Table 4.

Approved combination therapies

Combination therapy	FDA approval date	Line of therapy	Trial	Comparator	Efficacy outcomes						Side-effect profile	Comments	Ref.
					OS (exp) (Mo)	OS (contr) (Mo)	PFS (exp) (Mo)	PFS (contr) (Mo)	RR (exp) (%)	RR (contr) (%)
Bevacizumab + IFN-α	2009	1st	AVOREN	IFN-α	23.3	21.3	10.2	5.4	30.6	12.4		No significant increase in SEs in combination vs IFN; OS difference not significant	[35]
Bevacizumab + IFN-α	2009	1st	CALGB	IFN-α	18.3	17.4	8.5	5.2	25.5	13.1		Increased toxicity in combination; No significant increase in OS	[36]
Lenvatinib + Everlimus	2016	2nd		Everolimus	25.5	15.4	14.6	5.5			Fatigue, mucosal inflammation, proteinuria, diarrhea (20%), vomiting, hypertension, and nausea, Grade 3-4 SEs occurred in 71% compared with 50% in everlimus group	Median OS for lenvatinib alone was 18.4 mo	[41]
Nivolumab + Ipilimumab	2018		CheckMate 214	Sunitinib	Not reached	26			42	27	Similar SE profile but discontinuation in 22% vs 12% in comparison group		[44]
Pembrolizumab + axitinib	2019	1st	KEYNOTE-426	Sunitinib			15.1	11.1	59.3	35.7	Gr3 or higher adverse event of any cause occurred in 75.8% of patients in the pembrolizumab-axitinib group and in 70.6% in sunitinib group		[45]
Avelumab + axitinib	2019	1st	JAVELIN Renal 101	Sunitinib	ongoing	ongoing	13.8	8.4	51.4	25.7	Grade 3 or higher treatment-elated AEs in the overall population groups, were reported in 71.2% of patients in combination arm vs 71.5% in sunitinb arm with discontinuation in 7.6% and 13.4% respectively	Similar responses were observed for PFS and ORR in the PD-L1positive patients	[46]

DFS: Disease-free survival; ORR: Objective response rate; OS: Overall survival; PD-L1: Programmed cell death-ligand 1; PFS: Progression-free survival.