Current Treatment Options in Oncology

, Volume 8, Issue 1, pp 15–27 | Cite as

Role of Anti-angiogenesis Agents in Treating NSCLC: Focus on Bevacizumab and VEGFR Tyrosine Kinase Inhibitors

Lung Cancer

Opinion statement

Successful inhibition of angiogenesis with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has improved the efficacy seen with standard cytotoxic therapy in NSCLC. The addition of bevacizumab to first-line chemotherapy improved response rate and progression free survival and added 2 months to median overall survival for those patients with advanced stage NSCLC on the treatment arm of E4599. Bevacizumab is now a standard agent to add to frontline carboplatin and paclitaxel for patients with newly diagnosed NSCLC who meet the eligibility criteria from the landmark E4599 trial. Unfortunately about half of all patients are not eligible either because they have squamous histology, brain metastases, or are on anti-coagulation. Ongoing trials are further exploring the safety of bevacizumab in these patient populations, as well as in combination with other cytotoxic regimens. Exploration of other applications of bevacizumab in the second-line and adjuvant setting are ongoing as well. The largest class of drugs that block angiogenesis are the multi-targeted tyrosine kinase inhibitors (TKIs) that target the VEGF receptor (VEGFR). These drugs are still in development, and though two are now on the market for treating other malignancies, their role in NSCLC is under investigation. These agents have the advantages of hitting multiple targets, convenient oral administration, and potential for lower cost. Their lack of target specificity leads to unexpected toxicity, but also promising efficacy. For example, the overall objective response rate of 9.5% with single agent sunitinib compares similarly to that of pemetrexed or docetaxel in previously treated NSCLC patients, but toxicity, notably fatigue, lead to discontinuation in 38% of patients. Hypertension, hemorrhage and cavitation are common toxicities amongst this class of agents. Rash, fatigue, myalgia, and hand-foot syndrome are more specifically seen with TKIs. These compounds may also be synergistic or additive with traditional cytotoxic chemotherapy drugs and other novel compounds. In early trials sorafenib as a single agent has shown no clinical response in previously treated NSCLC patients, whereas clinical benefit in combination with erlotinib or chemotherapy has been seen in early studies. Vandetanib has demonstrated objective responses as a single agent and in combination with chemotherapy in previously treated NSCLC patients. A phase I trial of AZD2171 with carboplatin and paclitaxel in newly diagnosed advanced stage NSCLC also demonstrated promising results with 6 of 15 patients achieving partial responses. NSCLC specific trials are also underway, or in development for pazopanib, axitinib, AMG 706, XL647, enzastaurin, and other TKIs. Other anti-angiogenesis agents with different mechanisms of action include thalidomide and its derivatives, monoclonal antibodies to the VEGFRs, and VEGF Trap, a chimeric molecule which combines extracellular portions of VEGFR1 and VEGFR2 with the Fc portion of immunoglobulin G1 to form a molecule that binds and “traps” VEGF. Despite modest improvements, prognosis continues to be poor for patients with advanced NSCLC. Bevacizumab is a first step into the world of angiogenesis inhibitors for NSCLC and though it only offers a modest survival benefit in a limited patient population, it paves the way for the development of the next generation of anti-angiogenesis inhibitors. We can hope that further improvements in survival will follow.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: •Of importance ••Of major importance

  1. 1.
    Jemal A, Siegel R, Ward E, et al.: Cancer statistics, 2006. CA Cancer J Clin 2006, 56:106–130PubMedCrossRefGoogle Scholar
  2. 2.
    Mountain C: Revisions in the international system for staging lung cancer. Chest 1997, 111:1710–1717PubMedGoogle Scholar
  3. 3.•
    Folkman J: Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg 1972, 175:409–416PubMedCrossRefGoogle Scholar

