Editor’s note:

The combination of immune checkpoint inhibitors and anti-angiogenic therapy has become a first-line treatment option for advanced renal cell carcinoma (aRCC), with previous studies including patients of all IMDC risk levels. During a dedicated session on urological oncology at the 2023 ESMO Congress, Professor Sheng Xinan from Peking University Cancer Hospital, on behalf of a clinical research team, presented the results of the first Phase 3 study focusing on immune combination therapy for high-risk IMDC patients with advanced kidney cancer, making it the first domestic Phase 3 study of first-line immune combination therapy for advanced kidney cancer. The positive results offer a new first-line treatment option for patients with advanced kidney cancer.

Study Overview:

Background: The combination of anti-PD-1 antibodies with anti-angiogenesis treatment has shown synergistic anti-tumor effects in the treatment of advanced kidney cancer. Toripalimab is a humanized monoclonal antibody targeting PD-1. Here, we report the results of a randomized, open-label, Phase 3 trial (NCT04394975) aimed at evaluating the efficacy and safety of toripalimab in combination with axitinib compared to sunitinib for first-line treatment of advanced kidney cancer.

Methods:

Patients eligible for the study had unresectable or metastatic clear cell renal cell carcinoma and were classified as intermediate or high risk according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Patients were randomized in a 1:1 ratio to receive toripalimab (240 mg, q3w, iv) in combination with axitinib (5 mg, qd, po) or sunitinib (50 mg, qd, for 4 weeks [6 weeks per cycle] or 2 weeks [3 weeks per cycle]). The primary endpoint was investigator-assessed progression-free survival (PFS) based on RECIST.

Results:

A total of 421 patients were enrolled, with 210 in the toripalimab group and 211 in the sunitinib group. Baseline characteristics showed that 81.5% of patients were intermediate risk, and 18.5% were high risk.

With a median follow-up of 14.6 months, the toripalimab group demonstrated significantly prolonged median PFS compared to the sunitinib group (18.0 vs. 9.8 months, HR 0.65, 95% CI: 0.49–0.86, P = 0.0028). PFS benefits were consistent across all subgroups.

The toripalimab group had an objective response rate (ORR) of 56.7% (95% CI: 49.7–63.5), while the sunitinib group had an ORR of 30.8% (95% CI: 24.6–37.5) (P < 0.0001). The median overall survival (OS) in the toripalimab group was not reached, while it was 26.8 months in the sunitinib group (HR 0.61, 95% CI: 0.40–0.92, P = 0.0186).

Both groups showed similar rates of grade 3 or higher adverse events (AE) (71.2% vs. 67.1%), treatment interruptions due to AE (14.4% vs. 8.1%), and fatal AEs (1.0% vs. 1.0%).

Conclusion:

In untreated advanced intermediate to high-risk kidney cancer patients, toripalimab in combination with axitinib demonstrated significantly longer PFS and a higher ORR compared to sunitinib. These results support the use of toripalimab in combination with axitinib as a first-line treatment for advanced kidney cancer.

Remarks from the Researchers:

Renal cell carcinoma (RCC) accounts for approximately 80%-90% of kidney tumors, with approximately 431,000 new cases and 179,000 deaths worldwide each year. Although most localized RCC can be cured through surgery, the prognosis for metastatic RCC patients is poor, with a 5-year overall survival rate of only 12%. Immune checkpoint inhibitors combined with anti-angiogenic agents have synergistic anti-tumor effects and have become the standard first-line treatment for advanced RCC.

RENOTORCH is a Phase 3 randomized controlled trial led by Professor Guo Jun from Peking University Cancer Hospital and Professor Huang Yiran from Renji Hospital, Shanghai Jiao Tong University School of Medicine. It is also the first domestic Phase 3 trial of immune combination therapy for advanced RCC. In similar studies reported internationally, the benefits of immune combination therapy are mainly seen in intermediate to high-risk IMDC patients. However, there is a lack of data specifically focusing on the combination of PD-1 antibodies with TKI targeted drugs for first-line treatment in intermediate to high-risk kidney cancer patients. RENOTORCH is the world’s first Phase 3 randomized controlled study specifically targeting intermediate to high-risk IMDC patients with anti-PD-1 in combination with TKI, providing valuable reference for the selection of first-line treatment for patients with advanced clear cell renal cell carcinoma. Therefore, this study was selected for presentation at the ESMO Congress, providing an opportunity for global exchange of knowledge.

This study has yielded excellent data, with the toripalimab in combination with axitinib group showing a significant 35% reduction in the risk of disease progression (18.0 vs. 9.8 months, HR 0.65, P = 0.0028) and a 39% reduction in the risk of death (not reached vs. 26.8 months, HR 0.61, P = 0.0186) compared to the sunitinib group. The safety and tolerability of combination therapy are also favorable. It is believed that these positive results will help these drugs obtain domestic indications and propel the field of advanced kidney cancer treatment in China into a new era of immune combination therapy, benefiting more kidney cancer patients.

Chief Physician, Professor, Doctoral Supervisor

Deputy Director of the Department of Urological Tumors, Peking University Cancer Hospital

Director of the Chinese Society of Clinical Oncology (CSCO)

Member and Secretary-General of the CSCO Kidney Cancer Expert Committee

Member of the CSCO Urothelial Carcinoma Expert Committee

Member of the National Cancer Quality Control Center Bladder Cancer Quality Control Expert Committee

Member of the Chinese Anti-Cancer Association Urological Tumor Professional Committee

Deputy Group Leader of the Chinese Anti-Cancer Association Urological Tumor Professional Committee’s Rare Types of Kidney Cancer Collaboration Group

President-elect of the Beijing Cancer Prevention and Control Research Association Urological Tumor Branch

Chairman of the Beijing Anti-Cancer Association Urological and Reproductive Tumor Professional Committee Youth Committee

Executive Member of the Beijing Medical Association Tumor Branch