Lessons from phase III clinical trials on anti-VEGF therapy for cancer

Nature Clinical Practice Oncology

Volumn 3, Issue 1, 2006, Pages 24-40

  Jain, Rakesh K ^a   Duda, Dan G ^a   Clark, Jeffrey W ^b   Loeffler, Jay S ^a  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b DANA FARBER CANCER INSTITUTE   (United States)

Author keywords

Anti vascular endothelial growth factor (anti VEGF); Antiangiogenic; Bevacizumab; Multitargeted; Normalization

Indexed keywords

AE 941; ALPHA INTERFERON; ANTINEOPLASTIC AGENT; ANTISENSE OLIGONUCLEOTIDE; BEVACIZUMAB; BIOLOGICAL MARKER; CETUXIMAB; DEHYDRODIDEMNIN B; FLUOROURACIL; FOLINIC ACID; ICS 283; IRINOTECAN; MONOCLONAL ANTIBODY; MONOCLONAL ANTIBODY IMC 18F1; OXALIPLATIN; PACLITAXEL; PEGAPTANIB; PROTEIN KINASE; PROTEIN KINASE INHIBITOR; PROTEIN TYROSINE KINASE INHIBITOR; RANIBIZUMAB; SORAFENIB; SUNITINIB; TB 403; TRASTUZUMAB; UNCLASSIFIED DRUG; UNINDEXED DRUG; VASCULOTROPIN; VASCULOTROPIN ANTIBODY; VASCULOTROPIN RECEPTOR; VATALANIB; VEGLIN;

ANGIOGENESIS; ANTIBODY SPECIFICITY; ASTHENIA; BLEEDING DISORDER; BONE MARROW SUPPRESSION; BREAST CANCER; CANCER CELL; CANCER CHEMOTHERAPY; CANCER SURVIVAL; CANCER THERAPY; CLINICAL TRIAL; COLORECTAL CANCER; CONGESTIVE HEART FAILURE; DIARRHEA; DIGESTIVE SYSTEM PERFORATION; DISEASE COURSE; DIZZINESS; DRUG CYTOTOXICITY; DRUG EFFICACY; DRUG ERUPTION; DRUG HALF LIFE; DRUG MECHANISM; DRUG SAFETY; DRUG SELECTIVITY; DRUG TARGETING; DRUG TOLERABILITY; ENDOTHELIUM CELL; FATIGUE; GASTROINTESTINAL STROMAL TUMOR; HAND FOOT SYNDROME; HUMAN; HYPERTENSION; INTESTINE PERFORATION; IONIZING RADIATION; KIDNEY CARCINOMA; LUNG CANCER; LUNG EMBOLISM; METASTASIS; MICROENVIRONMENT; MUCOSA INFLAMMATION; NAUSEA; NEUROPATHY; NEUTROPENIA; PRIORITY JOURNAL; PROTEINURIA; REVIEW; THROMBOCYTOPENIA; THROMBOEMBOLISM; THROMBOPHLEBITIS; THROMBOSIS; TUMOR VASCULARIZATION; VOMITING; WOUND HEALING IMPAIRMENT;

ANGIOGENESIS INHIBITORS; ANTIBODIES, MONOCLONAL; ANTINEOPLASTIC AGENTS; CLINICAL TRIALS, PHASE III; HUMANS; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; PROTEIN-TYROSINE KINASES; TUMOR MARKERS, BIOLOGICAL; VASCULAR ENDOTHELIAL GROWTH FACTORS;

EID: 30944446883     PISSN: 17434254     EISSN: 17434262     Source Type: Journal    
DOI: 10.1038/ncponc0403     Document Type: Review

References (95)

