Development of second-generation VEGFR tyrosine kinase inhibitors: Current status

Current Oncology Reports

Volumn 13, Issue 2, 2011, Pages 103-111

  Bhargava, Pankaj ^a   Robinson, Murray O ^a  

^a AVEO ONCOLOGY   (United States)

Author keywords

Angiogenesis; Axitinib; Cediranib; Growth factors; Pazopanib; Renal cell carcinoma; Sorafenib; Sunitinib; Tivozanib; Tyrosine kinase inhibitors; Vascular endothelial growth factor

Indexed keywords

ALPHA INTERFERON; ANTINEOPLASTIC AGENT; AXITINIB; BEVACIZUMAB; BRIVANIB ALANINATE; CARBOPLATIN; CEDIRANIB; CISPLATIN; DOCETAXEL; DOVITINIB; EVEROLIMUS; FLUOROURACIL; FOLINIC ACID; FULVESTRANT; GEMCITABINE; INTEDANIB; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MOTESANIB; OXALIPLATIN; PACLITAXEL; PAZOPANIB; PLACEBO; PROTEIN TYROSINE KINASE INHIBITOR; SORAFENIB; SUNITINIB; TEMSIROLIMUS; TIVOZANIB; UNINDEXED DRUG; VANDETANIB; VASCULOTROPIN RECEPTOR;

ABDOMINAL PAIN; ACUTE GRANULOCYTIC LEUKEMIA; ADVANCED CANCER; ANOREXIA; ARTHRALGIA; ASTHENIA; BILIARY TRACT CANCER; BINDING AFFINITY; BONE MARROW SUPPRESSION; BREAST CANCER; CANCER COMBINATION CHEMOTHERAPY; CASTRATION RESISTANT PROSTATE CANCER; CHEMOTHERAPY INDUCED EMESIS; COLORECTAL CANCER; DEHYDRATION; DESQUAMATION; DIARRHEA; DIGESTIVE SYSTEM CANCER; DOSE RESPONSE; DRUG APPROVAL; DRUG CHOICE; DRUG DOSE ESCALATION; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG POTENCY; DRUG SAFETY; DRUG SELECTIVITY; DRUG WITHDRAWAL; DRY SKIN; DYSPEPSIA; DYSPHONIA; DYSPNEA; FATIGUE; FEBRILE NEUTROPENIA; GASTROINTESTINAL SYMPTOM; GLIOBLASTOMA; HAIR DISCOLORATION; HAND FOOT SYNDROME; HEAD AND NECK CANCER; HEART MUSCLE ISCHEMIA; HEMATOLOGIC DISEASE; HEPATOBILIARY DISEASE; HUMAN; HYPERTENSION; HYPOTENSION; KIDNEY CARCINOMA; LEUKEMIA; LIMB PAIN; LIVER CELL CARCINOMA; LIVER DYSFUNCTION; LIVER TOXICITY; LUNG CANCER; LUNG NON SMALL CELL CANCER; LUNG SMALL CELL CANCER; LYMPHOCYTOPENIA; MELANOMA; METASTASIS; MONOTHERAPY; MUCOSA INFLAMMATION; MYALGIA; MYELODYSPLASTIC SYNDROME; NAUSEA; NEUTROPENIA; OPTIMAL DRUG DOSE; OVARY CANCER; PANCREAS CANCER; PERITONEUM CANCER; RASH; REVIEW; SIDE EFFECT; SOFT TISSUE SARCOMA; SOLID TUMOR; STOMACH CANCER; STOMATITIS; THROMBOCYTOPENIA; THYROID DISEASE; THYROID MEDULLARY CARCINOMA; UTERINE TUBE CARCINOMA; WEIGHT REDUCTION;

ANTINEOPLASTIC AGENTS; CARCINOMA, RENAL CELL; HUMANS; KIDNEY NEOPLASMS; PROTEIN KINASE INHIBITORS; RECEPTORS, VASCULAR ENDOTHELIAL GROWTH FACTOR;

