Metastatic RCC

 

Antiangiogenic TKI	Indication	Side effects
Sunitinib	TKIs (axitinib, cabozantinib, lenvatinib, tivozanib): These are approved for advanced or metastatic RCC, often as first-line or subsequent therapy. Axitinib and lenvatinib are used in combination with immune checkpoint inhibitors (ICIs) such as pembrolizumab or avelumab ( no OS benefit with avelumab + axitinib) for first-line therapy. Cabozantinib is preferred as a single agent after progression on ICI-based therapy, with robust evidence supporting its use in this setting. Tivozanib is specifically approved for relapsed/refractory RCC after two or more prior systemic therapies	Hypertension, diarrhea, fatigue, hand-foot syndrome, and hepatotoxicity are common. Tivozanib has a lower incidence of severe diarrhea and rash compared to sorafenib, but hypertension and asthenia are notable
Axitinib
Cabozantinib
Lenvatinib
Tovozanib
Pazopanib
Belzutifan	A HIF-2α inhibitor, FDA-approved for advanced RCC after prior PD-1/PD-L1 inhibitor and VEGF-TKI. It is recommended as a subsequent therapy, particularly after IO and VEGF-TKI exposure.	Anemia, fatigue, hypoxia, and dyspnea are most common. It has a favorable safety profile and lower rates of treatment discontinuation compared to everolimus

 

 

	mTOR inhibitor
	Everolimus
Indication	An mTOR inhibitor, used as subsequent therapy after VEGF-TKI failure, especially in heavily pretreated patients
Side effect monitoring	Stomatitis, fatigue, rash, and pneumonitis (<15%) are typical.

 

Combination Therapies:

• TKIs: Frequently combined with ICIs (e.g., axitinib + pembrolizumab, lenvatinib + pembrolizumab, cabozantinib + nivolumab) for first-line therapy, improving response rates and survival.^[6]
• Everolimus: Can be combined with lenvatinib for improved efficacy over monotherapy, but with increased toxicity.
• Tivozanib and belzutifan: Used as single agents in later lines; no established combination regimens in mRCC.

Effectiveness:

• Cabozantinib offers superior PFS, OS, and ORR compared to everolimus and other TKIs in the post-ICI setting.^[2]
• Tivozanib improves PFS over sorafenib in heavily pretreated patients (median PFS 5.6 vs. 3.9 months) with similar OS and lower grade ≥3 AEs.
• Belzutifan shows a significant PFS and objective response rate advantage over everolimus (ORR 22% vs. 3.6%; median PFS 5.6 months for both, but more durable responses with belzutifan), with improved quality of life and tolerability.
• Everolimus provides modest PFS benefit over placebo, but is less effective than newer agents and combinations

 

In summary, cabozantinib is the preferred VEGF-TKI after ICI-based therapy, tivozanib is an option for heavily pretreated patients, everolimus is reserved for refractory cases, and belzutifan is now favored over everolimus for patients progressing after IO and VEGF-TKI, with a better side effect and quality of life profile.