Combination drug regimens for metastatic clear cell renal cell carcinoma

Table 2 Food and Drug Administration approval monotherapies for the treatment of renal cell carcinoma

Drug	Mechanism of action	Line of therapy	Study	PFS	OS	ORR	Associated toxicities	Ref.
Pazopanib	TKI	First	Pazopanib vs placebo	9.2 mo vs 4.2 mo HR 0.46; 95%CI: 0.34 to 0.62; P < 0.0001	22.9 mo (95%CI: 19.9 to 25.4) vs 20.5 (95%CI: 15.6 to 27.6) mo; HR 0.91; 95%CI: 0.71-1.16; one sided stratified log rank P = 0.224	30% (95%CI: 25.1 to 35.6) vs 3% (95%CI: 0.5 to 6.4), median duration of response 58.7 wk by independent review1	Diarrhea, hypertension, hair color changes, nausea, anorexia, vomiting. Grade 3 toxicities included elevated ALT (30%) and AST (28%)	[99,100]; Comment: Lack of correlation between OS and PFS was attributed to extensive crossover of placebo-treated patients to pazopanib group
Pazopanib	TKI	Second	Pazopinibvs placebo after prior progression on sunitinib or bevacizumab	7.5 mo (95%CI: 5.4 to 9.4) vs 7.5 mo (95%CI: 5.5 to 14.1) vs 6.7 mo (95%CI: 3.6 to 9.3)	14.8 mo (95%CI: 12 to 28.8) vs 24.2 mo (95%CI: 14.7 to not reached) vs 10.9 (95%CI: 8.2 to 12)	27% (95%CI: 17% to 40%) vs 26% (95%CI: 15% to 41) vs 31% (95%CI: 14 to 55%)	Grade 1 and 2 toxicities were common. Grade 3 and 4 occurring in ≥ 10% included fatigue (185), proteinuria (13%), hypertension (13%), and diarrhea (11%)	[101]
Sunitinib	TKI	First	Sunitinib vs interferon	11 mo (95%CI: 11 to 13 mo vs 5 mo (95%CI: 4 to 6); HR 0.42 (95%CI: 0.451 to 0.643); P < 0.001	26.4 mo (95%CI: 23 to 32.9) vs 21.8 (95%CI: 17.9 to 26.9); HR, 0.821; 95%CI: 0.673 to 1.001; P = 0.051	31% (95%CI: 26 to 36) vs 6% (95%CI: 4 to 9; P < 0.001)	Grade 3 events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%)	[102,103]
Axitinib	TKI	First	Axitinib vs sorafenib	10.1 mo (95%CI: 7.2 to 12.1) vs 6.5 mo (95%CI: 4.7 to 8.3); Stratified HR; 0.77 (95%CI: 0.56 to 1.05)1	Median OS (95%CI: 21.7 mo (18.0-31.7) with axitinib vs 23.3 mo (18.1-33.2) with sorafenib (stratified HR, 0.995; 95%CI: 0.731-1.356; 1-sided P = 0.4883)	32% vs 15%; risk ratio 2.21; (95%CI: 1.31 to 3.75; stratified one-sided P = 0.0006)	Diarrhea (50%), hypertension (49%), weight decrease (40%), decreased appetite (29%), dysphonia (23%). Any grade events were more common n axitinib vs sorafenib ≥ 10%	[104,105]
Axitinib	TKI	Second	AXIS: Axitinibvssorafenib after 1 prior systemic therapy	8.3 mo (95%CI: 6.7 to 9.2) vs 4.7 mo (95%CI: 4.7 to 6.5); HR 0.656, 95%CI: 0.552 to 0.779; one sided P < 0.001	20.1 mo (95%CI: 16.7 to 23.4) vs 19.2 (95%CI: 17.5 to 22.3)	19% (95%CI: 15.4 to 23.9) vs 34% (95%CI: 6.6 to 12.9), P = 0.0001	Adverse events of all grades were more frequent with axitinib were hypertension, fatigue, dysphonia, and hypothyroidism. Adverse events more frequent with sorafenib with hand-foot syndrome, rash, alopecia, and anemia	[57,106]
Sorafenib	TKI	Second line	TARGET: Sorafenib vs placebo for patients who progressed on prior therapy	5.5 mo vs 2.8 mo	17.8 mo vs 14.3 mo, HR= 0.88; P = 0.146		Skin rash/ desquamation, hand foot skin reaction, fatigue. Hypertension and cardiac ischemia were rare but SAEs.	[107]
