Checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4 have significantly advanced treatment options for metastatic clear cell renal cell carcinoma (ccRCC)RCC ^[1][25]. However, many patients exhibit resistance initially or relapse following monotherapy ^[2][3][56,57]. Both preclinical and clinical evidence suggest the potential utility of combination strategies, either pairing checkpoint inhibitors or integrating agents such as VEGF inhibitors or immunomodulators ^[4][5][58,59]. These combinatorial regimens aim to exert a broader anticancer effect, with goals to improve response rates, extend response duration, and overcome resistance mechanisms in immunogenic tumors. The synergy observed in these combinations could markedly alter therapeutic approaches for metastatic ccRCC ^[4][58]. (See Table 1 for a summary of key studies.)

The efficacy of this combination strategy was solidified in the phase III CheckMate 214 trial ^[6][60]. This first-line study in untreated metastatic ccRCC patients compared nivolumab/ipilimumab to sunitinib and demonstrated notable improvements in OS, ORR, and PFS versus sunitinib, particularly among intermediate/poor-risk patients. The combination therapy yielded an ORR of 42% compared to 27% with sunitinib. Complete response rates were 11% and 2% for the combination and sunitinib arms, respectively. The combination also showed superior median PFS (11.6 vs. 8.4 months with sunitinib). These pivotal findings have underpinned guidelines endorsing nivolumab/ipilimumab as a first-line therapy for intermediate/poor-risk metastatic ccRCC ^[6][60].

An extended five-year follow-up from CheckMate 214 further reinforced the combinatorial efficacy ^[7][61]. OS was longer for nivolumab/ipilimumab versus sunitinib (47.0 vs. 26.6 months), with five-year survival rates of 43% and 31%, respectively. The combination therapy also maintained superior ORR (42% vs. 27%) and complete response rates (11% vs. 2%) over sunitinib. More patients on combination therapy achieved complete responses without subsequent progression (9.6% vs. 2.4%). While the median DOR was unreached for nivolumab/ipilimumab, it was 24.8 months with sunitinib ^[7][61], underscoring the potential for durable responses with combination immunotherapy.

The nivolumab/ipilimumab combination was also assessed as a second-line therapy in the phase I CheckMate 016 trial ^[8][62]. Patients with metastatic ccRCC received nivolumab/ipilimumab followed by nivolumab maintenance. Severe toxicity precluded assessment of the nivolumab 3 mg/kg + ipilimumab 3 mg/kg cohort. In the nivolumab 3 mg/kg + ipilimumab 1 mg/kg and nivolumab 1 mg/kg + ipilimumab 3 mg/kg cohorts (n = 47 each), severe adverse events occurred in 38.3% and 61.7% of patients, respectively, alongside a 40.4% ORR in both groups. After a 22.3-month follow-up, ongoing responses were 42.1% and 36.8%. Two-year survival rates were 67.3% and 69.6% for the respective cohorts ^[8][62], revealing significant antitumor activity for second-line nivolumab/ipilimumab in metastatic ccRCC.

A promising therapeutic strategy in oncology entails the combination of immune checkpoint inhibitors with VEGF inhibitors, such as cabozantinib and axitinib ^[9][63]. VEGF inhibitors target the VEGF signaling cascade, a crucial mechanism in tumor angiogenesis ^[10][64]. By suppressing VEGF, angiogenesis may be hindered, thereby potentially restricting tumor growth. The combination of VEGF inhibitors with a checkpoint blockade could enhance antitumor immune responses and mitigate tumor-induced immunosuppression.

The JAVELIN Renal 101 phase III trial evaluated the efficacy of first-line avelumab plus axitinib compared to sunitinib in patients with advanced ccRCC ^[11][65]. This research tudy demonstrated pronounced improvements in PFS and ORR with combination therapy compared to sunitinib monotherapy for untreated metastatic ccRCC. Among 886 randomized participants, the subgroup with PD-L1-positive tumors exhibited a superior median PFS of 13.8 months with avelumab-axitinib versus 7.0 months with sunitinib. This PFS benefit persisted in the overall population, with medians of 13.3 and 8.0 months for the combination and sunitinib arms, respectively. The combination therapy also yielded a higher ORR of 53% compared to 27% for sunitinib ^[11][65]. An extended follow-up analysis demonstrated sustained improvements in survival, response rates, and DOR with the combination of avelumab and axitinib compared to sunitinib. The median OS was not reached for the combination of avelumab and axitinib, compared to 37.8 months for sunitinib. The median PFS was 13.9 months for avelumab and axitinib, versus 8.5 months for sunitinib ^[12][66]. In summary, avelumab-axitinib demonstrated enhanced efficacy and acceptable safety compared to sunitinib, although rwesearchers await more comprehensive data.

The KEYNOTE-426 phase III trial evaluated the efficacy of combined pembrolizumab plus axitinib compared to sunitinib monotherapy in patients with previously untreated advanced or metastatic ccRCC ^[13][67]. Across 861 randomized participants, the treatment arms consisted of pembrolizumab-axitinib combination therapy versus sunitinib alone, with primary endpoints of OS, PFS, and ORR. After a median follow-up of 42.8 months, results demonstrated superior efficacy for the combination regimen. The median OS was not reached with pembrolizumab-axitinib, showing marked improvement compared to 35.7 months for sunitinib. The combination yielded a higher ORR of 59.3% versus 35.7% for sunitinib, alongside complete response rates of 5.8% and 1.9%, respectively. Combination therapy also conferred a superior median PFS of 15.4 months compared to 11.1 months with sunitinib ^[13][67]. These findings underlie the FDA approval of pembrolizumab-axitinib as a first-line therapy for advanced ccRCC.