1. Folkman J (1971) Tumor angiogenesis: Therapeutic implications. N Engl J Med 285: 1182-1186
2. Carmeliet P and Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407: 249-257
3. Dvorak HF (2002) Vascular permeability factor/vascular endothelial growth factor: A critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 20: 4368-4380
4. Kerbel R and Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2: 727-739
5. Ferrara N et al. (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3: 391-400
6. Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438: 932-936
7. Jain RK (2005) Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science 307: 58-62
8. Bevacizumab (Avastin™) for Treatment of Solid Tumors: NCI Fact Sheet [http://www.cancer.gov/cancertopics/factsheet/AvastinFactSheet] (accessed in 24 November 2005)
9. Hurwitz H et al. (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350: 2335-2342
10. Miller KD et al. (2005) Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23: 792-799
11. [No authors listed] News in Brief (2005) Nat Rev Drug Discov 4: 448-449
12. Rini BI et al. (2005) Therapy targeted at vascular endothelial growth factor in metastatic renal cell carcinoma: Biology, clinical results and future development. BJU Int 96: 286-290
13. Branca MA (2005) Multi-kinase inhibitors create buzz at ASCO. Nat Biotechnol 23: 639
14. Fukumura D et al. (1998) Tumor induction of VEGF promoter activity in stromal cells. Cell 94: 715-725
15. Rafii S et al. (2002) Vascular and haematopoietic stem cells: Novel targets for anti-angiogenesis therapy? Nat Rev Cancer 2: 826-835
16. Ferrara N et al. (2003) The biology of VEGF and its receptors. Nat Med 9: 669-676
17. Gorski DH et al. (1999) Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res 59: 3374-3378
18. Bocci G et al. (2004) Increased plasma vascular endothelial growth factor (VEGF) as a surrogate marker for optimal therapeutic dosing of VEGF receptor-2 monoclonal antibodies. Cancer Res 64: 6616-6625
19. Willett CG et al. (2005) Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: Continued experience of a phase I trial in rectal cancer patients. J Clin Oncol 23: 8136-8139
20. Willett CG et al. (2004) Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10: 145-147
21. Sandler AB (2005) Clinical trials comparing carboplatin/paclitaxel with or without bevacizumab in patients with metastatic NSCLC. Lung Cancer Update 2: 6-10
22. Tuma RS (2005) Success of bevacizumab trials raises questions for future studies. J Natl Cancer Inst 97: 950-951
23. Chen HX (2004) Expanding the clinical development of bevacizumab. Oncologist 9 (Suppl 1): S27-S35
24. Rosen LS (2005) VEGF-targeted therapy: Therapeutic potential and recent advances. Oncologist 10: 382-391
25. Eskens FA (2004) Angiogenesis inhibitors in clinical development; where are we now and where are we going? Br J Cancer 90: 1-7
26. Mross K et al. (2005) Phase I clinical and pharmacokinetic study of PTK/ ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours. Eur J Cancer 41: 1291-1299
27. Hecht JR et al. (2005) A randomized, double-blind, placebo-controlled, phase III study in patients with metastatic adenocarcinoma of the colon or rectum receiving first-line chemotherapy with oxaliplatin/ 5-fluorouracil/leucovorin and PTK787/ZK222584 or placebo [abstract]. J Clin Oncol 23: LBA3
28. Wilhelm SM et al. (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64: 7099-7109
29. Marx J (2005) Cancer. Encouraging results for second-generation antiangiogenesis drugs. Science 308: 1248-1249
30. Beaumont J et al. (2005) Patient reported outcomes in a phase 2 trial of SU11248 for metastatic renal cell carcinoma [abstract #8167]. Proc Am Soc Clin Oncol
31. Slamon DJ et al. (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344: 783-792
32. Piccart-Gebhart MJ et al. (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353: 1659-1672
33. Romond EH et al. (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353: 1673-1684
34. Clark JW et al. (2005) Safety and pharmacokinetics of the dual action raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. Clin Cancer Res 11: 5472-5480
35. Midgley R and Kerr D (2005) Bevacizumab - current status and future directions. Ann Oncol 16: 999-1004