First description of anti-angiogenesis as a potential anti-tumor target

  1. 4.
    Fan TP, Jaggar R, Bicknell R: Controlling the vasculature: angiogenesis, anti-angiogenesis and targeting of gene therapy. Trends Pharmacol Sci 1995, 16:57–66PubMedCrossRefGoogle Scholar
  1. 5.
    Augustin HG: Antiangiogenic tumour therapy: will it work? Trends Pharmacol Sci 1998, 19:216–222PubMedCrossRefGoogle Scholar
  2. 6.
    Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med 1971, 285:1182–1186PubMedCrossRefGoogle Scholar
  3. 7.
    Robinson CJ, Stringer SE: The splice variants of vascular endothelial growth factor (VEGF) receptors. J Cell Sci 2001, 114:853–865PubMedGoogle Scholar
  4. 8.
    Hanahan D, Christofori G, Naik P, Arbeit J: Transgenic mouse models of tumour angiogenesis: the angiogenic molecular controls, and prospects for preclinical therapeutic models. Eur J Cancer 1996, 32A:2386–2393PubMedCrossRefGoogle Scholar
  5. 9.
    Liotta LA, Steeg PS, Stetler-Stevenson WG: Cancer metastasis and angiogenesis: an imbalance of positive and regulation. Cell 1991, 64:327–336PubMedCrossRefGoogle Scholar
  6. 10.
    Senger DR, Van de Water L, Brown LF, et al.: Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer Metastasis Rev 1993, 12:303–324PubMedCrossRefGoogle Scholar
  7. 11.
    Brown LF, Berse B, Jackman RW, et al.: Expression of vascular permeability factor (vascular endothelial factor) and its receptors in breast cancer. Hum Pathol 1995, 26:86–91PubMedCrossRefGoogle Scholar
  8. 12.••
    Ferrara N, Gerber HP, LeCouter J The biology of VEGF and its receptors. Nat Med 2003, 9:669–676PubMedCrossRefGoogle Scholar

Good review of VEGF and their receptors

  1. 13.
    Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L: VEGF-receptor signal transduction. Trends Biochem Sci 2003, 28:488–494PubMedCrossRefGoogle Scholar
  1. 14.
    Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z: Vascular endothelial growth factor (VEGF) and its receptors. Faseb J 1999, 13:9–22PubMedGoogle Scholar
  2. 15.
    Dvorak HF: Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2002, 20:4368–4380PubMedCrossRefGoogle Scholar
  3. 16.
    Kolch W, Martiny-Baron G, Kieser A, Marme D: Regulation of the expression of the VEGF/VPS and its receptors: tumor angiogenesis. Breast Cancer Res Treat 1995, 36:139–155PubMedCrossRefGoogle Scholar
  4. 17.
    Breier G, Risau W: The role of vascular endothelial growth factor in blood vessel. Trends Cell Biol 1996, 6:454–456PubMedCrossRefGoogle Scholar
  5. 18.
    Presta LG, Chen H, O’Connor SJ, et al.: Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 1997, 57:4953–4599Google Scholar
  6. 19.
    Johnson DH, Fehrenbacher L, Novotny WF, et al.: Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004, 22:2184–2191PubMedCrossRefGoogle Scholar
  7. 20.••
    Sandler AB, Gray R, Perry MC, et al. Paclitaxel-Carboplatin Alone or with Bevacizumab for Non-Small Cell Lung Cancer. NEJM 2006, 355:2542ΓÇô50PubMedCrossRefGoogle Scholar