EID: 79955829332     PISSN: 15233790     EISSN: None     Source Type: Journal    
DOI: 10.1007/s11912-011-0154-3     Document Type: Review

References (66)

1. Liekens S, De CE, Neyts J: Angiogenesis: regulators and clinical applications. Biochem Pharmacol 2001, 61:253-270. (Pubitemid 32126663)
2. Bergers G, Benjamin LE: Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003, 3:401-410. (Pubitemid 37328844)
3. Rini BI: Vascular endothelial growth factor-targeted therapy in renal cell carcinoma: current status and future directions. Clin Cancer Res 2007, 13:1098-1106.
4. Rini BI, Michaelson MD, Rosenberg JE, et al: Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumabrefractory metastatic renal cell carcinoma. J Clin Oncol 2008, 26:3743-3748. This is a phase 2 study demonstrating substantial antitumor activity with sunitinib in patients with bevacizumabrefractory metastatic RCC.
5. Valtola R, Salven P, Heikkila P, et al: VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am J Pathol 1999, 154:1381-1390. (Pubitemid 29226433)
6. Jia H, Bagherzadeh A, Bicknell R, et al: Vascular endothelial growth factor (VEGF)-D and VEGF-A differentially regulate KDR-mediated signaling and biological function in vascular endothelial cells. J Biol Chem 2004, 279:36148-36157. (Pubitemid 39100623)
7. Zhang F, Tang Z, Hou X, et al: VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis. Proc Natl Acad Sci USA 2009, 106:6152-6157.
8. Rini BI: Metastatic renal cell carcinoma: many treatment options, one patient. J Clin Oncol 2009, 27:3225-3234.
9. Kondo K, Kim WY, Lechpammer M, Kaelin WG, Jr: Inhibition of HIF2a is sufficient to suppress pVHL-defective tumor growth. PLoS Biol 2003, 1:439-444.
10. Maranchie JK, Vasselli JR, Riss J, et al: The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell 2002, 1:247-255. (Pubitemid 41039149)
11. Ferrara N, Hillan KJ, Gerber HP, Novotny W: Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004, 3:391-400. (Pubitemid 38618122)
12. Escudier B, Eisen T, Stadler WM, et al: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007, 356:125-134. This phase 3 randomized placebo-controlled study demonstrates prolongation of PFS with sorafenib treatment in advanced clear cell RCC that was resistant to standard therapy.
13. Motzer RJ, Hutson TE, Tomczak P, et al: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007, 356:115-124. This is a phase 3 randomized study demonstrating improved efficacy of sunitinib versus interferon-α against metastatic RCC.
14. Motzer RJ, Michaelson MD, Rosenberg J, et al: Sunitinib efficacy against advanced renal cell carcinoma. J Urol 2007, 178:1883-1887. (Pubitemid 47538608)
15. Sternberg CN, Davis ID, Mardiak J, et al: Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010, 28:1061-1068. This is a phase 3 randomized placebo-controlled study demonstrating improved PFS and tumor response with pazopanib in advanced RCC.
16. Shepard DR, Garcia JA: Toxicity associated with the long-term use of targeted therapies in patients with advanced renal cell carcinoma. Expert Rev Anticancer Ther 2009, 9:795-805.
17. Food and Drug Administration. NDA 22465: VOTRIENT™ (pazopanib) Tablets. Applicant: GlaxoSmithKline. FDA Presentation ODAC Meeting Oct. 5, 2009. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ Drugs/OncologicDrugsAdvisoryCommittee/UCM186336.pdf. Accessed October 28, 2010.
18. Nakamura K, Taguchi E, Miura T, et al: KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties. Cancer Res 2006, 66:9134-9142. (Pubitemid 44521133)
