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

(UroToday.com) The 2023 European Society of Medical Oncology (ESMO) Annual Congress held in Madrid, Spain between October 20^th and 24^th, 2023 was host to a non-prostate genitourinary proffered paper session. Dr. Astrid van der Veldt delivered the discussant for 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).

Dr. Van der Veldt began by highlighting the current published trials for 1^st line therapy in patients with intermediate and poor-risk advanced RCC. RENOTORCH is the 1^st phase 3 trial to assess IO-based doublet therapy in Chinese patients. The median follow-up for this trial remains relatively short (14.6 months) compared to the other trials. However, to date, the efficacy outcomes are comparable with a median PFS of 18 months with combination toripalimab + axitinib. The ORR of 57% is also in the ‘ballpark’ range of those from the other trials (42% to 73%). As such, at ‘face value’, the results of RENOTORCH appear to be comparable to those from other trials in this disease space.

How do the results from RENOTORCH specifically compare to those from the other trial (KEYNOTE-426¹) evaluating axitinib + another PD-1 agent (pembrolizumab)?
There are important differences between the two trials. KEYNOTE-426 included patients from all IMDC risk groups and had dual primary endpoints of PFS and OS. Conversely, RENOTORCH included IMDC intermediate and poor risk group patients only, with a primary endpoint of PFS.
With regards to PFS, these trials had comparable relative benefits with HRs of 0.68 and 0.65 for KEYNOTE-426 and axitinib, respectively.

Additionally, the ORR in the experimental combination arms was identical at 57% in both trials. However, the complete response rate was higher in KEYNOTE-426 with axitinib + pembrolizumab (10.9% versus 4.8%).
OS data from RENOTORCH remains immature at the current time, prohibiting any meaningful comparisons.
What about the safety profiles? While grade 3 or worse adverse events were similar in both arms (68 – 71%), any serious events occurred more commonly in RENOTORCH (45% versus 29%). However, treatment discontinuation due to a treatment related adverse events was less common with toripalimab + axitinib (14% versus 33% with pembrolizumab + axitinib).

There additionally does not appear to be any significant differences in the nature of the adverse events between the two combination regimens.

While there are important differences in the baseline characteristics between the two trials, including IMDC risk group and the proportion of patients with a prior nephrectomy, and 2+ metastatic sites, the biggest difference is in the geographic participating sites. As illustrated below, RENOTORCH was based in China, which has historically been underrepresented in these trials.
This historic underrepresentation has had important implications for clinical guidelines synthesis. As demonstrated below, the 2021 Pan-Asian ESMO guidelines still included sunitinib as an alternative option for patients with intermediate-poor risk clear cell RCC, secondary to the paucity of approved agents for this patient population.

• The RENOTORCH trial has led to the first approval of 1^st line combination therapy with toripalimab plus axitinib for patients with advanced RCC in China
• As a significant number of patients with RCC worldwide live in China, the RENOTORCH trial is expected to be practice changing for a large population of patients with advanced RCC worldwide

Presented by: Astrid A. Van der Veldt, MD, PhD, Medical Oncologist, Erasmus Medical Center, Rotterdam, Netherlands

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 20^th and 24^th, 2023

Reference:

1. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380(12):1116-1127.