36. Moore M et al. (2005) Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann Oncol 16: 1688-1694
37. Motzer RJ et al. (2005) Phase 2 trials of SU11248 show antitumor activity in second-line therapy for patients with metastatic renal cell carcinoma (RCC) [abstract #4508]. Proc Am Soc Clin Oncol
38. Thomas AL et al. (2005) Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. J Clin Oncol 23: 4162-4171
39. Teicher BA (1996) A systems approach to cancer therapy. (Antioncogenics + standard cytotoxics - >mechanism(s) of interaction). Cancer Metastasis Rev 15: 247-272
40. Jain RK (2005) Antiangiogenic therapy for cancer: Current and emerging concepts. Oncology (Williston Park) 19 (Suppl): S7-S16
41. Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy. Nat Med 7: 987-989
42. Winkler F et al. (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, angiopoietin-1 and matrix metalloproteinases. Cancer Cell 6: 553-563
43. Ansiaux R et al. (2005) Thalidomide radiosensitizes tumors through early changes in the tumor microenvironment. Clin Cancer Res 11: 743-750
44. Huber PE et al. (2005) Trimodal cancer treatment: Beneficial effects of combined antiangiogenesis, radiation, and chemotherapy. Cancer Res 65: 3643-3655
45. Salnikov AV et al. (2005) Inhibition of TGF-beta modulates macrophages and vessel maturation in parallel to a lowering of interstitial fluid pressure in experimental carcinoma. Lab Invest 85: 512-521
46. Tong RT et al. (2004) Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 64: 3731-3736
47. Vosseler S et al. (2005) Angiogenesis inhibition by vascular endothelial growth factor receptor-2 blockade reduces stromal matrix metalloproteinase expression, normalizes stromal tissue, and reverts epithelial tumor phenotype in surface heterotransplants. Cancer Res 65: 1294-1305
48. Wildiers H et al. (2003) Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. Br J Cancer 88: 1979-1986
49. Segers J et al.: Potentiation of cyclophosphamide chemotherapy using the antiangiogenic drug thalidomide: Importance of optimal scheduling to exploit the normalization window of the tumor vasculature. Cancer Lett, in press
50. Morgan B et al. (2003) Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: Results from two phase I studies. J Clin Oncol 21: 3955-3964
51. Jain RK (2003) Molecular regulation of vessel maturation. Nat Med 9: 685-693
52. Izumi Y et al. (2002) Tumour biology: Herceptin acts as an anti-angiogenic cocktail. Nature 416: 279-280
53. Saltz LB et al. (2005) Randomized Phase II trial of Cetuximab/ Bevacizumab/Irinotecan (CBI) versus Cetuximab/Bevacizumab (CB) in Irinotecan-refractory colorectal cancer [abstract #3508]. Proc Am Soc Clin Oncol
54. Herbst RS et al. (2005) Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer. J Clin Oncol 23: 2544-2555
55. Hudis CA (2005) Clinical implications of antiangiogenic therapies. Oncology (Williston Park) 19 (Suppl): 26-31
56. Kim JJ and Tannock IF (2005) Repopulation of cancer cells during therapy: An important cause of treatment failure. Nat Rev Cancer 5: 516-525
57. Browder T et al. (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60: 1878-1886
58. Kerbel RS and Kamen BA (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4: 423-436
59. Garcia-Barros M et al. (2003) Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300: 1155-1159
60. Ch'ang HJ et al. (2005) ATM regulates target switching to escalating doses of radiation in the intestines. Nat Med 11: 484-490
61. Wey JS et al. (2005) Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines. Cancer 104: 427-438
62. Fan F et al. (2005) Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene 24: 2647-2653
63. Akagi M et al. (2003) Induction of neuropilin-1 and vascular endothelial growth factor by epidermal growth factor in human gastric cancer cells. Br J Cancer 88: 796-802
64. Bachelder RE et al. (2001) Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells. Cancer Res 61: 5736-5740
65. Klagsbrun, M et al. (2002) The role of neuropilin in vascular and tumor biology. Adv Exp Med Biol 515: 33-48
66. Kabbinavar F et al. (2003) Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21: 60-65
67. Ince WL et al. (2005) Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J Natl Cancer Inst 97: 981-989