Cabozantinib	Inhibitor of multiple TKReceptors including MET, VEGFRs, and AXL	First	The Alliance A031203 CABOSUN Trial: Cabozantinib vs sunitinib	8.2 mo (95%CI: 6.2 to 8.8 mo) vs 5.6 mo (95%CI: 3.4 to 8.1 mo); Adjusted HR, 0.66; 95%CI: 0.46 to 0.95; one-sided P = 0.012	30.3 mo (95%CI: 14.6 to 35.0 mo) vs 21.8 mo (95%CI: 16.3 to 27.0 mo); Adjusted HR, 0.80; 95%CI: 0.50 to 1.26	33% (95%CI: 23% to 44%) vs 12% (95%CI: 5.4% to 21%)	Fatigue, hypertension, diarrhea, AST/ALT elevation	[62]
Cabozantinib		Second	METEOR: Cabozatinib vs everolimus for those that progressed on anti VEGF therapy	7.4 mo (95%CI: 5.6 to 9.1) vs 3.8 mo (95%CI: 3.7 to 5.4); HR 0.51 (95%CI: 0.41 to 0.62); P < 0.001	21.4 mo (95%CI: 18.7-not estimable) vs 16.5 mo (95%CI: 14.7 to 18.8); HR 0.66 (95%CI: 0.53 to 0.83; P = 0.00026)	17% (95%CI: 13 to 22) vs 3% (95%CI: 2 to 6), P < 0.0001	Grade 3 or 4 events were hypertension (15%), diarrhea (13%), fatigue (11%), palmar-plantar erythrodysaesthesia syndrome (8%)	[63,108]
Everolimus	mTOR Inhibitor	Third	RECORD-1: Patients who progressed on sunitinib, sorafenib, or both were given everolimus vs placebo	4.9 mo (95%CI: 3.7 to 5.5) vs 1.9 (95%CI: 1.8 to 1.9); HR 0.33, 95%CI: 0.25 to 0.43; P < 0.001	14.8 mo vs 14.4 mo; HR 0.87, 95%CI: 0.65 to 1.15; P = 0.162	1% vs 0%	Stomatitis (40% vs 8%), rash (25% vs 4%), fatigue (20% vs 16%), pneumonitis (8%)	[109,110]
Temsirolimus	mTOR Inhibitor	First	IFN-α-alone vs temosirolimus alone vs IFN-α+ temosirolimus1, poor risk patients with ≥ 3 of 6 unfavorable prognostic factors.	3.1 mo (95%CI: 2.2 to 3.8) vs 5.5 (95%CI: 3.9 to 7) vs 4.7 (95%CI: 3.9 to 5.8); (P < 0.001)	7.3 mo (95%CI: 6.1 to 8.8) vs 10.9 mo (95%CI: 8.6 to 12.7) vs 8.4 mo (6.6 to 10.3); HR for death, 0.73; 95%CI: 0.58 to 0.92; P = 0.008	4.8% (95%CI: 1.9 to 7.8) vs 8.6% (95%CI: 4.8 to 12.4) vs 8.1% (95%CI: 4.4 to 11.8); HR, 0.96; 95%CI: 0.76 to 1.20; P = 0.70)	Rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common in the temsirolimusgroup, asthenia was more common in the interferon group (26% vs 11%)	[33]
Temsirolimus	mTOR Inhibitor	Second	INTORSECT: Temsirolimus vs sorafenib as second line after treatment with sunitinib1 with response duration < 180 d	4.3 mo (95%CI: 4 to 5.4) vs 3.9 mo (95%CI: 2.8 to 4.2); Stratified HR = 0.87; 95%CI: 0.71 to 1.07; two-sided P = 0.19	12.3 mo (95%CI: 10.1 to 14.8) vs 16.6 mo (95%CI: 13.6 to 18.7); Stratified HR, 1.31; 95%CI: 1.05 to 1.63, P = 0.01 (two sided log-rank)	8% vs 8%	Rash and fatigue more commonly associated with temsirolimus and PPE + diarrhea higher in sorafenib group	[111]
Nivolumab	ICI- Anti PD-1 Inhibitor	Second	Checkmate 025: Nivolumab vs everolimus	4.6 mo (95%CI: 3.7 to 5.4) vs 4.4 mo (95%CI: 3.7 to 5.5); HR, 0.88; 95%CI: 0.75 to 1.03; P = 0.11	25.0 mo (95%CI: 21.8– NR for nivolumab) vs 19.6 mo (95%CI: 17.6–23.1)	25% vs 5%; odds ratio, 5.98 (95%CI: 3.68 to 9.72); P < 0.001	Fatigue	[66,67]

¹Not statistically significant. HR: Hazards Ratio; NR: Not reached; mAb: Monoclonal antibody; DFS: Disease-free survival; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival.