Skip to main content

Advertisement

SpringerLink
Log in

Bevacizumab in Advanced NSCLC: Chemotherapy Partners and Duration of Use

  • Lung Cancer (HA Wakelee, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Bevacizumab is an effective targeted therapy with demonstrated survival benefits for many patients with advanced nonsquamous non-small cell lung cancer (NSCLC). Some patient populations are at higher risk for bleeding complications and bevacizumab should be avoided, but advanced age should not be used as the sole exclusion criterion for use. Bevacizumab is generally a well-tolerated therapy that can be safely given in combination with multiple chemotherapy agents in the induction and maintenance phases of therapy. The optimal maintenance strategy is yet to be determined and is the focus of ongoing trials, such as ECOG 5508. Early use of bevacizumab in the adjuvant setting and continued use in the second-line setting are being investigated in current clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

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

  1. American Cancer Society. Cancer facts & figures 2013. Atlanta: American Cancer Society; 2013.

    Google Scholar 

  2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.

    Article  PubMed  Google Scholar 

  3. Gibbons D, Johnson F, Eapen GA. The MD Anderson Manual of Medical Oncology Chapter 15. Non-small cell lung cancer. In: Kantarjian RAW, Koller CA, editors. 2011.

  4. Vokes EE, Salgia R, Karrison TG. Evidence-based role of bevacizumab in non-small cell lung cancer. Ann Oncol. 2013;24:6–9.

    Article  PubMed  CAS  Google Scholar 

  5. Kris MG, Johnson BE, Kwiatkowski DJ. Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: the NCI's Lung Cancer Mutation Consortium (LCMC). J Clin Oncol. 2011;29:abst CRA7506.

    Google Scholar 

  6. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–57.

    Article  PubMed  CAS  Google Scholar 

  7. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12:735–42.

    Article  PubMed  CAS  Google Scholar 

  8. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239–46.

    Article  PubMed  CAS  Google Scholar 

  9. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13:1011–9.

    Article  PubMed  CAS  Google Scholar 

  10. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.

    Article  PubMed  CAS  Google Scholar 

  11. Folkman J. What is the evidence that tumors are angiogenesis dependent. J Natl Cancer Inst. 1990;82:4–6.

    Article  PubMed  CAS  Google Scholar 

  12. Ferrara N. The role of vascular endothelial growth-factor in pathological angiogenesis. Breast Cancer Res Treat. 1995;36:127–37.

    Article  PubMed  CAS  Google Scholar 

  13. Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001;7:987–9.

    Article  PubMed  CAS  Google Scholar 

  14. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669–76.

    Article  PubMed  CAS  Google Scholar 

  15. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.

    Article  PubMed  CAS  Google Scholar 

  16. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–50.

    Article  PubMed  CAS  Google Scholar 

  17. Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010;21:1804–9.

    Article  PubMed  CAS  Google Scholar 

  18. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92–8.

    Article  PubMed  CAS  Google Scholar 

  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 untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004;22:2184–91.

    Article  PubMed  CAS  Google Scholar 

  20. Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009;27:1227–34.

    Article  PubMed  CAS  Google Scholar 

  21. Soria JC, Mauguen A, Reck M, et al. Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol. 2013;24:20–30.

    Article  PubMed  Google Scholar 

  22. Botrel TE, Clark O, Clark L, et al. Efficacy of bevacizumab (Bev) plus chemotherapy (CT) compared to CT alone in previously untreated locally advanced or metastatic non-small cell lung cancer (NSCLC): systematic review and meta-analysis. Lung Cancer. 2011;74:89–97.

    Article  PubMed  Google Scholar 

  23. Niho S, Kunitoh H, Nokihara H, et al. Randomized phase II study of first-line carboplatin-paclitaxel with or without bevacizumab in Japanese patients with advanced non-squamous non-small-cell lung cancer. Lung Cancer. 2012;76:362–7.

    Article  PubMed  Google Scholar 

  24. Yang K, Wang YJ, Chen XR, et al. Effectiveness and safety of bevacizumab for unresectable non-small-cell lung cancer: a meta-analysis. Clin Drug Investig. 2010;30:229–41.

    Article  PubMed  CAS  Google Scholar 

  25. Herbst RS, O'Neill VJ, Fehrenbacher L, et al. Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non small-cell lung cancer. J Clin Oncol. 2007;25:4743–50.