Proof in principle of the efficacy of anti-angiogenesis in lung cancer

  1. 21.
    Sandler AB, Johnson DH, Brahmer J, Schiller JH, Ostland M, Gray R, Tran S, Dimery I: Retrospective study of clinical and radiographic risk factors associated with early onset, severe pulmonary hemorrhage in bevacizumab-treated patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2006, 24 Google Scholar
  1. 22.
    Gatzemeier U, Blumenschein G, Fosella F, Simantov R, Elting J, Bigwood D, Cihon F, Reck M: Phase II trial of single-agent sorafenib in patients with advanced non-small cell lung carcinoma. Paper presented at: American Society of Clinical Oncology, 2006Google Scholar
  2. 23.
    Socinski MA, Novello S, Sanchez JM, Brahmer JA, Govindan R, Belani CP, Atkins JN, Gillenwater HH, Palleres C, Chao RC: Efficacy and safety of sunitinib in previously treated, advanced non-small cell lung cancer (NSCLC): Preliminary results of a multicenter phase II trial. Paper presented at: American Society of Clinical Oncology, 2006Google Scholar
  3. 24.
    Lee D: Phase II data with ZD6474, a small-molecule kinase inhibitor of growth factor receptor and vascular endothelial growth factor previously treated advanced non-small-cell lung cancer. Clin Lung Cancer 2005, 7:89–91PubMedGoogle Scholar
  4. 25.
    Wedge SR, Kendrew J, Hennequin LF, et al.: AZD2171: a highly potent, orally bioavailable, vascular factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 2005, 65:4389–4400PubMedCrossRefGoogle Scholar
  5. 26.
    Hurwitz H, Dowlati A, Savage S, Fernando N, Lasalvia S, Whitehead B, Suttle B, Collins D, Ho P, Pandite L: Safety, tolerability and pharmacokinetics of oral administration of GW786034 in pts with solid tumors. Paper presented at: American Society of Clinical Oncology, 2005Google Scholar
  6. 27.
    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, 23:5474–5483PubMedCrossRefGoogle Scholar
  7. 28.
    Rosen L, Kurzrock R, Jackson E, Wathen L, Parson M, Eschenberg M, Mulay M, Purdom M, Yan L, Herbst RS: Safety and pharmacokinetics of AMG 706 in patients with advanced solid tumors. Paper presented at: American Society of Clinical Oncology, 2005Google Scholar
  8. 29.
    Wakelee HA, Adjei A, Halsey J, Lensing JL, Dugay JD, Hanson LG, Reid JM, Piens JR, Sikic BI: A phase I dose-escalation and pharmacokinetic (PK) study of a novel spectrum selective kinase inhibitor, XL647, in patients with advanced solid malignancies (ASM). Paper presented at: American Society of Clinical Oncology, 2006Google Scholar
  9. 30.
    Carducci MA, Musib L, Kies MS, et al.: Phase I dose escalation and pharmacokinetic study of enzastaurin, protein kinase C beta inhibitor, in patients with advanced cancer. J Clin Oncol 2006, 24:4092–4099PubMedCrossRefGoogle Scholar
  10. 31.
    Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al.: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005, 353:123–132PubMedCrossRefGoogle Scholar
  11. 32.
    Fehrenbacher L, O’Neil V, Belani CP, Bonomi P, Hart L, Melnyk O, Sandler A, Ramies D, Herbst RS: A phase II, multicenter, randomized clinical trial to evaluate the efficacy and safety of bevacizumab in combination with either chemotherapy (docetaxel or pemetrexed) or erlotinib hydrochloride compared with chemotherapy alone for treatment of recurrent or refractory non-small cell lung cancer. Paper presented at: American Society of Clinical Oncology, 2006Google Scholar
  12. 33.
    Wilhelm SM CC, Tang L, et al.: 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 2004, 64:7099–7109PubMedCrossRefGoogle Scholar
  13. 34.
