Critical appraisal of pazopanib as treatment for patients with advanced metastatic renal cell carcinoma

Figures & data

Figure 1 Flow diagram illustrating decision factors and therapeutic alternatives in patients with locally advanced and metastatic renal cell carcinoma.

Figure 2 Molecular structure and chemical name of pazopanib.²¹

Table 1 In vitro activity of pazopanib in purified human kinase and cell-based receptor assays²⁴

	Activity against purified kinasesa	Cellular IC50: inhibition of ligand-induced receptor autophosphorylationb
Kinase or receptor	Pazopanib (nM)	Cells	Pazopanib IC50 (nM)
VEGFR1	15	ND	ND
VEGFR2	8	HUVEC	8
VEGFR3	10	ND	ND
PDGFRα	30	HFF	3
PDGFRβ	14	ND	ND
c-Kit	2.4	NCI-H526	2.6
Flt-3	230	RS4;11	≥1,000

a Notes: Tyrosine kinase inhibitors tested in a panel of kinases at 03 and 10.0 μM utilizing Profile Express (Millipore, Billerica, MA);

b cellular inhibitory activity of tyrosine kinase inhibitors against wild-type receptors on cells noted employing autophosphorylation inhibition.

Abbreviations: IC, inhibitory concentrations; VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet derived growth factor receptor; HUVEC, human umbilical vein endothelial cells; ND, not done.

Table 2 Progression free survival in frontline metastatic renal cell cancer randomized trials

Clinical trial/Agent or regimen	Sunitinib vs IFN-α^Citation15 (n = 750)	Bevacizumab+ IFN-α vs IFN-α		Pazopanib vs placebo^Citation17 (n = 233)	Sorafenib vs IFN-α^Citation32 (n = 189)	Sorafenib ± AMG386^Citation33 (3.0, 10 mg)
		Avoren^Citation20 (n = 151) (n = 649)	CALGB 90206^Citation31 (n = 732)
Sunitinib, bevacizumab + IFN-α, sorafenib, pazopanib	11.0 mos	10.2 mos	8.5 mos	11.1 mos	5.7 mos	9.0 mos
INF-α, placebo, AMG 386 + sorafenib	5.0 mos	5.4 mos	5.2 mos	2.8 mos	5.6 mos	8.5, 9.0 mos
P value	<0.001	<0.0001	<0.0001	<0.0001	0.504	0.532

Abbreviation: INF-α, interferon-alpha.

Table 3 Overall survival in randomized trials: frontline metastatic renal cell cancer patients

Clinical trial/Agent or regimen	Sunitinib vs IFN-α^Citation34	AVOREN^Citation35	CALGB 90206^Citation36	Sorafenib vs IFN-α^Citation32	Pazopanib vs placebo^Citation29
Sunitinib, bevacizumab+ IFN-α, pazopanib	26.4 mos	23.3 mos	18.3 mos	NR	22.9 mos
INF-α, placebo	21.8 mos	21.3 mos	17.4 mos	NR	20.5 mos
P value	0.051	0.1291	0.069	NA	0.224
Hazard ratio (95% CI)	0.821 (0.673, 1.001)	0.91 (0.76, 1.10)	0.86 (0.73, 1.01)	NA	0.91 (0.71, 1.16)

Abbreviations: CI, confidence interval; INF-α, interferon-alpha; mos, months.

Figure 3 Comparison of progression free survival data from recent phase II and II randomized clinical trials utilizing a variety of targeted agents in treatment-naïve or cytokine refractory patients with metastatic renal cell carcinoma.

Notes: ^apatient number; ^bhazard ratio (95% confidence interval).

Table 4 Phase II trial pazopanib in patients refractory to sunitinib or bevacizumab⁴⁰

	All patients	Previous sunitinib	Previous bevacizumab
Number	44	32	12
ORR	9 (20%)	5 (16%)	4 (33%)
DCR (CR + PR + SD)	31 (77%)	21 (66%)	10 (83%)
Median PFS (months)	9.23 (95% CI: 5.42, NA)	12.06 (95% CI: 6.14, NA)	8.05 (95% CI: 2.76, 11.93)

Abbreviations: CI, confidence interval; ORR, overall response rate; DCR, disease control rate; NA, not available, PFS, progression free survival; CR, complete response; PR, partial response; SD, stable disease.

Table 5 Genotypes for single nucleotide polymorphisms associated with pazopanib efficacy^45,46

Polymorphisms		Progression free survival		Overall survival
		Median (weeks)	P value	Median (mos)	P value
IL-8	AA	48	0.009	29.6	0.002
2767 A>T	TT	27		14.8
HIF1A	GG	44	0.03	NA	–
1790 G>A	TT	20		NA
VEGFA	GG	NA	–	25.3	0.004
1154 A>G	AA	NA		16.7
NR1l2	CC	48	0.07	NA	–
−25385 C>T	TT	58		NA

Abbreviations: HIF1A, Hypoxia-inducible factor 1, alpha subunit; IL-8, interlukin-8; NA, not available; VEGFA, vascular endothelial growth factor A.

