Targeted treatments in advanced renal cell carcinoma: focus on axitinib

Figures & data

Figure 1 Chemical structure of axitinib.

Table 1 IC₅₀ values determined by receptor phosphorylation assays

Target kinase	IC50 (nmol/L)	Assayed cells
VEGFR-1	0.06	HUVEC
VEGFR-2	0.1	HUVEC
VEGFR-3	0.1–0.3	PAE
PDGFR-β	2.9	NIH-3T3

Notes: IC₅₀ values were measured by immunoprecipitation/immunoblotting in the presence of 1% fetal bovine serum (HUVEC) or 0.1% fetal bovine serum (PAE or NIH3T3). The data were corrected for protein binding with the consideration that the presence of 2.3% bovine serum albumin typically shifted cellular IC₅₀ values up by a factor of ten. Reprinted from Clinical Cancer Research, 2008, 14(22), 7272–7283,³² Hu-Lowe D, Zou H, Grazzini M, et al, Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3, with permission from AACR. Copyright © 2008, American Association for Cancer Research.

Abbreviations: PAE, porcine aortic endothelial; PDGFR-β, platelet-derived growth factor receptor-beta; VEGFR, vascular endothelial growth factor receptor; HUVEC, human umbilical vein endothelial cells.

Figure 2 Mean steady-state plasma concentrations on day 15 of dosing (maximum concentration versus dose).

Note: Patson B, Cohen RB, Olszanski AJ, Expert Opinion on Drug Metabolism & Toxicology, 8(2):259–270.³⁰ Copyright © 2012, informa Healthcare. Reproduced with permission of informa Healthcare.
Abbreviations: bid, twice daily; qd, once daily; C_max, maximum concentration.

Table 2 Main CYP 3A4 inducers

Inducer	Reference
Carbamazepine	Yap et al,^Citation39 2008; Kiran,^Citation40 2011
Corticosteroids	Kiran,^Citation40 2011
Efavirenz	Kiran,^Citation40 2011
Felbamate	Yap et al,^Citation39 2008
Modafinil	Kiran,^Citation40 2011
Nevirapine	Kiran,^Citation40 2011
Omeprazole	Kiran,^Citation40 2011
Oxcarbazepine	Yap et al,^Citation39 2008; Kiran,^Citation40 2011
Phenobarbital	Yap et al,^Citation39 2008
Phenytoin/phosphophenytoin	Yap et al,^Citation39 2008; Kiran,^Citation40 2011
Primidone	Yap et al,^Citation39 2008; Kiran,^Citation40 2011
Rifabutin	Kiran,^Citation40 2011
Rifampin	Kiran,^Citation40 2011
St John’s wort (Hypericum perforatum)	Kiran,^Citation40 2011
Topiramate	Yap et al,^Citation39 2008

Figure 3 Maximum percentage tumor decrease of target lesions by Response Evaluation Criteria In Solid Tumors.

Notes: Bars represent individual patients. Zero represents baseline (no change); −100% represents potential complete response; greater than −30% represents potential partial response. Excludes four patients who progressed without post-baseline scans. Reprinted from The Lancet Oncology, vol 8, Rixe O, Bukowski RM, Michaelson MD, et al, Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study, Pages 975–984,⁴² Copyright © 2014, with permission from Elsevier.

Figure 4 Kaplan–Meier estimated median progression-free survival in patients who received axitinib or sorafenib as second-line therapy for metastatic renal cell cancer. (A) All patients, (B) patients previously treated with cytokine-based regimen, and (C) patients previously treated with sunitinib-based regimen (full analysis set, by independent review committee assessment).

Note: P-values based on one-sided, stratified log-rank test. Reprinted from The Lancet, Vol 378, Rini BI, Escudier B, Tomczak P, et al, Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial, Pages 1931–1939,²⁸ Copyright © 2011, with permission from Elsevier.
Abbreviations: HR, hazard ratio; PFS, progression-free survival; CI, confidence interval.

Table 3 Treatment-related adverse events in AGiLe 1046

	Axitinib (n=189)			Sorafenib (n=96)
	All grades, n (%)	Grade 3	Grade 4	All grades	Grade 3	Grade 4
Diarrhea	94 (50)	17 (9)	0	38 (40)	5 (5)	0
Hypertension	92 (49)	25 (13)	1	28 (29)	1 (1)	0
Weight decrease	69 (37)	16 (8)	0	23 (24)	3 (3)	0
Fatigue	62 (37)	9 (5)	1	25 (26)	1 (1)	0
Decreased appetite	54 (29)	4 (2)	0	18 (19)	0	0
PPE	50 (26)	14 (7)	0	37 (39)	15 (16)	0
Dysphonia	44 (23)	2 (1)	0	10 (10)	0	0
Asthenia	39 (21)	13 (7)	3	15 (16)	5 (5)	0
Hypothyroidism	39 (21)	0	0	7 (7)	0	0
Nausea	37 (20)	2 (1)	0	14 (15)	1 (1)	0
Rash	18 (10)	2 (1)	0	19 (20)	1 (1)	0

Abbreviation: PPE, palmar-plantar erythrodysesthesia.

Hu-LoweDZouHGrazziniMNonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3Clin Cancer Res200814227272728319010843

 PubMed Web of Science ®Google Scholar

PatsonBCohenRBOlszanskiAJPharmacokinetic evaluation of axitinibExpert Opin Drug Metab Toxicol20128225927022248343

 PubMed Web of Science ®Google Scholar

YapKYChuiWKChanADrug interactions between chemotherapeutic regimens and antiepilepticsClin Ther20083081385140718803983

 PubMed Web of Science ®Google Scholar

KiranPTypical drug interactions in oncologyUS Pharm201136179

 Google Scholar

RixeOBukowskiRMMichaelsonMDAxitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II studyLancet Oncol200781197598417959415

 PubMed Web of Science ®Google Scholar

RiniBIEscudierBTomczakPComparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trialLancet201137898071931193922056247

 PubMed Web of Science ®Google Scholar