Editor's Note:  In recent years, some immunotherapy approaches for renal cancer have faced setbacks, failing to meet primary endpoints. However, with ongoing advancements in targeted therapy, immunotherapy, and other treatment modalities, significant progress has been made in managing advanced renal cancer. Notably, the success of multiple large-scale Phase III trials on targeted and immunotherapy combinations has marked the beginning of a new era in first-line treatment for advanced renal cancer. In 2024, several major breakthroughs were achieved. To provide deeper insights, Oncology Frontier invited Xinan Sheng, professor at Peking University Cancer Hospital, to summarize the key research developments that may serve as valuable references for future renal cancer treatment and research.

First-Line Treatment for Clear Cell Renal Cell Carcinoma

Since the first randomized Phase III clinical trial of immunotherapy combinations for advanced clear cell renal cell carcinoma was announced in late 2018, multiple Phase III trials have demonstrated that immune-based combination therapy can improve treatment outcomes in first-line settings. At the 2023 ESMO Congress, the RENOTORCH trial results were presented, showing that the combination of toripalimab and axitinib achieved a median progression-free survival (PFS) of 18.0 months, significantly longer than the 9.8 months observed in the sunitinib monotherapy group, reducing the risk of disease progression or death by 35%.

In April 2024, the National Medical Products Administration (NMPA) approved toripalimab plus axitinib for the first-line treatment of intermediate- and high-risk unresectable or metastatic renal cell carcinoma. This regimen was also included in the 2024 Chinese Society of Clinical Oncology (CSCO) guidelines as a Category I recommendation for first-line treatment, signifying the official entry of advanced renal cancer treatment into the era of targeted therapy combined with immunotherapy in China. As the number of first-line combination regimens increases, future efforts should focus on identifying predictive biomarkers to select patients most likely to benefit and optimize personalized treatment strategies.

Progress in PD-L1 Inhibitor-Based Combination Therapy

Since the introduction of PD-1 and PD-L1 checkpoint inhibitors into the treatment of advanced clear cell renal carcinoma, several randomized Phase III clinical trials have been conducted, primarily based on PD-1 inhibitors. However, only two major trials—IMmotion151 and JAVELIN RENAL 100—have evaluated PD-L1 inhibitors in combination therapy. The IMmotion151 trial failed to demonstrate a significant advantage of atezolizumab plus bevacizumab over sunitinib monotherapy.

The JAVELIN RENAL 100 study, however, showed that axitinib plus avelumab significantly improved PFS in first-line treatment, leading to FDA approval for advanced renal cancer. However, the final overall survival (OS) analysis presented at the 2024 ASCO Annual Meeting raised concerns. With a median follow-up of 68 months, the median OS for PD-L1-positive patients was 43.2 months in the combination group versus 36.2 months in the control group (HR=0.86). In the intent-to-treat (ITT) population, median OS was 44.8 months in the combination group compared to 38.9 months in the control group (HR=0.88). Although the combination therapy extended OS by nearly seven months, it did not reach statistical significance, casting uncertainty over the long-term effectiveness of PD-L1 inhibitor-based combinations.

At the 2024 ESMO Congress, an interim analysis of the ETER-100 trial, led by Peking University Cancer Hospital and the Chinese Academy of Medical Sciences Cancer Hospital, was presented. This Phase III study is the second major Chinese trial evaluating PD-L1 inhibitor combinations for advanced clear cell renal cell carcinoma and the third such global study. The trial compared anlotinib plus bemosugib (TQB2450) against sunitinib as first-line treatment, with PFS as the primary endpoint.

After a median follow-up of 19.52 months, the combination therapy group significantly prolonged PFS (HR 0.53; P<0.0001), with median PFS of 18.96 months compared to 9.76 months in the sunitinib group. The combination also improved the objective response rate (ORR) to 71.59%, compared to 25.10% in the sunitinib group (P<0.0001). Although OS data remains immature, early findings suggest a favorable trend for the combination therapy. The safety profile was consistent with previous studies. These results reignited hope for the role of PD-L1 inhibitors in targeted therapy combinations for advanced renal cancer.

Benefit Analysis Across Different IMDC Risk Groups

Data from first-line immunotherapy combination trials for advanced renal cancer consistently show significant benefits for intermediate- and high-risk patients, a finding confirmed by multiple Phase III trials, long-term follow-up data, and the RENOTORCH study designed specifically for these risk groups.