19. Eskens FALM, De Jonge MJA, Esteves B, et al: Updated results from a phase I study of AV-951 (KRN951), a potent and selective VEGFR-1, -2 and -3 tyrosine kinase inhibitor, in patients with advanced solid tumors. Proceedings of the 99th Annual Meeting of the American Association for Cancer Research, San Diego, CA; April 12-16, 2008.
20. Bhargava P, Esteves B, Al-Adhami M, et al: Activity of tivozanib (AV-951) in patients with renal cell carcinoma (RCC): subgroup analysis from a phase II randomized discontinuation trial (RDT). J Clin Oncol 2010, 28: Abstract 4599. This is a phase 2 study demonstrating antitumor activity and good tolerability of tivozanib in patients with RCC, particularly those with clear cell RCC who had undergone nephrectomy.
21. Nosov DA, Bhargava P, Esteves B, et al: Phase 2 randomized discontinuation trial (RDT) of tivozanib in patients with renal cell carcinoma (RCC): results in patients randomized to tivozanib vs. placebo [abstract 4906]. Presented at the 35th Annual Congress of the European Society for Medical Oncology, Milan, Italy; October 11-12, 2010. Phase 2 study results demonstrating significant efficacy for patients randomized to tivozanib versus placebo.
22. Bhargava P, Esteves B, Al-Adhami M, et al: Effect of hypertension, nephrectomy and prior treatment on the efficacy of tivozanib (AV-951) in a phase 2 randomized discontinuation trial (RDT) in patients with renal cell carcinoma (RCC) [abstract 342]. Presented at the American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, San Francisco, CA; March 5-7, 2010.
23. Fishman MN, Srinivas S, Hauke RJ, et al: Combination of tivozanib (AV-951) and temsirolimus in patients with renal cell carcinoma (RCC): preliminary results from a phase 1 trial. Mol Cancer Ther 2009, 8: Abstract B60.
24. Rugo HS, Herbst RS, Liu G, et al: Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol 2005, 23:5474-5483.
25. Rixe O, Bukowski RM, Michaelson MD, et al: Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol 2007, 8:975-984. This phase 2 study shows clinical activity of axitinib in metastatic RCC that did not respond to previous cytokine-based therapy.
26. Rini BI, Wilding G, Hudes G, et al: Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol 2009, 27:4462-4468. This is a phase 2 study demonstrating antitumor activity of axitinib in metastatic RCC that did not respond to prior VEGF-targeted therapy, including sorafenib.
27. Rixe O, Dutcher J, Motzer R, et al: Diastolic blood pressure (dBP) and pharmacokinetics (PK) as predictors of axitinib efficacy in metastatic renal cell cancer (mRCC). J Clin Oncol 2009, 27: Abstract 5045.
28. Cohen EE, Rosen LS, Vokes EE, et al: Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol 2008, 26:4708-4713. This is a phase 2 study demonstrating promising activity of axitinib in thyroid cancer.
29. Fruehauf JP, Lutzky J, McDermott DF, et al: Axitinib (AG-013736) in patients with metastatic melanoma: a phase II study. J Clin Oncol 2008, 26: Abstract 9006.
30. Schiller JH, Larson T, Ou SH, et al: Efficacy and safety of axitinib in patients with advanced non-small-cell lung cancer: results from a phase II study. J Clin Oncol 2009, 27:3836-3841. This is a phase 2 study showing antitumor activity and good tolerability of axitinib in advanced NSCLC.
31. Martin LP, Kozloff MF, Krzakowski M, et al: Axtinib (AG-013736; AG) combined with chemotherapy in patients (pts) with advanced non-small cell lung cancer (NSCLC) and other solid tumors. J Clin Oncol 2009, 27: Abstract 3559.
