New advancements and developments in treatment of renal cell carcinoma: focus on pazopanib

Figures & data

Figure 1 Key molecular pathways in renal cell carcinoma pathogenesis and the points at which the currently approved agents function.

Abbreviations: HIF, hypoxia inducible factor; RCC, renal cell carcinoma; PDGF, platelet-derived growth factor; TK, tyrosine kinase; VEGF, vascular endothelial growth factor; VHL, von Hippel-Lindau protein.

Table 1 Kinase inhibitory concentrations (IC₅₀, nmol) for multitargeted tyrosine kinase inhibitors for renal cell carcinoma (includes tivozanib and axitinib which are in Phase III study, but not yet approved) arranged in order of VEGFR2 potency

Drug	VEGFR1	VEGFR2	VEGFR3	PDGF-α	PDGF-β	c-kit	Flt-3	RAF
Tivozanib^Citation36	0.21	0.16	0.24	–	1.72	1.63	–	–
Axitinib^Citation37	0.1	0.2	0.1–0.3	5	1.6	1.7	>1000	–
Sunitinib^Citation38	2	10	17	5–10	10	13	1–10	–
Pazopanib^Citation16	10	30	47	71	84	74	>2000	–
Sorafenib^Citation39	–	90	20	50–60	50–60	68	46	5–10

Abbreviations: PDGF, platelet-derived growth factor; VEGFR, vascular endothelial growth factor receptor.

Table 2 Toxicities of pazopanib from the Phase III study in renal cell carcinoma (n = 290) which occurred at a rate of 10% or more. The toxicities are arranged in order of the most common adverse (any grade) to the least common. Grade 3/4 toxicities with frequency of occurrence are listed as well

Adverse events	Any grade		Grade 3/4
	Number	%	Number	%
ALT elevation	152	53	35	12
AST elevation	152	53	23	8
Diarrhea	150	52	11	4
Hypertension	115	40	13	4
Hyperglycemia	115	41	2	1
Hair depigmentation	109	38	1	0
Leukopenia	103	37	0	0
Total bilirubin elevation	102	36	9	3
Hypophosphatemia	95	34	11	4
Neutropenia	94	34	4	1
Hypocalcemia	91	33	8	3
Thrombocytopenia	89	32	3	1
Hyponatremia	86	31	15	5
Lymphocytopenia	86	31	12	4
Nausea	74	26	2	1
Anorexia	65	22	6	2
Vomiting	61	21	7	2
Fatigue	55	19	7	2
Hypoglycemia	47	17	1	0
Asthenia	41	14	8	3
Abdominal pain	32	11	6	2
Hypomagnesemia	31	11	9	3
Headache	30	10	0	0

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Table 3 Results from Phase III trials of currently approved agents for the treatment of renal cell carcinoma

Study agent	Class	Comparator	Setting	Primary outcome	Overall survival benefit
Sorafenib	VEGF TKI	Placebo	Cytokine-pretreated	Improved PFS (5.5 versus 2.8 months)	No
Sunitinib	VEGF TKI	Interferon	Treatment-naïve	Improved PFS (11 versus 5 months)	No
Temsirolimus	mTOR inhibitor	Interferon	Treatment-naïve	Improved OS (10.9 versus 7.3 months)	Yes
Everolimus	mTOR inhibitor	Placebo	Prior TKI	Improved PFS (4.9 versus 1.9 months)	No
Bevacizumab-interferon	Monoclonal antibody to VEGF	Interferon	Treatment-naïve	Improved PFS (AVOREN, 10.2 versus 5.4 months; CALGB, 8.5 versus 5.2 months)	No
Pazopanib	VEGF TKI	Placebo	Treatment-naïve or cytokine-pretreated	Improved PFS (9.2 versus 4.2 months)	Data immature

Abbreviations: CALGB, Cancer and Leukemia Group B; VEGF, vascular endothelial growth factor; TKI, tyrosine kinase inhibitor; PFS, progression-free survival; OS, overall survival.

Table 4 Level 1 evidence for use of molecularly targeted agents in renal cell carcinoma showing potential treatment settings and agents which have a high level of clinical evidence supporting their use

Treatment setting	Agents with high level of evidence
Treatment-naïve, good- or intermediate-risk	Sunitinib
	Bevacizumab-interferon
	pazopanib
Treatment-naïve, poor-risk	Temsirolimus
Cytokine-refractory	Sorafenib
	pazopanib
Prior VEGF inhibitor or VEGF-refractory	Everolimus
Prior mTOR inhibitor	?

Abbreviation: VEGF, vascular endothelial growth factor.

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