    Brose MS, Volpe P, Feldman M, et al.: BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 2002, 62:6997–7000PubMedGoogle Scholar
  14. 35.
    Gondek K, Dhanda R, Simantov R, Gatzemeier U, Blumenschein G, Reck M: Health-related quality of life measures in advanced non-small cell lung cancer patients receiving sorafenib. Paper presented at: American Society of Clinical Oncology, 2006Google Scholar
  15. 36.
    Adjei AA, Mandrekar S, Marks RS, Hanson LJ, Aranguren D, Jett JR, Simantov R, Schwartz B, Croghan GA: A Phase I study of BAY 43-9006 and gefitinib in patients with refractory or recurrent non-small-cell lung cancer (NSCLC). Paper presented at: American Society of Clinical Oncology, 2005Google Scholar
  16. 37.
    Schiller JH, Flaherty KT, Redlinger M, Binger K, Eun J, Petrenciuc O, O’Dwyer P: Sorafenib combined with carboplatin/paclitaxel for advanced non-small cell lung cancer: a phase I subset analysis. Paper presented at: American Society of Clinical Oncology, 2006Google Scholar
  17. 38.
    Abrams TJ, Murray LJ, Pesenti E, et al.: Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with “standard of care” for the treatment of breast cancer. Mol Cancer Ther 2003, 2:1011–1021PubMedGoogle Scholar
  18. 39.
    Koukourakis MI, Giatromanolaki A, O’Byrne KJ, et al.: Platelet-derived endothelial cell growth factor expression tumour angiogenesis and prognosis in non-small-cell lung cancer. Br J Cancer 1997, 75:477–481PubMedGoogle Scholar
  19. 40.
    Faivre S, Delbaldo C, Vera K, et al.: Safety, pharmacokinetic, and antitumor activity of SU11248, a multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006, 24:25–35PubMedCrossRefGoogle Scholar
  20. 41.
    Maki RG, Fletcher J, Heinrich MC, Morgan JA, George S, Desai J, Scheu K, Fletcher CD, Baum C, Demetri GD: Results from a continuation trial of SU11248 in patients (pts) with imatinib (IM)-resistant gastrointestinal stromal tumor (GIST). Paper presented at: American Society of Clinical Oncology, 2005Google Scholar
  21. 42.
    Ciardiello F, Caputo R, Damiano V, et al.: Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase. Clin Cancer Res 2003, 9:1546–1556PubMedGoogle Scholar
  22. 43.
    Holden SN, Eckhardt SG, Basser R, et al.: Clinical evaluation of ZD6474, an orally active inhibitor of VEGF receptor signaling, in patients with solid, malignant tumors. Ann Oncol 2005, 16:1391–1397PubMedCrossRefGoogle Scholar
  23. 44.
    Minami H, Ebi H, Tahara M, Sasaki Y, Yamamoto N, Yamada Y, Tamura T, Saijo N: A phase I study of an oral VEGF receptor tyrosine kinase inhibitor ZD6474, in Japanese patients with solid tumors. Paper presented at: American Society of Clinical Oncology, 2003Google Scholar
  24. 45.
    Johnson BE, Ma P, West H, Kerr R, Prager D, Sandler A, Herbst RS, Stewart DJ, Dimery IW, Heymach JV: Preliminary phase Ii safety evaluation of ZD6474, in combination with carboplatin and paclitaxel, as 1st-line treatment in patients with NSCLC. Paper presented at: American Society of Clinical Oncology, 2005Google Scholar
  25. 46.
    Natale RB, Bodkin D, Govindan R, Sleckman B, Rizvi N, Capo A, Germonpré P, Stockman P, Kennedy S, Ranson M: ZD6474 versus gefitinib in patients with advanced NSCLC: final results from a two-part, double-blind, randomized phase II trial. Paper presented at: American Society of Clinical Oncology, 2006Google Scholar
  26. 47.
    Drevs J, Medinger M, Mross K, Zirrgiebel U, Strecker R, Unger C, Puchalski TA, Fernandes N, Roberston J, Siegert P: Phase I clinical evaluation of AZD2171, a highly potent VEGF receptor tyrosine kinase inhibitor, in patients with advanced tumors. Paper presented at: American Society of Clinical Oncology, 2005Google Scholar
