Table 1:

Treatment of Metastatic Clear Cell RCC by FDA Approval Date

Therapy	FDA Approval	Mechanism of Action	Treatment Line	Risk Groups	Comparison Arm	Endpoint	Route
Interleukin-2	May 1992	Cytokine immunotherapy	First-line	Favorable	Phase II - None	ORR	IV
Sorafenib	Dec 2005	VEGFR, PDGFR, KIT inhibitor	Cytokine failure	Favorable Intermediate	Placebo	OS	PO
Sunitinib	Jan 2006	VEGFR, PDGFR inhibitor	First-line	Favorable Intermediate	IFN-α	PFS	PO
Temsirolimus	May 2007	mTOR inhibitor	First-line	Intermediate Poor	IFN-α	OS	IV
Everolimus	Mar 2009	mTOR inhibitor	VEGFR failure	All groups	Placebo	PFS	PO
Bevacizumab + IFN-α	Jul 2009	Anti-VEGF monoclonal antibody	First-line	Favorable Intermediate	IFN-α ± Placebo	OS	IV + SC
Pazopanib	Oct 2009	VEGFR, PDGFR, KIT inhibitor	First-line or Cytokine failure	Favorable Intermediate	Placebo	PFS	PO
Axitinib	Jan 2012	VEGFR inhibitor	Second-line		Sorafenib	PFS	PO
Nivolumab	Nov 2015	Anti-PD1 monoclonal antibody	Second-line	All groups	Everolimus	OS	IV
Cabozantinib	Apr 2016	VEGFR, MET, AXL inhibitor	Second-line	All groups	Everolimus	PFS	PO
Lenvantinib + Everolimus	May 2016	VEGFR, PDGFR, KIT, FGFR, RET inhibitor mTOR inhibitor	Second-line	All groups	Everolimus or Levantinib	PFS	PO
Cabozantinib	Dec 2017	VEGFR, MET, AXL inhibitor	First-line	Intermediate Poor	Sunitinib	PFS	PO
Nivolumab + Ipilimumab	Apr 2018	Anti-PD1 monoclonal antibody Anti-CTLA-4 monoclonal antibody	First-line	Intermediate Poor	Sunitinib	OS ORR PFS	IV + IV
Pembrolizumab + Axitinib	Apr 2019	Anti-PD1 monoclonal antibody VEGFR inhibitor	First-line	All groups	Sunitinib	OS PFS	IV + PO
Avelumab + Axitinib	May 2019	Anti-PD-L1 monoclonal antibody VEGFR inhibitor	First-line	All groups PD-L1+ tumor	Sunitinib	OS PFS	IV + PO
Nivolumab + Cabozantinib	Jan 2021	Anti-PD1 monoclonal antibody VEGFR, MET, AXL inhibitor	First-line	All groups	Sunitinib	PFS OS ORR	IV + PO
Tivozanib	Mar 2021	VEGFR inhibitor	Third-line	All groups	Sorafenib	PFS OS ORR	PO
Lenvatinib + Pembrolizumab	Aug 2021	VEGFR, PDGFR, KIT, FGFR, RET inhibitor Anti-PD1 monoclonal antibody	First-line	All groups	Sunitinib	PFS OS ORR	PO + IV
Pembrolizumab (adjuvant)	Nov 2021	Anti-PD1 monoclonal antibody	Adjuvant	High risk locoregional Full resected M1	Placebo	DFS OS	IV