68. Jubb AM et al. Impact of vascular endothelial growth factor-A expression, thrombospondin 2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J Clin Oncol, in press
69. Park JW et al. (2004) Rationale for biomarkers and surrogate end points in mechanism-driven oncology drug development. Clin Cancer Res 10: 3885-3896
70. Boucher Y et al. (1991) Interstitial hypertension in superficial metastatic melanomas in humans. Cancer Res 51: 6691-6694
71. Boucher Y et al. (1997) Interstitial fluid pressure in intracranial tumours in patients and in rodents. Br J Cancer 75: 829-836
72. Gutmann R et al. (1992) Interstitial hypertension in head and neck tumors in patients: Correlation with tumor size. Cancer Res 52: 1993-1995
73. Less JR et al. (1992) Interstitial hypertension in human breast and colorectal tumors. Cancer Res 52: 6371-6374
74. Milosevic M et al. (2001) Interstitial fluid pressure predicts survival in patients with cervix cancer independent of clinical prognostic factors and tumor oxygen measurements. Cancer Res 61: 6400-6405
75. Nathanson SD and Nelson L (1994) Interstitial fluid pressure in breast cancer, benign breast conditions, and breast parenchyma. Ann Surg Oncol 1: 333-338
76. Padera T et al. (2002) Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296: 1883-1886
77. Roh HD et al. (1991) Interstitial hypertension in carcinoma of uterine cervix in patients: Possible correlation with tumor oxygenation and radiation response. Cancer Res 51: 6695-6698
78. Dunst J et al. (1998) A 2-week pretreatment with 13-cis-retinoic acid + interferon-alpha-2a prior to definitive radiation improves tumor tissue oxygenation in cervical cancers. Strahlenther Onkol 174: 571-574
79. Verheul HM and Pinedo HM (1998) Tumor growth: A putative role for platelets? Oncologist 3: 2
80. Beaudry P et al. (2005) Differential effects of vascular endothelial growth factor receptor-2 inhibitor ZD6474 on circulating endothelial progenitors and mature circulating endothelial cells: Implications for use as a surrogate marker of antiangiogenic activity. Clin Cancer Res 11: 3514-3522
81. Bertolini F et al. (2003) Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res 63: 4342-4346
82. Shaked Y et al. (2005) Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; Implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell 7: 101-111
83. Collins JM (2005) Imaging and other biomarkers in early clinical studies: One step at a time or re-engineering drug development? J Clin Oncol 23: 5417-5419
84. Jennens RR et al. (2004) Complete radiological and metabolic response of metastatic renal cell carcinoma to SU5416 (semaxanib) in a patient with probable von Hippel-Lindau syndrome. Urol Oncol 22: 193-196
85. Liu G et al. (2005) Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: Results from a phase I study. J Clin Oncol 23: 5464-5473
86. Miller JC et al. (2005) Imaging angiogenesis: Applications and potential for drug development. J Natl Cancer Inst 97: 172-187
87. Chan LW et al. (2004) Urinary VEGF and MMP levels as predictive markers of 1-year progression-free survival in cancer patients treated with radiation therapy: A longitudinal study of protein kinetics throughout tumor progression and therapy. J Clin Oncol 22: 499-506
88. Moses MA et al. (1998) Increased incidence of matrix metalloproteinases in urine of cancer patients. Cancer Res 58: 1395-1399
89. Roy R et al. (2004) ADAM 12 cleaves extracellular matrix proteins and correlates with cancer status and stage. J Biol Chem 279: 51323-51330
90. Rugo HS et al. (2005) Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: Pharmacokinetic and clinical results. J Clin Oncol 23: 5474-5483
91. McShane LM et al. (2005) Identification of clinically useful cancer prognostic factors: What are we missing? J Natl Cancer Inst 97: 1023-1025
92. Mundhenke C et al. (2001) Tissue examination to monitor antiangiogenic therapy: A phase I clinical trial with endostatin. Clin Cancer Res 7: 3366-3374
93. Blann AD et al. (2005) Circulating endothelial cells. Biomarker of vascular disease. Thromb Haemost 93: 228-235
94. Kraft A et al. (1999) Vascular endothelial growth factor in the sera and effusions of patients with malignant and nonmalignant disease. Cancer 85: 178-187
95. Sack U et al. (2005) Vascular endothelial growth factor in pleural effusions of different origin. Eur Respir J 25: 600-604