    Article  PubMed  CAS  Google Scholar 

  26. Crino L, Dansin E, Garrido P, et al. Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study. Lancet Oncol. 2010;11:733–40. This is the largest clinical trial ever conducted with bevacizumab and is the best representation of toxicities expected from bevacizumab.

    Article  PubMed  CAS  Google Scholar 

  27. Clinical Trial Result Information, Protocol number: BO19734. Hoffmann-La Roche Ltd, 2009. (Accessed June 26, 2013, at http://www.roche-trials.com/studyResultGet.action?studyResultNumber=BO19734).

  28. Hainsworth JD, Fang L, Huang JE, et al. BRIDGE: an open-label phase II trial evaluating the safety of bevacizumab + carboplatin/paclitaxel as first-line treatment for patients with advanced, previously untreated, squamous non-small cell lung cancer. J Thorac Oncol. 2011;6:109–14.

    Article  PubMed  Google Scholar 

  29. Gordon MS, Margolin K, Talpaz M, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol. 2001;19:843–50.

    PubMed  CAS  Google Scholar 

  30. Socinski MA, Langer CJ, Huang JE, et al. Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases. J Clin Oncol. 2009;27:5255–61. This study demonstrates the safety of bevacizumab when given to patients with brain metastases.

    Article  PubMed  CAS  Google Scholar 

  31. Besse B, Lasserre SF, Compton P, et al. Bevacizumab safety in patients with central nervous system metastases. Clin Cancer Res. 2010;16:269–78.

    Article  PubMed  CAS  Google Scholar 

  32. Herbst RS, Ansari R, Bustin F, et al. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet. 2011;377:1846–54.

    Article  PubMed  CAS  Google Scholar 

  33. Patel JD, Socinski MA, Garon EB, et al. A randomized, open-label, phase 3, superiority study of Pemetrexed (Pem) + Carboplatin (Cb) + Bevacizumab (B) followed by maintenance Pem + B versus Paclitaxel (Pac) + Cb + B followed by maintenance B in patients (pts) with stage IIIB or IV Non-squamous Non-small Cell Lung Cancer (NS-NSCLC). J Thorac Oncol. 2012;7:S336. Abst LBPL1.

    Article  Google Scholar 

  34. Dahlberg SE, Ramalingam SS, Belani CP, et al. A randomized phase III study of maintenance therapy with bevacizumab (B), pemetrexed (Pm), or a combination of bevacizumab and pemetrexed (BPm) following carboplatin, paclitaxel and bevacizumab (PCB) for advanced nonsquamous NSCLC: ECOG trial 5508 (NCT01107626). ASCO Meet Abstr. 2011;29, TPS218.

    Google Scholar 

  35. Besse B, Le Moulec S, Senellart H, et al. Phase II study of bevacizumab in combination with 1st-line chemotherapy or 2nd-line erlotinib in patients with asymptomatic untreated brain metastases (ML21823). Ann Oncol. 2012;23:ix426. Abst. 1299P.

    Article  Google Scholar 

  36. Barlesi F, Scherpereel A, Rittmeyer A, et al. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013. The results of this study suggest that adding pemetrexed to bevacizumab during the maintenance phase of treatment improves progression-free survival.

  37. Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst. 2007;99:1232–9.

    Article  PubMed  Google Scholar 

  38. Mir O, Ropert S, Alexandre J, et al. Hypertension as a surrogate marker for the activity of anti-VEGF agents. Ann Oncol. 2009;20:967–70.

    Article  PubMed  CAS  Google Scholar 

  39. Dahlberg SE, Sandler AB, Brahmer JR, et al. Clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599. J Clin Oncol. 2010;28:949–54.

    Article  PubMed  CAS  Google Scholar 

  40. Bono P, Elfving H, Utriainen T, et al. Hypertension and clinical benefit of bevacizumab in the treatment of advanced renal cell carcinoma. Ann Oncol. 2009;20:393–4.

    Article  PubMed  CAS  Google Scholar 

  41. Hurwitz HI, Douglas PS, Middleton JP, et al. Analysis of early hypertension and clinical outcome with bevacizumab: results from seven phase III studies. Oncologist. 2013;18:273–80.