32. Rugo HS, Stopeck A, Joy AA, et al: A randomized, double-blind phase II study of the oral tyrosine kinase inhibitor (TKI) axitinib (AG-013736) in combination with docetaxel (DOC) compared to DOC plus placebo (PL) in metastatic breast cancer (MBC). J Clin Oncol 2007, 25: Abstract 1003.
33. Sharma S, Abhyankar V, Burgess RE, et al: A phase I study of axitinib (AG-013736) in combination with bevacizumab plus chemotherapy or chemotherapy alone in patients with metastatic colorectal cancer and other solid tumors. Ann Oncol 2010, 21:297-304.
34. Spano JP, Chodkiewicz C, Maurel J, et al: Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study. Lancet 2008, 371:2101-2108.
35. Kindler HL, Ioka T, Richel DJ, et al: A double-blinded, placebocontrolled, randomized, phase III study of axitinib (AG-013736; A) plus gemcitabine (G) vs. G plus placebo (P) in advanced pancreatic cancer (PC) patients (pts). Eur J Cancer Suppl 2009, 7:361. Abstract O-6502.
36. Lindsay CR, MacPherson IR, Cassidy J: Current status of cediranib: the rapid development of a novel anti-angiogenic therapy. Future Oncol 2009, 5:421-432.
37. Mulders P, Hawkins R, Nathan P, et al: Final results of a phase II randomised study of cediranib (RECENTIN™) in patients with advanced renal cell carcinoma (RCC). Eur J Cancer Suppl 2009, 7:21. Abstract 49LBA.
38. Sridhar SS, Mackenzie MJ, Hotte SJ, et al: Activity of cediranib (AZD2171) in patients (pts) with previously untreated metastatic renal cell cancer (RCC). A phase II trial of the PMH Consortium. J Clin Oncol 2008, 26: Abstract 5047.
39. Saura C, Baselga J, Herbst R, et al: Antitumor activity of cediranib in patients with metastatic or recurrent head and neck cancer (HNC) or recurrent non-small cell lung cancer (NSCLC): An open-label exploratory study. J Clin Oncol 2009, 27: Abstract 6023.
40. Batchelor TT, Duda DG, di TE, et al: Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol 2010, 28:2817-2823.
41. Matulonis UA, Berlin S, Ivy P, et al: Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol 2009, 27:5601-5606.
42. Adelberg D, Karakunnel JJ, Gulley JL, et al: A phase II study of cediranib in post-docetaxel, castration-resistant prostate cancer (CRPC) [abstract 63]. Presented at the American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, San Francisco, CA; March 5-7, 2010.
43. Gadgeel SM, Wozniak A, Edelman MJ, et al: Cediranib, a VEGF receptor 1, 2, and 3 inhibitor, and pemetrexed in patients (pts) with recurrent non-small cell lung cancer (NSCLC). J Clin Oncol 2009, 27: Abstract e19007.
44. Goss GD, Arnold A, Shepherd FA, et al: Randomized, double-blind trial of carboplatin and paclitaxel with either daily oral cediranib or placebo in advanced non-small-cell lung cancer: NCIC Clinical Trials Group BR24 study. J Clin Oncol 2010, 28:49-55.
45. Dy GK, Mandrekar SJ, Nelson GD, et al: A randomized phase II study of gemcitabine (G) and carboplatin (C) with or without cediranib (AZD2171 [CED]) as first-line therapy in advanced non-small cell lung cancer (NSCLC). J Clin Oncol (Meeting Abstracts) 2010, 28:7603.
46. Ramalingam SS, Belani CP, Mack PC, et al: Phase II study of cediranib (AZD 2171), an inhibitor of the vascular endothelial growth factor receptor, for second-line therapy of small cell lung cancer. J Thorac Oncol 2010, 5:1279-1284.
47. AstraZeneca. RECENTIN did not meet primary endpoint in Horizon III study in metastatic colorectal cancer. http://www.astrazeneca.com/media/latest-press- releases/2010-new/recoentinhorizon?itemId=8748245. Accessed August 5, 2010.