At the 2024 ASCO-GU Symposium, the CheckMate 9ER trial reported 55-month follow-up data, showing that for previously untreated advanced renal cell carcinoma (aRCC) patients, the nivolumab plus cabozantinib regimen improved PFS (16.4 vs. 8.4 months, HR 0.58), OS (46.5 vs. 36.0 months, HR 0.77), and ORR (55.7% vs. 27.7%) compared to sunitinib.

Stratified by IMDC risk groups, the combination therapy did not show a significant OS benefit in low-risk patients (HR=1.10). However, in intermediate- and high-risk patients, the combination therapy significantly improved PFS (15.4 vs. 7.1 months, HR=0.56) and OS (43.9 vs. 29.3 months, HR=0.73), with an ORR of 52.6%, significantly higher than that of sunitinib.

Further evaluation based on metastatic sites showed that patients with liver, bone, or lung metastases derived significant benefits in PFS, OS, and ORR from combination therapy. Consequently, international and domestic guidelines continue to recommend immunotherapy combinations as first-line treatment for intermediate- and high-risk advanced clear cell renal carcinoma, while targeted therapy remains an option for low-risk patients.

However, not all low-risk patients fail to benefit from combination therapy. The 2024 ASCO-GU Symposium presented eight-year follow-up data from the CheckMate-214 trial, showing that nivolumab plus ipilimumab continued to provide significant long-term survival benefits over sunitinib. In intention-to-treat (ITT) patients, median OS was longer with dual immunotherapy (52.7 vs. 37.8 months, HR 0.72, 95% CI: 0.62-0.83). Among low-risk patients, while the initial benefit was unclear, long-term follow-up demonstrated a survival advantage for the dual immunotherapy group (77.9 vs. 66.7 months), with longer duration of response (61.5 vs. 33.2 months) and higher complete response rates (16% vs. 8%).

Identifying Predictive Biomarkers for Treatment Response

Since no predictive biomarkers have been established, it remains crucial to identify patients who will benefit the most from targeted and immunotherapy combinations. The 2024 ESMO Congress presented biomarker analysis from the CheckMate 9ER study, suggesting that protein fucosylation and sialylation mechanisms may drive resistance to nivolumab plus cabozantinib and sunitinib in advanced renal cell carcinoma.

At the 2024 European Association of Urology (EAU) Congress, findings from the NORA real-world study identified prognostic factors for OS in patients receiving nivolumab plus ipilimumab as first-line treatment. Further long-term follow-up studies and biomarker research will be needed to refine patient selection and optimize treatment strategies for advanced renal cancer.

First-Line Treatment Failure in Clear Cell Renal Cell Carcinoma: What Comes Next?

The treatment landscape for advanced clear cell renal cell carcinoma (ccRCC) has entered the era of immunotherapy combinations. Although various untapped treatment options remain available after first-line failure, including continued targeted therapy or targeted therapy combined with immunotherapy, high-level evidence is still lacking to guide optimal sequencing strategies. Thus, post-first-line treatment selection remains a major clinical challenge and a key focus of future research.

Sequential Targeted Therapy After Immunotherapy Failure

For patients whose disease progresses after immunotherapy-based combination therapy, targeted therapy alone has emerged as the preferred second-line approach. The 2023 ASCO Annual Meeting presented results from the Phase III CONTACT-03 trial, which compared cabozantinib plus atezolizumab versus cabozantinib monotherapy. The study confirmed that adding a checkpoint inhibitor (ICI) did not provide additional benefit, reaffirming that reintroducing immunotherapy after failure is not an effective strategy.

Similarly, the TiNivo-2 trial, a global Phase III study, investigated nivolumab plus tivozanib versus tivozanib monotherapy in patients who had progressed on one to two prior lines of therapy, including immunotherapy. The study enrolled 343 patients, with 171 receiving nivolumab plus tivozanib and 172 receiving tivozanib alone. The primary endpoint was PFS, with OS, ORR, duration of response (DoR), and safety as key secondary endpoints.