Table 6 Phase II trial of pazopanib versus placebo in metastatic renal cell carcinoma – selected adverse events and clinical chemistry abnormalities^17,29,30

	Pazopanib		Placebo
	All grades	≥grade 3	All grades	≥grade 3
Adverse event
Any event	92%	41%	74%	20%
Diarrhea	52%	4%	9%	<1%
Hypertension	40%	4%	10%	1%
Hair color changes	38%	<1%	3%	0
Nausea	26%	<1%	9%	0
Vomiting	21%	2%	8%	2%
Fatigue	19%	2%	8%	2%
Asthenia	14%	3%	8%	0
Bleeding	13%	2%	5%	0
Hand-foot	6%	NS	<1%	NS
Headache	10%	0	5%	0
Chemistry
Increased ALT	53%	12%	22%	1%
Increased AST	53%	8%	19%	<1%
Hyperglycemia	41%	<1%	33%	1%
Increased bilirubin	36%	4%	10%	2%
Hypophosphatemia	34%	4%	11%	0
Hypocalcemia	33%	2%	26%	1%
Hypoglycemia	17%	<1%	3%	0
Neutropenia	34%	2%	2%	0
Thrombopenia	32%	1%	5%	<1%
Proteinuria	9%	NS	0	NS

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; NS, not stated.

Table 7 Selected adverse events (all grades and ≥grade 3): sunitinib, bevacizumab + IFN-α, and pazopanib pivotal trials

Treatment setting/Adverse event	First-line		First-line		First/second line
	Sunitinib^Citation15,Citation34		Bevacizumab + IFN-α^Citation20		Pazopanib^Citation17,Citation29,Citation30
	All grades (%)	≥grade 3 (%)	All grades (%)	≥grade 3 (%)	All grades (%)	≥grade 3 (%)
Fatigue	54	11	33	12	20	2
Asthenia	20	7	32	10	14	3
Diarrhea	61	9	20	2	52	4
Hemorrhage	18a	1	33	3	14b	1
Hand-foot syndrome	29	9	–	–	6	<1
Hypertension	30	12	26	3	40	4
Decline LVEF	13	3	NS	NS	<1	<1
Neutropenia	77	18	7	4	36	1
Thrombocytopenia	68	9	6	2	34	1
Increased ALT	51	3	NS	NS	53	13
Increased AST	56	2	NS	NS	53	8
Increased total bilirubin	20	1	NS	NS	36	4
Discontinuations due to adverse events	19		19c		14

a Notes: Epistaxsis;

b all causes;

c bevacizumab discontinuation rate, rate for either agent 28%.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; INF-α, interferon-alpha; LVEF, left ventricular ejection fraction; NS, not stated.

LiuDQChenTKMcGuireMAKordASAnalytical control of genotoxic impurities in the pazopanib hydrochloride manufacturing processJ Pharm Biomed Anal.200950214415019427156

 PubMed Web of Science ®Google Scholar

KumarRKnickVBRudolphSKPharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activityMol Cancer Ther.2007672012202117620431

 PubMed Web of Science ®Google Scholar

MotzerRJHutsonTETomczakPSunitinib versus interferon alfa in metastatic renal-cell carcinomaN Engl J Med.2007356211512417215529

 PubMed Web of Science ®Google Scholar

SternbergCNDavisIDMardiakJPazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trialJ Clin Oncol.20102861061106820100962

 PubMed Web of Science ®Google Scholar

EscudierBSzczylikCHutsonTERandomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinomaJ Clin Oncol.20092781280128719171708

 PubMed Web of Science ®Google Scholar

RiniBISzczylikCTannirNMAMG 386 in combination with sorafenib in patients (pts) with metastatic renal cell cancer (mRCC): a randomized, double-blind, placebo-controlled, phase II studyJ Clin Oncol201129Suppl 7 abstract 309

 Web of Science ®Google Scholar

EscudierBPluzanskaAKoralewskiPBevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trialLancet.200737096052103211118156031

 PubMed Web of Science ®Google Scholar

RiniBIHalabiSRosenbergJEPhase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206J Clin Oncol.201028132137214320368558

 PubMed Web of Science ®Google Scholar

MotzerRJHutsonTETomczakPOverall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinomaJ Clin Oncol.200927223584359019487381

 PubMed Web of Science ®Google Scholar

EscudierBBellmuntJNegrierSPhase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survivalJ Clin Oncol.201028132144215020368553

 PubMed Web of Science ®Google Scholar

RiniBIHalabiSRosenbergJEBevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206J Clin Oncol.200826335422542818936475

 PubMed Web of Science ®Google Scholar

SternbergCNHawkinsRESzczylikCRandomized, double- blind phase III study of pazopanib in patients with advanced/metastatic renal cell carcinoma (MRCC): final overall survival (OS) resultsAnn Oncol201021Suppl 8 abstract LBA22

 Google Scholar

ReevesJASpigelDRDanielDBFriedmanEKBurrisHAHainsworthJDPazopanib in patients with metastatic renal cell carcinoma previously treated with sunitinib or bevacizumab: a Sarah Cannon Research Institute phase II trialJ Clin Oncol201129Suppl abstract 4659

 PubMedGoogle Scholar

XuCBingNXBallHAPazopanib efficacy in renal cell carcinoma: evidence for predictive genetic markers in angiogenesis-related and exposure-related genesJ Clin Oncol.201129182557256421576632

 PubMed Web of Science ®Google Scholar

XuCBallHABingNAssociation of genetic markers in angiogenesis- or exposure-related genes with overall survival in pazopanib (P) treated patients (Pts) with advanced renal cell carcinomaJ Clin Oncol201129Suppl 7 abstract 303

 Web of Science ®Google Scholar

SternbergCNHawkinsRESzczylikCA randomized, double-blind phase III study (VEG105192) of pazopanib (paz) versus placebo (pbo) in patients with advanced/metastatic renal cell carcinoma (mRCC): updated safety resultsJ Clin Oncol201129Suppl 7 abstract 313

 Web of Science ®Google Scholar