Table 1.

Systemic therapy for mRCC based on risk category, mechanism, half-life, adverse events.

Treatment	Mechanism of Action	Drug Half Life	Perioperative Hold Time	Adverse Events	Clinical Trials
Axitinib + Pembrolizumab	Axitinib: Inhibits tyrosine kinase receptors VEGFR-1, −2, and −3; decreases angiogenesis, tumor growth, and metastases [30]	Axitinib: 2.5 – 6.1 hrs	Axitinib: minimum 24 hrs. Recommended hold time is ~5 half lives for TKI (12.5–30.5 hrs) [18]	Axitinib (TKI): Anemia, INR increase, thrombocytopenia, lymphocytopenia, thrombo-embolic events, macropapular rash, impaired wound healing [16,30]	KEYNOTE-426 (NCT02853331): Axitinib + Pembrolizumab showed improved PFS, OS, and objective response rate vs. Sunitinib in patients with advanced RCC and no prior treatment [32]
	Pembrolizumab: Monoclonal antibody; binds PD-1 receptor blocking interaction with PD-L1 and -L2; decreases PD-1 mediated immune inhibition [31]	Pembrolizumab: 22 d	Pembrolizumab: No need to hold ICI perioperatively unless due to ongoing AE [16]	Pembrolizumab (ICI): Immune mediated events including colitis, meningitis, pneumonitis, dermatitis, hepatitis, etc. which may require corticosteroid treatment, desmoplastic reaction [31]
Cabozantinib + Nivolumab	Cabozantinib: Inhibits MET, AXL, and VEGFR decreasing angiogenesis, invasiveness, metastasis, and immunomodulation of tumor microenvironment [33]	Cabozantinib: 55–99 hrs	Cabozantinib: Recommended hold time is ~5 half lives for TKI (11.5–20.6d)	Cabozantinib (TKI): See TKI mediated adverse events listed under Axitinib above	CheckMate 9ER (NCT03141177): Cabozantinib + Nivolumab showed improved PFS, OS, and objective response vs. Sunitinib in patients with advanced RCC with no prior treatment [34]
	Nivolumab: Monoclonal antibody; binds PD-1 receptor blocking interaction with PD-L1; decreases PD-1 mediated immune inhibition [34]	Nivolumab: ~25 d	Nivolumab: No need to hold ICI perioperatively unless due to ongoing AE [16]	Nivolumab (ICI): See ICI mediated adverse events listed under Pembrolizumab above
Lenvatinib + Pembrolizumab	Lenvatinib: Inhibits tyrosine kinase receptors VEGFR 1–3, FGFR 1–4, KIT, RET, and PDGRFα, decreases angiogenesis, lymphogenesis, tumor growth, and metastases [35]	Lenvatinib: ~28 hrs	Lenvatinib: Recommended hold time is ~5 half lives for TKI (5.8d)	Lenvatinib (TKI): See TKI mediated adverse events listed under Axitinib above	CLEAR Trial (NCT02811861): Lenvatinib + Pembrolizumab showed improved OS and PFS vs. Sunitinib in patients with advanced RCC [36]
	Pembrolizumab: Monoclonal antibody; binds PD-1 receptor blocking interaction with PD-L1 and -L2; decreases PD-1 mediated immune inhibition [29]	Pembrolizumab: 22 d	Pembrolizumab: No need to hold ICI perioperatively unless due to ongoing AE [16]	Pembrolizumab (ICI): See ICI mediated adverse events listed under Pembrolizumab above
Ipilimumab + Nivolumab	Ipilimumab: Monoclonal antibody; binds to CTLA-4 and blocks interactions with CD80/CD86; helps activate cytotoxic T cells; reduces T-regulatory cell function [37]	Ipilimumab: 15.4 d	Ipilimumab and Nivolumab: No need to hold ICI perioperatively unless due to ongoing AE [16]	Ipilimumab (ICI): See ICI mediated adverse events listed under Pembrolizumab above	CheckMate 214 (NCT02231749): Nivolumab + Ipilimumab showed improved OS and objective response vs. Sunitinib in intermediate and poor risk patients with mRCC and no prior treatment [38]
	Nivolumab: Monoclonal antibody; binds PD-1 receptor blocking interaction with PD-L1; decreases PD-1 mediated immune inhibition [34]	Nivolumab: ~25 d		Nivolumab (ICI): See ICI mediated adverse events listed under Pembrolizumab above