7 months, exhibiting a significant advantage over the 40.1 months in the sunitinib group [hazard ratio (HR), 0.73; 95% CI 0.60–0.88; P<0.001]. The JAVELIN Renal-101 study (38) evaluated the efficacy of avelumab combined with axitinib in patients with advanced RCC. Although this combination therapy showed a significant advantage in PFS, particularly among patients with PD-L1-positive tumors, the OS in the overall patient population did not reach statistical significance. However, in the high-risk patient subgroup, the combination therapy group demonstrated a significant improvement in OS, providing a new perspective and basis for the application of immune-targeted combination therapy in specific patient populations. Furthermore, the CheckMate 9ER study (39) explored the combined therapy of cabozantinib with nivolumab, comparing its effectiveness with sunitinib in patients with advanced RCC and bone metastases. The combination therapy significantly prolonged the PFS time in both patients with and without bone metastases, and the ORR was also significantly higher than that of the sunitinib group. Notably, for patients with bone metastases, the median PFS time of the combination therapy reached 18.2 months, far exceeding the 4.4 months in the sunitinib group (HR, 0.38; 95% CI, 0.25–0.59). Compared with studies conducted abroad, this type of research in China is scarce. The latest domestic research was the RENOTORCH study (40), jointly led by Professor Guo Jun from Peking University Cancer Hospital and Professor Huang Yiran from Renji Hospital (School of Medicine, Shanghai Jiao Tong University), which aimed to evaluate the efficacy and safety of the PD-1 immunotherapy drug toripalimab (developed in China) combined with axitinib as first-line treatment for patients with unresectable or mRCC, compared with sunitinib. The present study showed that the median PFS time in the toripalimab + axitinib group reached 18.0 months, while that in the sunitinib monotherapy group was 9.8 months, representing a nearly two-fold extension (HR, 0.66; 95% CI 0.490–0.864; P=0.0034). The ORR in the combination group was 56.7%, significantly higher than the 30.8% in the sunitinib monotherapy group. Although the median OS data are not available, the combination therapy group demonstrated a clear OS benefit trend, with a 39% reduction in the risk of death (HR, 0.61; 95% CI, 0.40–0.92) and 1-year and 2-year OS rates of 90.5 vs. 81.9% and 71.8 vs. 63.2%, respectively.
Despite the existence of numerous associated studies (36–40), to the best of our knowledge, there is currently a paucity of clinical research on toripalimab for the treatment of patients with mRCC, especially the first-line treatment of mRCC with the combination of pazopanib and toripalimab. The results of the present study are not directly comparable to those from large phase III trials such as KEYNOTE-426 (41) (pembrolizumab + axitinib) or CheckMate 9ER (nivolumab + cabozantinib), which were randomized, controlled studies and included hundreds of patients (39). These trials provided high-level evidence supporting the superiority of immune-TKI combinations over sunitinib. By contrast, the present single-arm, retrospective analysis of 22 patients can only offer hypothesis-generating observations. Direct cross-trial comparisons should be avoided and the present findings should be viewed as complementary real-world data rather than confirmatory evidence. The present study aimed to explore the clinical application effect of this combination therapy by treating patients with mRCC with pazopanib + toripalimab and observing the clinical efficacy and occurrence of adverse reactions.
In the present study, among all patients, there was 1 case of CR, 7 cases of PR, 9 cases of SD and 5 cases of PD. The overall ORR was 36.4%, indicating that approximately one-third of patients experienced positive treatment outcomes; the DCR was 77.3%, suggesting that the condition of most patients was somewhat controlled. Given the small sample size, these rates should be interpreted as descriptive statistics only; that is, no comparative inferences can be drawn. Treatment was interrupted due to AEs in 27.3% of patients, with half of these patients having their pazopanib dosage reduced to 600 mg. However, given the small sample size, no definitive conclusion can be drawn regarding the impact of dose reduction on efficacy; the observation that some patients maintained disease control after reduction to 600 mg is hypothesis-generating and warrants further investigation. Regarding PFS, the decline in the PFS curve became gradual over time, which may be related to the time required for immunotherapy to take effect. In the initial stages of immunotherapy, the immune system may not be fully activated, requiring time to activate and expand T cells within the body to achieve sufficient numbers and activity to effectively kill tumor cells. This process involves multiple steps, including T-cell recognition, activation, proliferation and migration, all of which require time to complete.
In the present study, the safety profile during treatment revealed that common AEs included primarily fatigue (27.27%), nausea/vomiting (18.18%), diarrhea (31.82%), hypertension (31.82%), proteinuria (22.73%), elevated transaminases (63.64%), hypothyroidism (18.18%), hand-foot skin reaction (22.73%), rash (9.09%) and leukopenia (13.64%). Most patients experienced mild to moderate (grade 1–2) AEs, although some reported severe (grade 3–4) AEs such as hypertension, proteinuria, elevated transaminases and hypothyroidism. Among these, liver function abnormalities due to elevated transaminases were the most frequent AE, occurring in up to 63.64% of patients. Xu et al (42), through pharmacogenetic analysis, found that this elevation in transaminases was associated with the mechanism of pazopanib-induced liver injury. Ezponda et al (43) confirmed that pazopanib could improve PFS in patients with advanced non-lipogenic soft tissue sarcoma but could also trigger the occurrence of chronic active hepatitis. These findings further explain the higher incidence of liver function abnormalities and highlight the need to carefully consider appropriate dose titration of pazopanib in this combination therapy strategy.
In summary, within the constraints of the present small retrospective cohort, the combination of pazopanib and toripalimab showed preliminary signs of activity in the first-line treatment for mRCC, with a median PFS time of 17.1 months and a generally manageable safety profile. These real-world observations do not provide comparative evidence of benefit over standard therapies and should not be overinterpreted. The safety data were consistent with previous reports, but attention should be paid to the hepatotoxicity of pazopanib and the rational determination of its dosage.
The present study has several limitations that must be considered when interpreting the results. First, it is a retrospective, single-arm, single-center analysis with a small sample size (n=22), which notably limits the statistical power and generalizability of the findings. Second, no comparator group (such as pazopanib monotherapy or other standard first-line regimens) was included, making it impossible to determine the true added benefit of toripalimab. Third, the median follow-up of 14 months is relatively short for assessing OS in mRCC; therefore, OS data remained immature, and PFS was the primary focus of the present preliminary report. Fourth, the limited sample size precluded robust subgroup analyses (such as by IMDC risk groups or metastatic burden) and the reported 95% CIs for ORR and DCR should be interpreted with caution. Fifth, as a real-world study, potential selection bias and unmeasured confounders (such as performance status changes and concomitant medications) cannot be excluded. Consequently, these findings should be regarded as exploratory and hypothesis-generating, not as definitive evidence of efficacy. Prospective randomized controlled trials are essential to validate the role of pazopanib plus toripalimab in the first-line treatment of mRCC.
In conclusion, in the present real-world, single-center, retrospective study of 22 patients, first-line pazopanib combined with toripalimab for mRCC showed exploratory, hypothesis-generating signs of efficacy with a safety profile that appeared manageable. Owing to the lack of a control group and the small sample size, no definitive conclusions regarding superiority over existing standard therapies can be drawn. These observations support the feasibility of the combination and highlight the need for further prospective randomized controlled trials, but they do not justify current clinical recommendations.