Tivozanib in the treatment of renal cell carcinoma

Figures & data

Table 1 Receptor tyrosine kinase inhibitory activity at 50% of US Food and Drug Administration-approved TKIs in cell-free kinase assay (IC50)

TKI	Tivozanib	Axitinib	Sunitinib	Pazopanib	Sorafenib
VEGFR-1	30	ND	21	7	9
VEGFR-2	6.5	0.2	34	15	28
VEGFR-3	15	ND	3	2	7
PDGFR-B	49	1.6	75	215	1129
c-Kit	78	1.7	40	48	1862
FGFR-1	530	ND	437	80	64

Abbreviations: c-Kit, stem cell factor receptor; FGFR, fibroblast growth factor receptor; IC50, half-maximal inhibitory concentration; ND, not determined; PDGFR-B, platelet-derived growth factor receptor, beta; TKI, tyrosine kinase inhibitors; VEGFR, vascular endothelial growth factor.

Table 2 Overall radiologic response to tivozanib among patient subgroups

Patient group	Patient number	Median PFS (months)	ORR (%)	Duration of response (months)
All patients	272	11.7 (95% CI, 8.3–14.3)	24 (95% CI, 19–30)	16.1 (95% CI, 9.3–19.6)
Clear cell RCC	226	12.5 (95% CI, 9.0–17.7)	26 (95% CI, 19–30)	17.8 (95% CI, 12.0–21.0)
Clear cell RCC and prior nephrectomy	176	14.8 (95% CI, 10.3–19.2)	30 (95% CI, 23–37)	16.1 (95% CI, 11.2–19.6)

Abbreviations: CI, confidence interval; ORR, objective response rate; PFS, progression-free survival; RCC, renal cell carcinoma.

Table 3 Adverse events and laboratory abnormalities

Adverse event	All grades (%)	Grade 1/2 (%)	Grade 3/4 (%)
Hypertension	45	31	12
Dysphonia	22	22	0
Asthenia	10	7	3
Diarrhea	12	10	2
Fatigue	8	6	2
Hand–foot syndrome	4	4	<1
Stomatitis	4	6	<1
ALT elevation	29	28	1
AST elevation	27	26	1
Direct bilirubin	24	22	2

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

Table 4 Phase III trials utilizing VEGF inhibitors or VEGF antibodies in advanced RCC survival and toxicity data

Trial	Arms	N	MSKCC prognostic risk:^Citation76 Favorable Intermediate Poor	Toxicity all grades†		OS PFS ORR (CR + PR) CR
Motzer et al^Citation15,Citation51,Citation77	Tivozanib	260	27% versus 34%	Diarrhea	22%	28.8 versus 29.3 months
Phase III	Sorafenib	257	67% versus 62%	Fatigue	18%	11.9 versus 9.1 months
			7% versus 4%	HFS	13%	33% versus 23%
				HTN	44%	1% versus 1%
Escudier et al^Citation78	Sorafenib	451	NR	Diarrhea	43%	19.3 versus 15.9 months
Phase III	Placebo	452	48% versus 49%	Fatigue	37%	5.5 versus 2.8 months*
			52% versus 50%	HFS	30%	11% versus 2%*
				HTN	2%	<1% versus 0%
Motzer et al^Citation11	Sunitinib	375	38% versus 34%	Diarrhea	53%	26.4 versus 21.8 months
Phase III	INF-α	375	56% versus 59%	Fatigue	51%	11 versus 5 months*
			6% versus 7%	HFS	20%	47% versus 12%*
				HTN	24%	0% versus 0%
Escudier et al^Citation79	Bevacizumab + INF-α	327	27% versus 29%	Diarrhea	20%	23.3 versus 21.3 months
Phase III	Placebo + INF	322	56% versus 56%	Fatigue	33%	10.2 versus 5.4 months*
			9% versus 8%	HFS	NR	31% versus 13%*
				HTN	26%	1% versus 2%
Rini et al^Citation80	Bevacizumab + INF-α	369	26% versus 26%	Diarrhea	NR	18.3 versus 17.4 months
Phase III	INF	363	64% versus 64%	Fatigue	93%	8.5 versus 5.2 months*
			10% versus 10%	HFS	NR	13% versus 9%
				HTN	28%	<1% versus <1%
Sternberg et al^Citation81	Pazopanib	290	39% versus 39%	Diarrhea	52%	22.9 versus 20.5 months
Phase III	Placebo	145	55% versus 53%	Fatigue	40%	9.2 versus 4.2 months*
			3% versus 3%	HFS	<10%	30% versus 3%*
				HTN	40%	<1% versus 0%
Rini et al^Citation82	Axitinib	361	28% versus 28%	Diarrhea	55%	Not reported
Phase III	Sorafenib	362	37% versus 36%	Fatigue	39%	6.7 versus 4.7 months*
			33% versus 33%	HFS	27%	19% versus 9%*
				HTN	40%	0% versus 0%

Notes:

* Not significant;

† toxicity for agent in the intervention arm.

Abbreviations: CR, complete response; HFS, hand–foot syndrome; HTN, hypertension; INF, interferon; MSKCC, Memorial Sloan-Kettering Cancer Center; N, number; NR, not reported; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; RCC, renal cell carcinoma; VEGF, vascular endothelial growth factor.

Table 5 Phase III trials utilizing VEGF inhibitors or VEGF antibodies in advanced RCC discontinuation data

Trial	Arms	N	Reasons to discontinue therapy
			PD or death		Toxicity		Patient choice
			N	%	N	%	N	%
Motzer et al^Citation15,Citation77	Tivozanib	260	189	72	4	1	NR	NR
Phase III	Sorafenib	257	226	87	5	2	NR	NR
Escudier et al^Citation78	Sorafenib	451	246	55	18	4	7	2
Phase III	Placebo	452	300	66	17	4	11	2
Motzer et al^Citation11	Sunitinib	375	92	25	30	8	4	1
Phase III	INF-α	375	170	45	47	13	16	4
Escudier et al^Citation79	Bevacizumab + INF-α	327	151	46	86	26	10	10
Phase III	Placebo + INF-α	322	224	70	32	10	11	11
Rini et al^Citation80	Bevacizumab + INF-α	369	200	54	85	23	40	11
Phase III	INF-α	363	218	60	66	18	33	3
Sternberg et al^Citation81	Pazopanib	290	158	54	41	14	18	6
Phase III	Placebo	145	121	83	5	3	4	4
Rini et al^Citation82	Axitinib	361	172	48	22	6	10	3
Phase III	Sorafenib	362	193	53	33	9	7	2

Abbreviations: INF, interferon; N, number; NR, not reported; PD, progressive disease; RCC, renal cell carcinoma; VEGF, vascular endothelial growth factor.

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