Combination drug regimens for metastatic clear cell renal cell carcinoma

Table 1 Renal cell carcinoma prognostic models

Model	Prognostic factors	Prognostic risk groups
Memorial Sloan Kettering Cancer Center[6]	(1) Interval from diagnosis to treatment of less than 1 year; (2) Karnofsky performance status less than 80%; (3) Serum lactate dehydrogenase greater than 1.5 times the upper limit of normal (ULN); (3) Corrected serum calcium greater than the ULN; and (4) Serum hemoglobin less than the lower limit of normal	(1) Low-risk group: No prognostic factors; (2) Intermediate-risk group: One or two prognostic factors; and (3) Poor-risk group: Three or more prognostic factors
International Metastatic RCC Database Consortium[7]	(1) Less than one year from time of diagnosis to systemic therapy; (2) Performance status < 80% (Karnofsky); (3) Hemoglobin < lower limit of normal; (4) Calcium > upper limit of normal; (5) Neutrophil > upper limit of normal; and (6) Platelets > upper limit of normal	(1) Favorable-risk group: No prognostic factors; (2) Intermediate-risk group: One or two prognostic factors; and (3) Poor-risk group: Three to six prognostic factors
Tumor, Nodes, Metastasis Staging System for Kidney Cancer[5]	(A) Primary tumor (T): (1) Primary tumor cannot be assessed (TX); (2) No evidence of primary tumor (T0); (3) Tumor ≤ 7 cm in greatest dimension, limited to the kidney (T1); (4) Tumor > 7 cm in greatest dimension, limited to the kidney (T2); (5) Tumor extends into major veins or perinephric tissues, but not into the ipsilateral adrenal gland and not beyond Gerota’s Fascia (T3); and (6) Tumor invades beyond Gerota’s fascia (including contiguous extension into the ipsilateral adrenal gland) (T4); (B) Regional Lymph Nodes (N): (1) Regional lymph nodes cannot be assessed (NX); (2) No regional lymph node metastasis (N0); and (3) Metastasis in regional lymph node(s) (N1); and (C) Distant Metastasis (M): (1) No distant metastasis (M0); and (2) Distant metastasis (M1)	Stage I: T: T1; N: N0; M: M0; Stage II: T: T2; N: N0; M: M0; Stage III: T: T1-T2; N: N1; M: M0; and T: T3; N: NX,N0-N1; M: M0; Stage IV: T: T4; N: Any N; M: M0; and T: Any T; N: Any N; M: M1

RCC: 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.

Table 3 Unsuccessful combination therapy trials

Combination therapy	TrialPhase	Comparator	Side-effect profile	Comments	Ref.
Bevacizumab + sunitinib	I	3 cohorts of escalating doses of Sunitinib	High degree of hypertension, vascular and hematologic toxicities, leading to discontinuation in 48%		[30]
Bevacizumab + everolimus	II		Increased proteinuria, pulmonary embolism, stomatitis and anorexia leading to discontinuation in 14%		[31]
Everolimus + sorafenib	I		Discontinuation due to high gastrointestinal toxicity and grade 3 rash		[32]
Temsirolimus + IFN-α	III	IFN-α		Failed to improve overall survival	[33]
Tremelimumb + sunitinib	I		Rapid onset renal failure		[34]

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.

Table 5 Ongoing phase 3 trials of combination therapy in renal cell carcinoma

Treatment	Trial name	ClinicalTrials.gov No.	Enrollment	Primary endpoint	Status
Nivolumab-cabozantinib vs sunitinib	CheckMate 9ER	NCT03141177	630	PFS	Estimated primary completion date: January 2020
Lenvatinib-everolimus or lenvatinib-pembrolizumab vs sunitinib	CLEAR	NCT02811861	1050	PFS	Estimated primary completion date: April 2020
Nivolumab-ipilimumab followed by nivolumab vs nivolumab-cabozantinib	NCI-2018-03694	NCT03793166	1046	OS	Estimated primary completion date: September 2021
NKTR-214-nivolumab vs sunitinib or cabozantinib	CA045002	NCT03729245	600	ORR	Estimated primary completion date: December 2021
Pazopanib-abexinostat vs pazopanib	XYN-602	NCT03592472	413	PFS	Estimated primary completion date: January 2022
Nivolumab-ipilimumab vs placebo	CheckMate 914	NCT03138512	800	DFS	Estimated primary completion date: September 2022
Nivolumab-ipilimumab vs nivolumab	CA209-8Y8	NCT03873402	418	PFS	Estimated primary completion date: December 2022

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