Effectiveness of systemic treatments for advanced non-clear cell renal cell carcinoma: a systematic review and meta-analysis

Background: Non-clear cell renal cell carcinoma (nccRCC) represents a heterogeneous group of malignancies with substantial differences in morphology, genetic profiles, clinical behavior, and prognosis. Optimal treatment for nccRCC remains unclear, largely extrapolated from evidence available for clear cell renal cell carcinoma (ccRCC). This study aimed to compare the efficacy of current mainstream drug treatments for nccRCC to provide clinical treatment guidance for advanced cases.

Methods: We systematically searched PubMed, Embase, and Cochrane databases for trials published up to January 2, 2024, including controlled and single-arm trials. Primary outcomes included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

Results: We selected six randomized controlled trials (RCTs) comparing mammalian target of rapamycin inhibitors (mTORi) with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs). These trials included four first-line and two second-line studies, with a total of 398 advanced nccRCC patients. Pooled results showed that VEGFR-TKIs significantly improved PFS compared to mTORi in first-line treatment (relative risk [RR] = 1.387; 95% confidence interval [CI]: 1.04-1.85; p = 0.026). In a single-arm meta-analysis, we included 22 VEGFR-TKI trials, three mTORi trials, 12 immune checkpoint inhibitor (ICI) therapies, five chemotherapy trials, and 10 combination therapy trials. The pooled ORR ranged from 6% (95% CI: 0–16%) to 36% (95% CI: 27–44%), and the pooled DCR ranged from 54% (95% CI: 50–58%) to 81% (95% CI: 70–91%). Subgroup analysis of ICI showed a higher ORR in the PD-L1 positive group compared to the PD-L1 negative group (RR = 3.044; 95% CI: 1.623-5.709; p = 0.001).

Conclusion: This systematic review and meta-analysis demonstrate that VEGFR-TKIs improve PFS in first-line treatment compared to mTORi. The single-arm meta-analysis suggest that combination therapies with different mechanisms result in better ORR and DCR. Furthermore, PD-L1 positive patients showed significantly better therapeutic responses with ICI treatment than PD-L1 negative patients.

1 Introduction

Renal cell carcinoma (RCC) is a common malignancy of the urinary and reproductive systems, making up 2-3% of systemic malignancies and 80-90% of renal malignancies (1). According to the 2016 World Health Organization (WHO) guidelines, RCC is classified histologically into renal clear cell carcinoma (ccRCC) and non-clear cell carcinoma (nccRCC) (2). NccRCC accounts for 15-30% of renal tumor, and includes various malignancies with significant differences in morphology, genetic profiles, immunohistochemical features, and clinical behaviors (3). Notable subtypes of nccRCC include papillary, chromophobe, collecting duct carcinoma (CDC), renal medullary, spindle cell, mucinous tubular, Xp11.2 translocation, carcinoma associated with neuroblastoma, and other rare entities (2). Papillary RCC (pRCC) and chromophobe RCC (chRCC) are the most prevalent, accounting for 10-15% and 4-5% of renal tumors, respectively (2). The sarcomatoid variant is not a distinct histologic entity but a high-grade transformation seen in various RCC subtypes, characterized by frequent metastasis to the lungs and bones and associated with poor prognosis (4).

Recent advancements in targeted therapy and immunotherapy have significantly improved ccRCC treatment outcomes (5–7). However, due to the heterogeneity and rarity of nccRCC, most RCC clinical trials primarily include ccRCC patients or a small subset of nccRCC patients. As a result, systemic therapy options for nccRCC are largely derived from ccRCC trials and retrospective studies (8, 9). Despite these efforts, nccRCC patients have significantly lower survival rates compared to those with ccRCC (1, 3). The National Comprehensive Cancer Network (NCCN) guidelines recommend clinical trials as the preferred treatment option for nccRCC patients (1), highlighting it as a critical and challenging research area.

