Overview of Kidney Cancer (RCC) Treatment
Advanced renal cell carcinoma (RCC) treatment has been transformed by combination immunotherapy-based regimens. First-line options now include IO+TKI combinations (pembrolizumab+axitinib, pembrolizumab+lenvatinib, nivolumab+cabozantinib, avelumab+axitinib) and dual checkpoint inhibitor blockade (nivolumab+ipilimumab) based on IMDC risk stratification. Later-line options include single-agent TKIs, mTOR inhibitors, and the HIF-2Ξ± inhibitor belzutifan.
First-Line Selection by IMDC Risk
Favorable Risk
- Pembrolizumab + Lenvatinib (CLEAR)
- Pembrolizumab + Axitinib (KEYNOTE-426)
- Avelumab + Axitinib (JAVELIN Renal 101)
Intermediate/Poor Risk
- Nivolumab + Ipilimumab (CheckMate-214)
- Nivolumab + Cabozantinib (CheckMate-9ER)
- Pembrolizumab + Lenvatinib (CLEAR)
Subsequent Therapy
- Cabozantinib, axitinib, or tivozanib (TKIs)
- Everolimus (mTOR inhibitor)
- Belzutifan for VHL-associated disease
Epidemiology & Impact
Kidney cancer is the ninth most common malignancy in the United States with approximately 84,680 new cases and 15,120 deaths expected in 2025. Clear cell RCC accounts for 70-80% of cases. The disease has a 2:1 male-to-female ratio with median diagnosis at age 64. Incidence has been rising partly from incidental detection on imaging. Risk factors include smoking, obesity, hypertension, VHL syndrome, and chronic dialysis. Five-year survival is approximately 78%.
Molecular Biology & Biomarkers
Clear cell RCC is characterized by near-universal VHL tumor suppressor loss on chromosome 3p, causing HIF pathway activation and VEGF overexpression driving tumor angiogenesis. Additional frequent mutations include PBRM1 (40%), SETD2 (15%), and BAP1 (10%). Non-clear cell subtypes include papillary (MET-driven type 1, NRF2-driven type 2), chromophobe, and collecting duct carcinoma. PD-L1 expression correlates with aggressive biology but also predicts immunotherapy benefit.
Evolving Treatment Landscape
Advanced RCC treatment has been transformed by IO-TKI combinations. CheckMate 214 established ipilimumab-nivolumab for intermediate/poor-risk. Pembrolizumab-axitinib, nivolumab-cabozantinib, and pembrolizumab-lenvatinib all demonstrated OS superiority over sunitinib. Adjuvant pembrolizumab (KEYNOTE-564) improved DFS after nephrectomy. For favorable-risk, TKI monotherapy or surveillance remain options.
Approved Therapies
sunitinib
FDA 2006Pfizer
Indication: Advanced renal cell carcinoma
Dosing: 50 mg orally once daily for 4 weeks, then 2 weeks off (6-week cycle)
FDA 2005Bayer
Indication: Advanced renal cell carcinoma
Dosing: 400 mg orally twice daily
axitinib
FDA 2012Pfizer
Indication: Advanced renal cell carcinoma after failure of one prior systemic therapy; With pembrolizumab or avelumab for first-line treatment
Dosing: 5 mg orally twice daily, may titrate to 10 mg twice daily
nivolumab + ipilimumab
FDA 2018Bristol Myers Squibb
Indication: Intermediate or poor-risk advanced renal cell carcinoma
Dosing: Nivolumab 3 mg/kg + ipilimumab 1 mg/kg IV every 3 weeks Γ 4, then nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks
pembrolizumab + axitinib
FDA 2019Merck/Pfizer
Indication: First-line treatment of advanced renal cell carcinoma
Dosing: Pembrolizumab 200 mg IV every 3 weeks + axitinib 5 mg orally twice daily
pembrolizumab + lenvatinib
FDA 2021Merck/Eisai
Indication: First-line treatment of advanced renal cell carcinoma
Dosing: Pembrolizumab 200 mg IV every 3 weeks + lenvatinib 20 mg orally once daily
cabozantinib
FDA 2016Exelixis
Indication: Advanced renal cell carcinoma; With nivolumab for first-line treatment
Dosing: 60 mg orally once daily (monotherapy) or 40 mg once daily (with nivolumab)
tivozanib
FDA 2021AVEO
Indication: Relapsed or refractory advanced renal cell carcinoma following 2 or more prior systemic therapies
Dosing: 1.34 mg orally once daily for 21 days on, 7 days off
belzutifan
FDA 2021Merck
Indication: Von Hippel-Lindau disease-associated renal cell carcinoma not requiring immediate surgery; Advanced renal cell carcinoma following PD-1/PD-L1 inhibitor and VEGF-TKI
Dosing: 120 mg orally once daily
Approved Indications (US/FDA)
Treatment of adult patients with advanced renal cell carcinoma (RCC) as first-line treatment.
Dosing Schedule
Nivolumab 240 mg IV every 2 weeks + Cabozantinib 40 mg orally once daily
Cycle Length
Nivolumab every 2 weeks; Cabozantinib continuous daily
Combination Therapy
IO + TKI combination (CheckMate 9ER regimen)
Approved Indications (US/FDA)
Treatment of adult patients with advanced renal cell carcinoma (RCC) as first-line treatment.
Dosing Schedule
Avelumab 800 mg IV every 2 weeks + Axitinib 5 mg orally twice daily
Cycle Length
Avelumab every 2 weeks; Axitinib continuous daily
Combination Therapy
IO + TKI combination (JAVELIN Renal 101 regimen)
Approved Indications (US/FDA)
Treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib.
Dosing Schedule
10 mg orally once daily
Cycle Length
Continuous daily dosing
Combination Therapy
Monotherapy (mTOR inhibitor)
Treatment Strategies
First-line favorable risk: Pembrolizumab + axitinib/lenvatinib OR sunitinib. Intermediate/poor risk: Nivolumab + ipilimumab OR pembrolizumab + axitinib/lenvatinib OR cabozantinib + nivolumab. Second-line: Cabozantinib, axitinib, or belzutifan (HIF-2Ξ± inhibitor).