After 67.2 months of extended follow-up (five-year analysis), pembrolizumab-axitinib maintained improved outcomes versus sunitinib for advanced ccRCC ^[14][68]. At 60 months, OS rates were 41.9% for pembrolizumab-axitinib and 37.1% for sunitinib, while PFS rates were 18.3% and 7.3%, respectively. The median DOR was longer with pembrolizumab-axitinib. Accounting for more subsequent therapies in the sunitinib arm, the OS advantage of pembrolizumab-axitinib remained significant ^[14][68]. Collectively, these data from KEYNOTE-426 demonstrate enhanced efficacy for pembrolizumab-axitinib combination therapy in advanced RCC ^[15][69].

The phase III CheckMate 9ER trial evaluated the nivolumab plus cabozantinib combination therapy compared to sunitinib monotherapy in untreated patients with advanced or metastatic ccRCC ^[16][70]. This international, open-label, randomized study of 651 patients set PFS as the primary endpoint, assessed by an independent blinded review. After a median follow-up of 18.1 months, the nivolumab-cabozantinib combination demonstrated a superior median PFS of 16.6 months versus 8.3 months with sunitinib. Additionally, the combination conferred a markedly higher ORR of 55.7% compared to 27.1% for sunitinib. At one year, OS rates were 85.7% for the combination versus 75.6% with sunitinib. These compelling data endorse nivolumab-cabozantinib as a notable first-line strategy integrating immunotherapy and targeted therapy for metastatic ccRCC ^[16][70].

Extended three-year follow-up data showed durable advantages for nivolumab-cabozantinib over sunitinib, including a median PFS of 16.6 versus 8.4 months and median OS of 49.5 versus 35.5 months ^[17][71]. The combination therapy also maintained a higher ORR (56% vs. 28%) and complete response rate (13% vs. 5%). While adverse events were slightly increased with nivolumab-cabozantinib, no new safety signals emerged. These sustained benefits further endorse nivolumab-cabozantinib as a first-line therapy for advanced ccRCC ^[17][71].

The phase III CLEAR trial assessed the combination therapy of lenvatinib and pembrolizumab compared to sunitinib monotherapy in untreated patients with advanced or metastatic ccRCC ^[18][72]. Across 1,069 randomized participants, the treatment arms consisted of lenvatinib-pembrolizumab, lenvatinib-everolimus, or sunitinib, with PFS as the primary endpoint. The lenvatinib-pembrolizumab combination demonstrated a superior median PFS of 23.9 months versus 9.2 months for sunitinib, alongside a higher ORR (71.0% vs. 36.1%) and complete response rates (16.1% vs. 4.2%). This combination also showed a pronounced OS advantage over sunitinib. Meanwhile, lenvatinib-everolimus conferred an improved median PFS of 14.7 months compared to 9.2 months with sunitinib ^[18][72].

In the extended follow-up from the CLEAR trial, lenvatinib-pembrolizumab maintained a superior PFS of 23.3 months versus 9.2 months for sunitinib after a median follow-up of 27.8 months ^[19][73]. Lenvatinib-pembrolizumab also exhibited prolonged OS (median not reached) compared to 33.7 months for sunitinib. Hazard ratios confirmed the significant benefits of the combination over sunitinib ^[19][73]. These durable efficacy data underscore the potential of lenvatinib-pembrolizumab as a first-line therapy for advanced ccRCC.

Separately, the phase Ib/II KEYNOTE-146 trial evaluated lenvatinib-pembrolizumab as a second-line therapy ^[20][74]. After initial dose-finding across multiple tumor types, the study focused on ccCC, with 65% of patients having received prior ICI and/or tyrosine kinase inhibitor (TKI) therapy. Early results indicated positive effects on PFS and response rates, supporting further research on lenvatinib-pembrolizumab in this setting ^[21][75].

Numerous clinical trials are currently in progress with the aim of advancing therapeutic approaches for ccRCC by harnessing synergistic combination immunotherapies ^[4][58]. These studies are exploring diverse regimens encompassing checkpoint inhibitors, VEGF inhibitors, and innovative agents. As summarized in Table 2, notable investigations include the assessment of a personalized vaccine (NCT05269381), the enzymatic inhibitor valemetostat (NCT04388852), the IL-8 inhibitor (NCT04572451), and aldesleukin (NCT03260504). There is also increasing interest in the monoclonal antibody SRF388 (NCT04374877) and the integration of radiation therapy (NCT05327686). Additional trials are evaluating neoadjuvant checkpoint inhibitor combinations, including NCT04393350 and NCT05319015.

Examining select examples illustrates the intricate details and objectives. The phase I trial NCT03260504 is evaluating aldesleukin plus pembrolizumab for metastatic ccRCC, based on the premise that aldesleukin can potentiate anti-cancer immune responses which pembrolizumab may enhance by blocking immune evasion ^[22][76]. The phase I/Ib study NCT04374877 is pioneering SRF388, a monoclonal antibody targeting IL-27, first as a monotherapy in advanced solid tumors, and then in combination with pembrolizumab in specific malignancies like ccRCC to assess potential synergistic benefits ^[23][77]. Another phase II trial, NCT05319015, is investigating neoadjuvant lenvatinib-pembrolizumab prior to surgical resection in ccRCC with inferior vena cava invasion, with the goal of optimizing pre-surgical anti-tumor effects.

Collectively, these clinical initiatives highlight promising progress in ccRCC therapeutic development and the vast potential of combination immunotherapy. Beyond advancing treatment modalities, these studies embody resilience and the commitment to transforming renal cancer care through pioneering research and cross-disciplinary collaboration. The breadth of strategies under exploration indicates a steadfast momentum to reshape the future landscape of ccRCC therapy.