Numerous endeavors have focused on developing mesenchymal-epithelial transition (MET) inhibitors, given that MET proto-oncogene has been found to have mutations and copy number changes of pRCC (10). A systematic review and meta-analysis evaluated the efficacy and safety of MET inhibitor (METi) in advanced pRCC, results indicated that the objective response rate (ORR) was 36.38% for MET+ pRCC, and an overall population ORR of 20.56% (11). Subgroup analysis of drugs showed that patients on cabozantinib had an ORR of 26.14%, on savolitinib had an ORR of 15.35% (11). METi represents a promising target for precision therapies, nevertheless, the available data remains limited, requiring further validation of this approach.

Due to the limited clinical trial data and guidance for nccRCC therapy selection, we conducted a systematic review and meta-analysis of existing data. This study aimed to evaluate the antitumor efficacy of vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs), mTORi, chemotherapy, immune checkpoint inhibitors (ICIs), and combination therapies in treating nccRCC to provide clinical treatment guidance. Additionally, we analyzed single-arm studies due to the scarcity of controlled trials.

2 Methods

2.1 Search strategy

This systematic review and meta-analysis evaluated the efficacy of VEGFR-TKIs, mTORi, chemotherapy, ICIs, and combination therapies for advanced nccRCC. Comprehensive searches were performed in the PubMed, Embase, and Cochrane databases for reports published up to January 2, 2024. Only English-language articles and abstracts from all available years were included, while case reports, case series, and review articles were excluded. The primary search term was “renal cell carcinoma”.

2.2 Inclusion and exclusion criteria

All trial designs were included, comprising randomized controlled trials (RCTs), non-randomized controlled trials, and single-arm studies.

Inclusion criteria: (1) Adult patients diagnosed histologically or cytologically with advanced nccRCC; (2) Controlled trials or single-arm studies assessing interventions such as VEGFR-TKIs, mTORi, chemotherapy, ICIs, or combination therapies; (3) Studies published in English; (4) Reports of at least one of the following outcomes: ORR, disease control rate (DCR), progression-free survival (PFS), or overall survival (OS); (5) When multiple reports were available from the same investigator for the same patient population, the most recent or comprehensive report was selected.

Exclusion criteria: (1) In vitro or in vivo studies; (2) Case reports, case series, or studies with fewer than 10 participants; (3) Reviews, abstracts, or letters; (4) Re-challenge therapies; (5) Non-English publications.

2.3 Literature screening and data extraction

Two researchers (Y.P.Z. and X.Y.W) independently screened titles and abstracts based on predefined inclusion and exclusion criteria. Data extraction adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (12). Discrepancies were resolved through discussion; if consensus was not reached, a third investigator (J.C.) was consulted to arbitrate, with final decisions determined by majority vote. If inclusion could not be established from the abstract or if essential data were missing, the full text was reviewed. A standardized data extraction form was created to collect the following information: study characteristics (first author, publication year, identifier, study design, study phase, treatment type, histological subgroups of nccRCC, treatment line), patient characteristics (number of evaluable patients, number of treatment arms, number of control arms, median age, sex), and outcome assessments (complete response [CR], partial response [PR], stable disease [SD], disease progression [PD], ORR, DCR, PFS, or OS).

2.4 Quality assessment

Two investigators (X.L.C. and J.F.H) independently performed the quality assessment. The risk of bias was evaluated in duplicate, with any discrepancies resolved by consensus or by consulting a third reviewer (H.W.). The methodological quality of the included RCTs was assessed using the Cochrane Risk of Bias Tool, as outlined in the Cochrane Handbook for Systematic Reviews of Interventions (13). A risk of bias summary was compiled using Review Manager Version 5.4 (Copenhagen: Nordic Cochrane Centre, Cochrane Collaboration, 2020).