    Article  PubMed  CAS  Google Scholar 

  42. William Jr WN, Kies MS, Fossella FV, et al. Phase 2 study of carboplatin, docetaxel, and bevacizumab as frontline treatment for advanced nonsmall-cell lung cancer. Cancer. 2010;116:2401–8.

    PubMed  CAS  Google Scholar 

  43. Kentepozidis N, Kotsakis A, Soultati A, et al. Docetaxel plus cisplatin and bevacizumab for untreated patients with advanced/metastatic non-squamous non-small-cell lung cancer: a multicenter phase II study of the Hellenic Oncology Research Group. Cancer Chemother Pharmacol. 2013;71:605–12.

    Article  PubMed  CAS  Google Scholar 

  44. Patel JD, Hensing TA, Rademaker A, et al. Phase II study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer. J Clin Oncol. 2009;27:3284–9.

    Article  PubMed  CAS  Google Scholar 

  45. Lopez-Vivanco G, Carrera S, Sancho A, et al. Bevacizumab (B), cisplatin (C), and pemetrexed (P) plus maintenance B in chemonaive patients (pts) with advanced nonsquamous non-small cell lung cancer (nsNSCLC): a phase II study. ASCO Meeting Abstracts. 2012;30:e18031.

    Google Scholar 

  46. Zappa F, Droege C, Betticher D, et al. Bevacizumab and erlotinib (BE) first-line therapy in advanced non-squamous non-small-cell lung cancer (NSCLC) (stage IIIB/IV) followed by platinum-based chemotherapy (CT) at disease progression: a multicenter phase II trial (SAKK 19/05). Lung Cancer. 2012;78:239–44.

    Article  PubMed  Google Scholar 

  47. Rittmeyer A, Scherpereel A, Gorbunova VA, et al. Effect of maintenance bevacizumab (Bev) plus pemetrexed (Pem) after first-line cisplatin/Pem/Bev in advanced nonsquamous non-small cell lung cancer (nsNSCLC) on overall survival (OS) of patients (pts) on the AVAPERL (MO22089) phase III randomized trial. ASCO Meeting Abstracts. 2013;31:8014.

    Google Scholar 

  48. Miller V, O'Connor P, Soh C, et al. A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2009;27.

  49. Kabbinavar F, Miller V, Johnson B, et al. Overall survival (OS) in ATLAS, a phase IIIb trial comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy (chemo) with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2010;28.

  50. Ferrara N. Pathways mediating VEGF-independent tumor angiogenesis. Cytokine Growth Factor Rev. 2010;21:21–6.

    Article  PubMed  CAS  Google Scholar 

  51. American Cancer Society. American Cancer Society. Cancer facts & figures 2013. Atlanta: American Cancer Society; 2013. 2013.

    Google Scholar 

  52. Herbst RS, Johnson DH, Mininberg E, et al. 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. 2005;23:2544–55.

    Article  PubMed  CAS  Google Scholar 

  53. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22:1589–97.

    Article  PubMed  CAS  Google Scholar 

  54. Adjei AA, Mandrekar SJ, Dy GK, et al. Phase II trial of pemetrexed plus bevacizumab for second-line therapy of patients with advanced non-small-cell lung cancer: NCCTG and SWOG study N0426. J Clin Oncol. 2010;28:614–9.

    Article  PubMed  CAS  Google Scholar 

  55. Gridelli C, Bennouna J, de Castro J, et al. Randomized phase IIIb trial evaluating the continuation of bevacizumab beyond disease progression in patients with advanced non-squamous non-small-cell lung cancer after first-line treatment with bevacizumab plus platinum-based chemotherapy: treatment rationale and protocol dynamics of the AvaALL (MO22097) trial. Clin Lung Cancer. 2011;12:407–11.

    Article  PubMed  CAS  Google Scholar 

  56. Gridelli C, Bennouna J, De Castro J, et al. AvaALL: open-label randomized phase IIIb trial evaluating the efficacy and safety of standard of care with or without continuous bevacizumab (BV) treatment beyond disease progression in patients (pts) with advanced nonsquamous non-small cell lung cancer (NSCLC) after first-line (1L) treatment with BV plus platinum-doublet chemotherapy (CT). ASCO Meeting Abstracts. 2012;30, TPS7612.

