(UroToday.com) The 2023 European Society of Medical Oncology (ESMO) Annual Congress held in Madrid, Spain between October 20th and 24th, 2023 was host to a non-prostate genitourinary proffered paper session. Dr. Xinan Sheng presented the results of RENOTORCH, a randomized, open-label, phase 3 study of toripalimab combined with axitinib versus sunitinib for the first line treatment of advanced renal cell carcinoma (RCC).
Toripalimab (Tuoyi™) is a selective, recombinant, humanized monoclonal antibody against programmed death protein 1 (PD-1) developed by Shanghai Junshi Bioscience Co., Ltd. Toripalimab received a conditional approval in China for the treatment of melanoma in the second line setting (December 2019), nasopharyngeal carcinoma in the 1st and 3rd line settings, and urothelial carcinoma in the 2nd line setting in 2021. Additionally, several orphan drug designations were granted to toripalimab by the US Food and Drug Administration. Given that most 1st line trials in the advanced RCC disease space have not included patients from Asian countries, there is a significant geographic, clinical unmet need for 1st line trials in the advanced RCC disease space for this patient population.
RENOTORCH is a randomized open label phase 3 trial of Chinese patients with unresectable or metastatic clear cell RCC (+/- sarcomatoid features) who had not received prior systemic, anti-tumor therapy and had intermediate/poor risk disease per IMDC criteria. Patients underwent 1:1 randomization, stratified by IMDC risk group, to either:
- Toripalimab (240 mg every 3 weeks) + axitinib (5 mg twice daily)
- Sunitinib (50 mg daily in 3- or 6-week cycles)
Treatment was continued until there was evidence of disease progression or intolerable toxicity. The primary endpoint was progression-free survival, assessed via blinded independent central review (BICR), using RECIST v1.1. The secondary endpoints included:
- Objective response rate (ORR)
- Overall survival (OS)
- Progression-free survival (PFS), per investigators (PFS)
- Duration of response (DoR)
- Disease control rate
- 1- and 2-year OS rates
- Safety
From a statistical standpoint, the sample size was determined based on the primary endpoint of BICR-assessed PFS, assuming an HR of 0.69 at 85% power with 267 PFS events in the ‘intention-to-treat’ population, at a 2-sided alpha of 0.05. A hierarchical testing strategy was applied to control the family-wise type 1 error at a 2-sided alpha of 0.05. The pre-specified testing order was PFS (BICR) ORR (BICR) OS. An interim analysis for PFS (BICR) was planned, and the O’Brien-Fleming type 1 spending function was approximated by the Lan-DeMets methods to control the type 1 error rate (efficacy boundary of a=0.0181, based on 197 PFS events with 73.8% information fraction). Formal testing of OS will take place once 204 death events have occurred, providing 87% power to detect a significant difference at a two-sided alpha=0.05, assuming an HR of 0.65.
The median patient age was 60 years. 82% of patients had IMDC intermediate risk disease, with the remaining 18% having IMDC poor risk. 62% of patients had undergone a prior nephrectomy.
For the primary endpoint of PFS assessed via BICR, the combination of toripalimab + axitinib was associated with significant survival benefits compared to sunitinib (HR: 0.65, 95% CI: 0.49 to 0.86. p=0.0028). The median PFS was 18 months in the experimental arm, compared to 9.8 months in the control arm.
The forest plot below demonstrates a PFS benefit across all evaluable subgroups, particularly those with a prior nephrectomy.
Similar results were observed for investigator assessed PFS (HR: 0.57, 95% CI: 0.44 to 0.75, p<0.001).
The ORR was 57% for toripalimab + axitinib versus 31% for sunitinib. The BICR-assessed duration of response was similarly longer in the experimental arm (median: not reached versus 16.7 months).
While OS data remains immature, there is a clear signal for OS benefit with toripalimab + axitinib (HR: 0.61, 95% CI: 0.40 to 0.92, p=0.019).
From a safety standpoint, grade 3+ treatment-emergent adverse events were similar for both groups (71% versus 67%). Adverse events leading to drug discontinuation (14% versus 8%) or interruption (69% versus 43%) were seen more commonly in the experimental arm.
Dr. Sheng concluded that:
- The addition of toripalimab to axitinib in the 1st line treatment setting for advanced RCC patients provides superior clinical outcomes compared to sunitinib.
- Median PFS: 18 versus 9.8 months (HR: 0.65, 95% CI: 0.49 – 0.86, p=0.0028)
- BICR-assessed ORR: 57% versus 31%, p<0.001
- Median OS: Not reached versus 26.8 months (HR: 0.61, 95% CI: 0.40 – 0.92); a formal OS testing is planned at 204 death events
- The combination of toripalimab and axitinib was generally well-tolerated, with a safety profile consistent with each individual agent
- Toripalimab in combination with axitinib has the potential to become a new standard first-line treatment for advanced RCC
Presented by: Xinan Sheng, MD, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital & Institute, Beijing, China
Written by: Rashid K. Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Congress held in Madrid, Spain between October 20th and 24th, 2023
Related Content: ESMO 2023: Invited Discussant – RENOTORCH: Toripalimab Combined with Axitinib versus Sunitinib in First-line Treatment of Advanced Renal-Cell Carcinoma: A randomized, Open-label, Phase 3 Study