2.5 Statistical analysis

Statistical analyses were performed using Stata 12.0 software (Stata Corporation, College Station, TX). Dichotomous data, including ORR and DCR, were compared using relative risk (RR). Hazard ratios (HR) for OS and PFS, along with their 95% confidence intervals (CIs), were extracted from each RCT. Summary HRs were calculated using either random or fixed-effects models, depending on the heterogeneity of the studies. Heterogeneity was assessed using the I² statistic and Chi-squared test, with I² ≥ 50% indicating significant heterogeneity. The random-effects model was employed when heterogeneity was substantial (I² > 50% or P < 0.05); otherwise, the fixed-effects model was applied (14). Additionally, the Begg test and funnel plots were used to assess potential publication bias among the studies. A two-tailed p-value of less than 0.05 was considered statistically significant.

3 Results

3.1 Literature selection

The electronic search identified 16,438 citations published between September 1994 and January 2024. After screening abstracts and titles, 576 full-text articles were reviewed, and 58 studies were included in the systematic review. These comprised six RCTs comparing the efficacy of mTORi and VEGFR-TKIs, 22 single-arm studies on VEGFR-TKIs, three on mTORi, 12 on immunotherapy, five on chemotherapy, and ten on combination therapy. The literature screening process is illustrated in the flowchart in Figure 1.

Figure 1

Figure 1. The flowchart of the study selection process for the meta-analysis.

3.2 Characteristics of six RCTs comparing mTORi and VEGFR-TKIs

Four studies compared mTORi with VEGFR-TKIs as first-line treatments (15–18), while two studies focused on second-line treatments (15, 19). The ESPN trial provided data for both first-line and second-line treatments separately (15), and we analyzed them as distinct studies. The meta-analysis included 398 patients, with 203 receiving mTORi and 195 receiving VEGFR-TKIs. Among the VEGFR-TKI group, 45 patients were treated with sorafenib, and the rest received sunitinib. Five of the six studies were randomized phase II trials (15–18), and one was a randomized phase III trial (19). Four studies exclusively recruited nccRCC patients (15–17), while two included both ccRCC and nccRCC patients (18, 19), providing separate data for each subgroup. In the three RCTs that reported pathological subgroups (15–17), papillary histology was the most common nccRCC type (113 out of 198 patients). The characteristics and main outcomes of the six RCTs are summarized in Table 1 and Table 2, separately.

Table 1

Table 1. General characteristics of the included randomized controlled trials (RCTs).

Table 2

Table 2. Summary of main outcomes of the included RCTs: Response Evaluation Criteria in Solid Tumors (RECIST), progression - free survival (PFS) and overall survival (OS).

3.3 Assessment of study quality and risk of bias

A total of 398 patients were included in the six RCTs. Five studies reported PFS (15–19), four reported ORR and DCR (15–17), and three reported OS (16, 17, 19). The studies exhibited some risks of bias, primarily in blinding of participants and personnel (15–17, 19), random sequence generation (15, 17, 19) and allocation concealment (15, 17, 19). Figure 2 presents the risk of bias summary and graph.

Figure 2

Figure 2. Risk of bias. (A) Graph: review authors’ judgments about each risk of bias item presented as percentages across all RCTs. (B) Summary: review authors’ judgments about each risk of bias item for each included RCT.

3.4 PFS and OS

A comparative meta-analysis of six RCTs examined the PFS of mTORi versus VEGFR-TKIs. Four of these trials were first-line treatments (15–18). The overall analysis showed no significant difference in PFS between the two treatment groups (RR = 1.240; 95% CI, 0.966-1.592; P = 0.091). However, a subgroup analysis revealed a significant PFS benefit for sunitinib over mTORi in first-line treatment (RR = 1.387; 95% CI, 1.040-1.850; P = 0.026) (Figure 3A). There was no significant heterogeneity among the studies.

Figure 3

Figure 3. The forest plot comparing of PFS, OS, ORR, DCR between mTORi and VEGFR-TKIs. (A) PFS, (B) OS, (C) ORR, (D) DCR.