The study found that PFS was 5.7 months in the combination group versus 7.4 months in the monotherapy group, while OS was 17.7 months in the combination group versus 22.1 months in the monotherapy group. ORR was similar between the two arms, at 33% and 34%, respectively. These results indicate that ICI rechallenge after initial immunotherapy failure does not provide meaningful clinical benefit, and tivozanib monotherapy demonstrated modest efficacy, offering a viable treatment option in this setting. The findings reinforce the consensus that after failure of first-line immunotherapy combinations, targeted therapy alone should be prioritized over continuing immunotherapy plus targeted therapy.

Novel Targeted Therapies

In recent years, hypoxia-inducible factor-2α (HIF-2α) inhibitors have gained significant attention as a promising class of targeted therapies for renal cancer. Belzutifan, a small-molecule inhibitor of HIF-2α, functions by binding and stabilizing the HIF-α subunit, preventing its translocation into the nucleus and downstream gene activation. This mechanism inhibits tumor angiogenesis and cell proliferation, offering a novel therapeutic approach for Von Hippel-Lindau (VHL)-associated tumors and advanced ccRCC.

In November 2024, the National Medical Products Administration (NMPA) approved belzutifan for the treatment of VHL-associated renal cell carcinoma and other tumors, providing a new treatment option for patients in China.

The LITESPARK-005 study, which compared belzutifan monotherapy against everolimus, enrolled 746 patients (374 in the belzutifan arm and 372 in the everolimus arm). Prior data confirmed that belzutifan significantly improved PFS (HR 0.75, P<0.001) and ORR (21.9% vs. 3.5%, P<0.00001) in patients with advanced ccRCC who had progressed after immune checkpoint inhibitors and anti-angiogenic therapy, whereas everolimus failed to demonstrate comparable efficacy.

Updated results presented at the 2024 ESMO Congress further confirmed PFS benefits and provided overall survival (OS) data. Compared to everolimus, belzutifan continued to show a PFS advantage (5.6 vs. 5.6 months, HR 0.75; 95% CI 0.63-0.88). The estimated 12-month PFS rate was 33.7% vs. 17.6%, while the 24-month PFS rate was 17.5% vs. 4.1%, favoring belzutifan.

For OS, median survival was 21.4 months in the belzutifan group versus 18.2 months in the everolimus group (HR 0.92; 95% CI 0.77-1.10; P=0.18). The estimated 12-month OS rate was 67.9% vs. 65.8%, while the 24-month OS rate was 45.2% vs. 41.2%, suggesting a trend toward improved survival with belzutifan, though the difference was not statistically significant. These findings highlight the superior PFS and ORR benefits of belzutifan over everolimus in advanced ccRCC.

Other HIF-2α inhibitors have also been under investigation. At the 2024 ASCO Annual Meeting, the DFF332 trial enrolled 40 patients with advanced renal cancer who had received a median of two prior lines of therapy, reporting an ORR of 5% and a disease control rate (DCR) of 52.5%. Meanwhile, the NKT2152 trial, presented at ESMO 2024, evaluated 100 patients who had undergone a median of three prior treatments, showing an ORR of 20% and PFS of 7.4 months. In the dose-escalation cohort, median PFS reached 9.2 months, suggesting a potential benefit of dose optimization.

While single-agent efficacy of HIF-2α inhibitors remains modest, combination strategies are attracting greater attention, with preliminary results demonstrating enhanced therapeutic potential.

The LITESPARK-010 trial, conducted by Peking University Cancer Hospital and a nationwide multi-center research team, is an open-label, two-cohort Phase I study evaluating belzutifan in combination with lenvatinib, with or without pembrolizumab, in Chinese patients with advanced ccRCC who had received prior therapy.

At the 2024 ASCO Annual Meeting, early data indicated that belzutifan plus lenvatinib demonstrated favorable anti-tumor activity in previously treated Chinese ccRCC patients. The combination of belzutifan (120 mg) and lenvatinib (20 mg) showed a safety profile consistent with that of the individual agents, confirming manageable tolerability. These findings suggest that for patients who have exhausted multiple prior treatments, HIF-2α inhibitor-based combination therapies may offer promising efficacy and warrant further clinical evaluation.

Treatment Strategies for Non-Clear Cell Renal Cell Carcinoma

Non-clear cell renal cell carcinoma (nccRCC) is characterized by distinct molecular features and clinical behavior, requiring individualized and innovative treatment approaches to enhance therapeutic efficacy and improve long-term survival outcomes.

