Renal cell carcinoma (RCC) has been reshaped by immunotherapy-based combinations and, more recently, by a novel oral agent targeting the disease's core biology — HIF-2α — now approved across advanced and adjuvant settings.
First-line therapy for advanced RCC
Immune-checkpoint-inhibitor plus tyrosine-kinase-inhibitor combinations are standard first-line for advanced clear-cell RCC. Lenvatinib plus pembrolizumab markedly improved progression-free survival over sunitinib in the CLEAR trial (about 24 vs 9 months), and nivolumab plus cabozantinib did likewise in CheckMate 9ER (about 17 vs 8 months), both with higher response rates and survival benefit. The dual-checkpoint combination nivolumab plus ipilimumab remains an option for intermediate- and poor-risk disease.
Belzutifan: HIF-2α inhibition, now across settings
Belzutifan, a first-in-class oral HIF-2α inhibitor, targets the central driver of clear-cell RCC biology. Its role has expanded well beyond its original niche: it is approved for VHL-disease-associated RCC (objective response around 49%), for advanced sporadic RCC after a PD-(L)1 inhibitor and a VEGF TKI (LITESPARK-005, approved 2023, on the basis of improved progression-free survival versus everolimus — though the overall-survival co-primary endpoint was not met), and, most recently, in the adjuvant setting combined with pembrolizumab for high-risk clear-cell RCC after nephrectomy (LITESPARK-022, approved 2026, on the basis of improved disease-free survival). Common effects include anemia and hypoxia.
Adjuvant and local therapy
Adjuvant pembrolizumab became standard of care for high-risk RCC after nephrectomy on the strength of the KEYNOTE-564 trial (improved disease-free and overall survival), and the belzutifan combination now builds on that foundation. For localized disease, partial or radical nephrectomy remains curative in most cases, with ablative techniques and stereotactic body radiotherapy for patients unsuitable for surgery.
| Therapy | Setting | Key result |
|---|---|---|
| Lenvatinib + pembrolizumab | First-line advanced | PFS ~24 vs 9 mo (CLEAR) |
| Nivolumab + cabozantinib | First-line advanced | PFS ~17 vs 8 mo (CheckMate 9ER) |
| Belzutifan | VHL RCC; advanced (post-IO/TKI); adjuvant (+pembrolizumab) | ORR ~49% (VHL); PFS benefit (LITESPARK-005); DFS benefit (LITESPARK-022) |
| Adjuvant pembrolizumab | Post-nephrectomy, high-risk | Improved DFS and OS (KEYNOTE-564) |
Further reading: CLEAR lenvatinib-pembrolizumab (Motzer et al., NEJM 2021); CheckMate 9ER (Choueiri et al., NEJM 2021); belzutifan in VHL (Jonasch et al., NEJM 2021), LITESPARK-005 and LITESPARK-022; KEYNOTE-564 adjuvant pembrolizumab.