Three articles provided specific OS data: two compared mTORi to VEGFR-TKIs in first-line treatment (16, 17), and one in second-line treatment (19). The results showed no significant difference in OS between mTORi and VEGFR-TKIs (RR = 1.243; 95% CI, 0.874-1.769; P = 0.227) (Figure 3B). Similar results were observed in the subgroup analysis of first- and second-line treatments.

3.4.1 ORR and DCR

The meta-analysis results for ORR and DCR are shown in Figures 3C, D. Statistical tests indicated low heterogeneity for both ORR (I² = 0%, P = 0.885) and DCR (I² = 0%, P = 0.720). Sunitinib did not demonstrate a significant advantage over mTORi in ORR (RR = 0.597; 95% CI, 0.289-1.232; P = 0.163) or DCR (RR = 0.983; 95% CI, 0.837-1.153; P = 0.830). Subgroup analysis for first-line and second-line treatments also showed no significant differences in ORR (RR = 0.548; 95% CI, 0.248-1.209; P = 0.136) or DCR (RR = 0.960; 95% CI, 0.817-1.127; P = 0.616).

3.5 Single-arm trials with VEGFR-TKIs

3.5.1 Characteristics

All included studies evaluated the efficacy of VEGFR-TKIs for advanced nccRCC. Among the 22 clinical trials, 12 were prospective (20–31) and 10 were retrospective (32–41), comprising a total of 1,597 patients. Of the 18 studies that specified pathological subgroups (21, 24–39, 41), papillary histology was the most common, accounting for 607 of 914 patients. The most frequently used VEGFR-TKI was sunitinib (1,025 patients), followed by sorafenib (192 patients), pazopanib (111 patients), axitinib (58 patients), and tivozanib (46 patients). Five studies involved only first-line treatments (20, 21, 32–34), while the remaining 17 either included patients with prior anti-tumor treatments or did not specify treatment history. Detailed information on these 22 single-arm experiments is provided in Table 3 and Table 4.

Table 3

Table 3. General characteristics of the included single-arm trials.

Table 4

Table 4. Summary of main outcomes of the included studies: Response Evaluation Criteria in Solid Tumors (RECIST), progression-free survival (PFS) and overall survival (OS).

3.5.2 ORR and DCR

All studies, except one retrospective trial (32), provided analyzable data for ORR and DCR. Both ORR and DCR exhibited significant heterogeneity, with I² values over 50% and p-values below 0.01 in the Q-test, indicating notable variability among the studies. The ORR ranged from 3.15% to 35.48%, with a pooled ORR of 14% (95% CI: 11–18%) (Figure 4A). Subgroup analysis showed a pooled ORR of 14% (95% CI: 9–19%) in prospective studies and 15% (95% CI: 10–20%) in retrospective studies. The DCR varied from 21.74% to 90.21%, with a pooled DCR of 70% (95% CI: 64–76%) (Figure 5A). Subgroup analysis revealed a pooled DCR of 69% (95% CI: 61–78%) in prospective studies and 71% (95% CI: 63–80%) in retrospective studies.

Figure 4

Figure 4. ORR for patients with nccRCC receiving VEGFR-TKIs, mTORi, ICIs, chemotherapy, and combination therapy. (A) VEGFR-TKIs, (B) mTORi, (C) ICIs, (D) chemotherapy, (E) combination therapy.

Figure 5

Figure 5. DCR for patients with nccRCC receiving VEGFR-TKIs, mTORi, ICIs, chemotherapy, and combination therapy. (A) VEGFR-TKIs, (B) mTORi, (C) ICIs, (D) chemotherapy, (E) combination therapy.

Sensitivity analysis for both ORR and DCR showed no significant interference from any single study, confirming the reliability of the meta-analysis results.