48. Hyams DM, de Oliveira C, Snyder R, et al: Cediranib in combination with fulvestrant in hormone-sensitive metastatic breast cancer: a phase II randomized study [abstract 204]. Presented at the 32nd Annual San Antonio Breast Cancer Symposium, San Antonio, TX; December 9-13, 2009.
49. Hilberg F, Roth GJ, Krssak M, et al: BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 2008, 68:4774-4782.
50. Ledermann JA, Rustin GJ, Hackshaw A, et al: A randomized phase II placebo-controlled trial using maintenance therapy to evaluate the vascular targeting agent BIBF 1120 following treatment of relapsed ovarian cancer (OC). J Clin Oncol 2009, 27: Abstract 5501.
51. Chow LQ, Laurie SA, Belani CP, et al: Phase I trial of BMS-690514 in combination with paclitaxel/carboplatin (PC) in patients with advanced or metastatic solid tumors. J Clin Oncol 2010, 28: Abstract 2547.
52. Cai ZW, Zhang Y, Borzilleri RM, et al: Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f] [1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215). J Med Chem 2008, 51:1976-1980.
53. Raoul JL, Finn RS, Kang YK, et al: An open-label phase II study of first- and second-line treatment with brivanib in patients with hepatocellular carcinoma (HCC). J Clin Oncol 2009, 27: Abstract 4577.
54. Angevin E, Grunwald V, Lin C-C, et al: A phase I/II study of TKI258 (dovitinib), a FGFR and VEGFR inhibitor, in patients (pts) with advanced or metastatic renal cell cancer (mRCC): preliminary phase II results. Ann Oncol 2010, 21: Abstract 507P.
55. Kim KB, Saro J, Moschos SS, et al: A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanoma. J Clin Oncol 2008, 26: Abstract 9026.
56. Blumenschein GR, Kabbinavar FF, Menon H, et al: Randomized, open-label phase II study of motesanib or bevacizumab in combination with paclitaxel and carboplatin (P/C) for advanced nonsquamous non-small cell lung cancer (NSCLC). J Clin Oncol 2010, 28:7528.
57. Price TJ, Lipton L, McGreivy J, et al: Safety and pharmacokinetics of motesanib in combination with gemcitabine for the treatment of patients with solid tumours. Br J Cancer 2008, 99:1387-1394.
58. Morabito A, Piccirillo MC, Falasconi F, et al: Vandetanib (ZD6474), a dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinases: current status and future directions. Oncologist 2009, 14:378-390.
59. Ko AH, Tabernero J, Garcia De Paredes M, et al: Phase II study of telatinib (T) in combination with capecitabine (X) and cisplatin (P) as first-line treatment in patients (pts) with advanced cancer of the stomach (G) or gastro-esophageal junction (GEJ). J Clin Oncol 2010, 28: Abstract e14575.
60. Kies MS, Blumenschein GR, Jr., Christensen O, et al: Phase I study of regorafenib (BAY 73-4506), an inhibitor of oncogenic and angiogenic kinases, administered continuously in patients (pts) with advanced refractory non-small cell lung cancer (NSCLC). J Clin Oncol 2010, 28: Abstract 7585.
61. Cook N, Basu B, Biswas S, et al: A phase 2 study of vatalanib in metastatic melanoma patients. Eur J Cancer 2010, 46:2671-2673.
62. SUTENT® (sunitinib malate) capsules, oral [package insert]. New York, NY: Pfizer Inc, 2010.
63. NEXAVAR (sorafenib) tablets, oral [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc, 2009.
64. Chow LQ, Eckhardt SG: Sunitinib: from rational design to clinical efficacy. J Clin Oncol 2007, 25:884-896. (Pubitemid 350002890)
65. Ratain MJ, Eisen T, Stadler WM, et al: Phase II placebocontrolled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2006, 24:2505-2512. (Pubitemid 46630627)
66. Sloan B, Scheinfeld NS: Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy. Curr Opin Investig Drugs 2008, 9:1324-1335.