Targeted Therapy and Immunotherapy Combinations

The KEYNOTE-B61 study, presented at the 2024 ASCO-GU Symposium, demonstrated the efficacy of lenvatinib plus pembrolizumab as first-line therapy for advanced nccRCC. Extended follow-up data showed an objective response rate (ORR) of 50.6% and a disease control rate (DCR) of 82.3%, with a median duration of response (DOR) of 19.5 months. The median progression-free survival (PFS) was 17.9 months, while median overall survival (OS) had not yet been reached. The treatment was well tolerated, with a manageable safety profile. Subgroup analysis indicated that this combination regimen achieved favorable ORR across different histological subtypes of nccRCC, offering a new therapeutic option for these patients. Beyond efficacy, the combination also improved patient quality of life and prolonged survival, reinforcing its potential as a promising first-line strategy for nccRCC. However, further studies are needed to refine patient selection criteria and optimize treatment sequencing.

At the 2024 ASCO Annual Meeting, a domestic multicenter, single-arm Phase II trial was presented, evaluating sintilimab plus axitinib in fumarate hydratase (FH)-deficient renal cell carcinoma. This study primarily assessed ORR and PFS. Among 38 evaluable patients, the combination demonstrated notable clinical efficacy, with an ORR of 60.5%, a DCR of 86.8%, and a median PFS of 19.83 months. These results highlight the potential of sintilimab plus axitinib in FH-deficient RCC, suggesting that FH mutation status may serve as a biomarker to guide personalized treatment strategies for this rare subtype.

Dual Immunotherapy Strategies

The SUNNIFORECAST trial, a randomized Phase II study presented at the 2024 ESMO Congress, investigated nivolumab plus ipilimumab in advanced nccRCC compared to standard treatment. The study found no significant difference in PFS (5.52 vs. 5.65 months) or OS (42.4 vs. 33.9 months) between the dual immunotherapy regimen and conventional therapies. However, patients with PD-L1 expression (CPS >1%) showed greater clinical benefit, suggesting that PD-L1 positivity may be an important predictor of response to dual immunotherapy in nccRCC.

In another study evaluating bispecific antibody therapy, 22 patients with nccRCC received first-line treatment with PM8002/BNT327, a novel dual-targeting agent. After a median follow-up of 9.0 months, the ORR was 36.4%, with papillary RCC showing the highest response rate. The DCR was 90.9%, and the median PFS was 15.1 months. Additionally, the incidence of grade 3 or higher adverse events was lower (41.5%) compared to the KEYNOTE-426 study (75.8%), suggesting better tolerability. These findings indicate that bispecific antibodies may offer a promising therapeutic alternative for nccRCC, particularly for subtypes with limited treatment options.

Future Perspectives in Non-Clear Cell RCC Treatment

The development of targeted and immunotherapy combinations, as well as dual immunotherapy approaches, has led to significant progress in the treatment of advanced renal cancer. With the exploration of predictive biomarkers, the future holds great potential for precision medicine strategies, further refining patient selection and maximizing treatment benefits. Ongoing research and novel therapeutic combinations will continue to improve outcomes for patients with non-clear cell renal cell carcinoma.

About Dr. Xinan Sheng

Xinan Sheng, MD, PhD, is a Professor, Chief Physician, and Doctoral Supervisor at Peking University Cancer Hospital, serving as Deputy Director of the Department of Urological Oncology.

He holds several prestigious positions, including:

• Vice Chairman of the Integrative Rehabilitation Committee for Urological and Reproductive Oncology, Chinese Anti-Cancer Association
• Standing Committee Member of the Urological Oncology Committee, Chinese Anti-Cancer Association
• Board Member of the Chinese Society of Clinical Oncology (CSCO)
• Secretary-General of the CSCO Kidney Cancer Expert Committee
• Standing Committee Member of the CSCO Urothelial Cancer Expert Committee
• Expert Committee Member of the National Tumor Quality Control Center for Bladder Cancer
• Incoming Chairman of the Urological Oncology Subcommittee, Beijing Cancer Prevention and Research Association
• Chairman of the Youth Committee, Beijing Anti-Cancer Association Urological and Reproductive Oncology Subcommittee
• Standing Committee Member of the Oncology Division, Beijing Medical Association