3.6 Single-arm trials with mTORi

3.6.1 Characteristics

Three relevant studies were included in this analysis after screening: RAPTOR (42), NCT00830895 (43), and Lee (44). RAPTOR (42) and NCT00830895 (43) were open-label, single-arm, non-randomized, multicenter studies, while Lee (16) integrated both prospective and retrospective data. A total of 215 patients were involved, with 181 in prospective analyses and 34 in retrospective studies. All 88 patients in RAPTOR (42) had pRCC. In the other two studies, pRCC was also the most common, followed by chRCC. Two studies used everolimus, while the third used temsirolimus. Only RAPTOR (42) included patients who had not received previous systemic therapy. Detailed information on these three single-arm studies is presented in Table 3 and Table 4.

3.6.2 ORR and DCR

The three articles provided data on ORR and DCR (42–44). The pooled ORR was 6% (95% CI: 0–16%), with significant heterogeneity (I² = 76.10%, P = 0.02) (Figure 4B). The pooled DCR was 70% (95% CI: 58–82%), also with high heterogeneity (I² = 68.31%, P = 0.04) (Figure 5B).

3.7 Single-arm trials with ICIs

3.7.1 Characteristics

A total of 622 patients participated in six prospective (45–50) and six retrospective studies (32, 51–55). Prior treatment with ICIs was excluded. Only three studies received first-line treatment (46–48). Among the prospective studies, two were Phase IIIb/IV trials (45, 48). Two retrospective studies analyzed various PD-1/PD-L1 inhibitors (53, 54). Nivolumab monotherapy was the most commonly used, appearing in six studies (32, 45, 46, 49, 51, 52). Combination therapy with ipilimumab and nivolumab was examined in two studies (48, 55). Both Vogelzang (45) and Koguchi (32) researched ccRCC and nccRCC but did not detail the nccRCC subtypes. Patients with pRCC were the most prevalent. Detailed information on these studies is presented in Table 3 and Table 4.

3.7.2 ORR and DCR

ORR was reported in six prospective (45–50) and five retrospective studies (51–55), while DCR was reported in five prospective (45–48, 50) and five retrospective studies (51–55). Both ORR and DCR showed no significant heterogeneity. The overall pooled ORR was 16% (95% CI: 13–19%) (Figure 4C). Subgroup analysis showed a pooled ORR of 18% (95% CI: 14–22%) in the prospective group and 13% (95% CI: 8–18%) in the retrospective group. The overall pooled DCR was 54% (95% CI: 50–58%), with a DCR of 58% (95% CI: 53–63%) in the prospective group and 46% (95% CI: 38–53%) in the retrospective group (Figure 5C). Additionally, ORR (RR = 3.044; 95% CI: 1.623-5.709%; P = 0.001) was higher in the PD-L1 positive group compared to the PD-L1 negative group (Figure 6).

Figure 6

Figure 6. The forest plot comparing of ORR between PD-L1 positive group and PD-L1 negative group.

3.8 Single-arm trials with chemotherapy

3.8.1 Characteristics

A total of 142 patients participated in four phase II trials (56–59) and one retrospective study (60), all excluding prior chemotherapy. Three patients received first-line treatment (56, 59, 60). Tsimafeyeu (58) focused on capecitabine monotherapy, while the other studies used combination chemotherapy. Oudard (56) and Rizzo (60) exclusively studied patients with CDC, whereas the remaining studies included various types of nccRCC. Detailed information is presented in Table 3 and Table 4.

3.8.2 ORR and DCR

Both ORR and DCR showed significant heterogeneity, with an I² > 50% in the Q-test. ORR ranged from 0% to 26.09% across studies, resulting in a pooled ORR of 16% (95% CI: 6–28%) (Figure 4D). DCR, which was not reported in Richey (57), ranged from 47.22% to 72.55%, with a pooled DCR of 62% (95% CI: 48–75%) (Figure 5D).

