Advanced Renal Cell Carcinoma: Systemic Therapy

Advanced Renal Cell Carcinoma: overview

This algorithm covers first-line and later-line systemic therapy for advanced renal cell carcinoma, starting from clear cell histology and branching by IMDC risk group. For IMDC favorable risk disease, the chart lists three immunotherapy plus TKI combinations: pembrolizumab plus axitinib (KEYNOTE-426), pembrolizumab plus lenvatinib (CLEAR) and nivolumab plus cabozantinib (CheckMate 9ER). For intermediate or poor risk disease, ipilimumab plus nivolumab is the dual-IO option (CheckMate 214), with an IO plus TKI combination as an alternative in any risk group. For non-clear-cell histology, the chart shows cabozantinib or a pembrolizumab-based regimen or clinical trial.

Later-line options are cabozantinib (METEOR), lenvatinib plus everolimus (Study 205), tivozanib (TIVO-3) and the HIF-2α inhibitor belzutifan (LITESPARK-005). In the site's summaries, LITESPARK-005 showed improved PFS and a higher response rate with belzutifan versus everolimus in previously treated clear cell RCC, without a statistically significant OS difference, and TIVO-3 showed improved PFS and response rate with tivozanib versus sorafenib in heavily pretreated disease.

Trials behind this algorithm

• KEYNOTE-426 trial Powles T et al, Lancet Oncol, 2020; PMID: 33284113
• CLEAR trial Motzer R et al, NEJM, 2021; PMID:33616314
• Checkmate 9ER trial Choueiri TK et al, NEJM, 2021; PMID:33657295
• CheckMate 214 trial Albiges L et al, ESMO Open, 2020; PMID: 33246931
• METEOR trial Choueiri TK et al, Lancet Oncol, 2016; PMID:27279544
• TIVO-3 Rini BI et al, Lancet Oncol, 2020; PMID: 31810797
• LITESPARK-005 Choueiri TK et al, NEJM, 2024; PMID: 39167807

Background reading: Renal cell carcinoma (RCC) board review notes.