    Google Scholar 

  57. Howlader N NA, Krapcho M, Neyman N, Aminou R, Altekruse SF, Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA, editors. SEER cancer statistics review, 1975–2009 (vintage 2009 populations), National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to the SEER web site, 2012.

  58. Zhu J, Sharma DB, Gray SW, et al. Carboplatin and paclitaxel with vs without bevacizumab in older patients with advanced non-small cell lung cancer. JAMA. 2012;307:1593–601.

    Article  PubMed  CAS  Google Scholar 

  59. Langer CJ, Socinski MA, Patel JD, et al. Efficacy and safety of paclitaxel and carboplatin with bevacizumab for the first-line treatment of patients with nonsquamous non-small cell lung cancer (NSCLC): analyses based on age in the phase III PointBreak and E4599 trials. ASCO Meeting Abstracts. 2013;31:8073. This pooled analysis from two large phase III trials indicates that the benefit of adding bevacizumab to chemotherapy exists across different age groups, except those older than age 75 years.

    Google Scholar 

  60. Socinski MA, Patel JD, Garon EB, et al. A phase III study of pemetrexed (Pem) plus carboplatin (Cb) plus bevacizumab (Bev) followed by maintenance pem plus bev versus paclitaxel (Pac) plus cb plus bev followed by maintenance bev in stage IIIb or IV nonsquamous non-small cell lung cancer (NS-NSCLC): overall and age group results. ASCO Meeting Abstracts. 2013;31:8004. PointBreak showed that paclitaxel and pemetrexed-based induction followed by two different bevacizumab-containing maintenance strategies are equivalent in terms of efficacy.

    Google Scholar 

  61. Wakelee HA, Wang W, Schiller JH, et al. Survival differences by sex for patients with advanced non-small cell lung cancer on Eastern Cooperative Oncology Group trial 1594. J Thorac Oncol. 2006;1:441–6. This analysis reveals that the improvement in outcomes associated with bevacizumab may not be equivalent in older women.

    Article  PubMed  Google Scholar 

  62. Wakelee HA, Dahlberg SE, Brahmer JR, et al. Differential effect of age on survival in advanced NSCLC in women versus men: analysis of recent Eastern Cooperative Oncology Group (ECOG) studies, with and without bevacizumab. Lung Cancer. 2012;76:410–5.

    Article  PubMed  CAS  Google Scholar 

  63. Spigel DR, Hainsworth JD, Shipley DL, et al. A randomized phase II trial of pemetrexed/gemcitabine/bevacizumab or pemetrexed/carboplatin/bevacizumab in the first-line treatment of elderly patients with advanced non-small cell lung cancer. J Thorac Oncol. 2012;7:196–202.

    Article  PubMed  CAS  Google Scholar 

  64. Dy G, Molina J, Qi Y, et al. N0821: a phase II first-line study of a combination of pemetrexed, carboplain and bevacizumab in elderly patients with good performance status (PS <2). J Clin Oncol. 2012;30(suppl):abstr 7555.

    Google Scholar 

  65. National Cancer Institute. Chemotherapy with of without bevacizumab in treating patients with stage IB, stage II or stage IIIA non-small cell lung cancer that was removed by surgery. In: ClinicalTrials.gov [Internet] Bethesda (MD): National Library of Medicine (US). 2000–2013. Available from: http://clinicaltrials.gov/ct2/show/NCT00324805?term=E1505&rank=1. 2013.

Download references

Conflict of Interest

Ryan D. Gentzler declares that he has no conflict of interest.

Sarah E. Yentz declares that she has no conflict of interest.

Jyoti D. Patel declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 676 North St. Clair, Suite 850, Chicago, IL, 60611, USA

    Ryan D. Gentzler MD, MS & Jyoti D. Patel MD

  2. Department of Internal Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA

    Sarah E. Yentz MD

Authors
  1. Ryan D. Gentzler MD, MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sarah E. Yentz MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jyoti D. Patel MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jyoti D. Patel MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gentzler, R.D., Yentz, S.E. & Patel, J.D. Bevacizumab in Advanced NSCLC: Chemotherapy Partners and Duration of Use. Curr. Treat. Options in Oncol. 14, 595–609 (2013). https://doi.org/10.1007/s11864-013-0255-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11864-013-0255-3

Keywords

Search

Navigation