3.9 Single-arm trials with combination therapy

3.9.1 Characteristics

This analysis included ten studies with a total of 523 patients (61–70). Of these, one study incorporated both prospective and retrospective data (66), while the others were prospective phase II trials (61–65, 67–70). All studies investigated anti-angiogenesis therapies, using either small molecule targeted agents, such as VEGFR-TKIs, or large molecule monoclonal antibodies, such as bevacizumab, often in combination with mTORi, ICIs, or chemotherapy. Notably, Suarez (69) focused exclusively on pRCC, and Sheng (70) examined only CDC. The remaining studies included various subtypes of nccRCC, with pRCC being the most common subtype. Detailed information on these ten single-arm studies is presented in Table 3 and Table 4.

3.9.2 ORR and DCR

All studies provided data on ORR (61–70), while only eight included DCR (61–64, 67–70). Statistical analysis indicated high heterogeneity for both ORR (I² = 76.59%, P < 0.01) and DCR (I² = 89.75%, P < 0.01). ORR across studies ranged from 7.69% to 50.6%, with a pooled estimate of 36% (95% CI: 27–44%) (Figure 4E). DCR varied from 36.59% to 97.50%, resulting in a pooled DCR of 81% (95% CI: 70–91%) (Figure 5E). Subgroup analysis revealed five studies using bevacizumab (62–66), seven utilizing VEGFR-TKIs (61, 63, 66, 68, 70), and five based on ICIs (63, 65, 67–69). All subgroups demonstrated significant heterogeneity for ORR. The pooled ORRs were 31% (95% CI: 17–45%) for bevacizumab, 41% (95% CI: 31–50%) for VEGFR-TKIs, and 40% (95% CI: 31–50%) for ICIs.

4 Discussion

The optimal therapeutic strategy for nccRCC remains contentious. The heterogeneity of nccRCC complicates the establishment of robust evidence for specific therapies, as it hinders the conduct of prospective randomized trials. While systemic treatments effective for ccRCC show some activity in nccRCC, their response rates are significantly lower. Therefore, the panel recommends prioritizing clinical trial enrollment for nccRCC patients (1).

Our analysis of six RCTs compared the efficacy of mTORi and VEGFR-TKIs. Unfortunately, we did not achieve positive results in terms of effectiveness and survival. However, subgroup analysis of the four first-line studies showed that PFS was superior with sunitinib compared to mTORi (RR = 1.387; 95% CI: 1.04-1.85; p = 0.026). This advantage was not reflected in ORR and DCR, possibly due to limited data, as only three articles reported on ORR and DCR. Further validation through large-scale studies is needed.

NccRCC is a heterogeneous disease with significant variability among studies in histological subtypes, populations recruited, and risk factors, complicating comparisons across studies. Despite these challenges, current research suggests sunitinib as a potential treatment option for advanced nccRCC. The ESPN study found that sunitinib tended to prolong OS in first-line treatment of nccRCC without sarcomatoid features (15). Among 49 patients without sarcomatoid features, median OS was 31.6 months with sunitinib compared to 10.5 months with everolimus (p = 0.075) (15). The ASPEN trial highlighted the benefit of VEGFR-TKI therapy in patients with good or intermediate risk according to MSKCC criteria compared to everolimus (16). The RECORD-3 study, through prespecified subgroup analysis of MSKCC prognosis, found that median PFS was longer for patients with favorable and intermediate risk treated with first-line sunitinib compared to everolimus (18). However, this study included both ccRCC and nccRCC, and did not separately report results for the nccRCC group based on MSKCC criteria. These findings indicate that future nccRCC studies should focus on differences in efficacy based on MSKCC risk groups.