  27. 48.
    Laurie SA, Arnold A, Gauthier I, Chen E, Goss G, Ellis P, Shepherd FA, Matthews S, Robertson J, Seymour L: Final results of a phase I study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor receptors (VEGFR), in combination with carboplatin (C) + paclitaxel (T) in patients with advanced non-small cell lung cancer (NSCLC): a study of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG). Paper presented at: American Society of Clinical Oncology, 2006Google Scholar
  28. 49.
    Polverino A, Coxon A, Starnes C, et al.: AMG 706, an oral, multikinase inhibitor that selectively targets endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression xenografts. Cancer Res 2006, 66:8715–8721PubMedCrossRefGoogle Scholar
  29. 50.
    Jackson E, Esparza-Coss E, Bankson JA, Coxon A, Patel V, Polverino T, Radinsky R, Starnes C: The effect of AMG 706, a novel multi-kinase inhibitor, on vascular permeability and blood flow as assessed by dynamic contrast enhanced magnetic resonance imaging in an in vivo preclinical tumor model. Paper presented at: American Society of Clinical Oncology, 2005Google Scholar
  30. 51.
    Crawford J, Burris H, Stein M, Stephenson J, Gilbert J, Underwood S, Sun Y, Yang L, Wiezorek J, Schwartzberg L: Safety and pharmacokinetics (PK) of AMG 706, panitumumab, and gemcitabine/cisplatin (GC) for the treatment of advanced solid malignancies. Paper presented at: American Society of Clinical Oncology, 2006Google Scholar
  31. 52.
    Blumenschein G Jr, Sandler A, O’Rourke T, Eschenberg M, Sun Y, Gladish G, Salgia R, Alden C, Herbst RS, Reckamp K: Safety and pharmacokinetics (PK) of AMG 706, panitumumab, and carboplatin/paclitaxel (CP) for the treatment of patients (pts) with advanced non-small cell lung cancer (NSCLC). Paper presented at: American Society of Clinical Oncology, 2006Google Scholar
  32. 53.
    Graff JR, McNulty AM, Hanna KR, et al.: The protein kinase Cbeta-selective inhibitor, Enzastaurin suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts. Cancer Res 2005, 65:7462–7469PubMedCrossRefGoogle Scholar
  33. 54.
    Keyes KA, Mann L, Sherman M, et al.: LY317615 decreases plasma VEGF levels in human tumor xenograft-bearing mice. Cancer Chemother Pharmacol 2004, 53:133–140PubMedCrossRefGoogle Scholar
  34. 55.
    Teicher BA, Alvarez E, Menon K, et al.: Antiangiogenic effects of a protein kinase Cbeta-selective small. Cancer Chemother Pharmacol 2002, 49:69–77PubMedCrossRefGoogle Scholar
  35. 56.
    Liu Y, Su W, Thompson EA, Leitges M, Murray NR, Fields AP: Protein kinase CbetaII regulates its own expression in rat intestinal epithelial cells and the colonic epithelium in vivo. J Biol Chem 2004, 279:45556–45563PubMedCrossRefGoogle Scholar
  36. 57.
    Keyes K, Cox K, Treadway P, et al.: An in vitro tumor model: analysis of angiogenic factor expression chemotherapy. Cancer Res 2002, 62:5597–5602PubMedGoogle Scholar
  37. 58.
    Nakajima E, Helfrich B, Chan D, Zhang Z, Hirsch FR, Chen V, Ma D, Bunn PA: Enzastaurin a protein kinase Cbeta-selective inhibitor inhibits the growth of SCLC and NSCLC cell lines. Paper presented at: American Society of Clinical Oncology, 2006Google Scholar
  38. 59.
    Watkins V, Hong S, Lin B: Enzastaurin safety review: data from phase I and phase II trials. Paper presented at: American Society of Clinical Oncology, 2006Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Department of Medicine, Division of OncologyStanford UniversityStanfordUSA
  2. 2.Stanford Cancer CenterStanfordUSA

Personalised recommendations