Sunitinib is a primary treatment option for nccRCC, but the search for a superior tyrosine kinase inhibitor (TKI) continues. Cabozantinib, an oral inhibitor of MET, VEGFR, and AXL, has shown promise. The randomized phase II SWOG 1500 trial (71) compared cabozantinib, crizotinib, and savolitinib with sunitinib in patients with advanced pRCC who had received up to one prior systemic therapy, excluding VEGFR- and MET-targeted TKIs. Only cabozantinib demonstrated significantly longer PFS and a higher ORR than sunitinib. As a dual VEGF-MET inhibitor, cabozantinib’s efficacy suggests that pRCC may involve both VEGF and MET signaling pathways. Although the SWOG 1500 trial focused on pRCC, the Meet-URO 2/NCT03354884 (20) trial treated 23 patients with CDC using cabozantinib, achieving an ORR of 34.78%, surpassing most previously reported targeted therapies. Consequently, NCCN guidelines now recommend cabozantinib as a preferred option alongside clinical trials (1).

Future research should focus on the genetic and molecular characteristics of nccRCC to better identify the target audience for these therapies. Given the limited number of RCTs, our analysis includes relevant single-arm trials to evaluate drug efficacy more comprehensively. Single-arm trials have shown limited efficacy of monotherapy for nccRCC, with mTORi demonstrating the lowest pooled ORR of only 6% (95% CI: 0-16%). In contrast, VEGFR-TKIs, chemotherapy, and ICIs had monotherapy effective rates of 14-16%. Koh (43) found that patients with chRCC treated with everolimus exhibited longer PFS and better ORR compared to other RCC subtypes. Conversely, Lee (44) reported no significant differences in PFS or OS among histological subtypes treated with temsirolimus, although patients with poor prognosis, as defined by ARCC criteria, had significantly shorter PFS and OS.

The pooled ORR for single-drug treatments with chemotherapy, VEGFR TKIs, and ICIs ranged from 14-16%. While the ORR and DCR of chemotherapy were similar to those of VEGFR-TKIs and ICIs, four of the five chemotherapy-related studies were published between 2007 and 2013, making them somewhat outdated. Additionally, the chemotherapy regimens varied: Tsimafeyeu (58) used oral capecitabine as a single agent for nccRCC, Richey (57) conducted a phase II trial with pemetrexed and gemcitabine, and the other three studies employed platinum-based combination chemotherapy (56, 59, 60).

Retrospective and recent prospective clinical trials have evaluated the antitumor activity of ICIs for nccRCC, either as monotherapy or combined with PD-1/PD-L1 inhibitors. Subgroup analysis revealed that PD-L1 positive patients had significantly better ORRs than PD-L1 negative patients, suggesting that PD-L1 expression levels could guide treatment choices for nccRCC patients. However, only three trials provided relevant data, and there was no standardized method for PD-L1 detection (46–48). Larger and more rigorous studies are needed to identify nccRCC patients who would benefit most from ICIs.

Treatment options for nccRCC are expanding, with drug combinations of different mechanisms entering clinical practice. Examples include lenvatinib plus everolimus, everolimus plus bevacizumab, pembrolizumab plus lenvatinib, and cabozantinib plus nivolumab. Our research indicates that combination therapies with different mechanisms show better ORR and DCR compared to single-agent therapies. Subgroup analysis found that combination therapies based on VEGFR-TKIs and ICIs achieved similar ORRs, both outperforming combination therapies based on bevacizumab.

5 Conclusions

In conclusion, the systematic review shows that sunitinib provides superior PFS compared to mTORi as a first-line treatment for advanced nccRCC. Due to limited data, single-arm trials were included to improve clinical guidance. The results indicated that PD-L1 positive patients had better ORR than PD-L1 negative patients, suggesting a need for further investigation. Additionally, combination therapies involving different mechanisms, especially those based on VEGFR-TKIs or ICIs, were more effective than single-agent treatments.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Author contributions

YZ: Conceptualization, Data curation, Writing – original draft. HF: Supervision, Visualization, Writing – review & editing. JC: Data curation, Writing – review & editing. XW: Data curation, Writing – review & editing. HW: Data curation, Writing – review & editing. XC: Data curation, Writing – review & editing. JH: Formal analysis, Writing – review & editing.

Funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Acknowledgments

We thank all the researchers who contributed to this study.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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