Skip to main content
Top

11-08-2017 | Colorectal cancer | Article

Bevacizumab in Colorectal Cancer: Current Role in Treatment and the Potential of Biosimilars

Journal: Targeted Oncology

Authors: Lee S. Rosen, Ira A. Jacobs, Ronald L. Burkes

Publisher: Springer International Publishing

Abstract

Colorectal cancer (CRC) is a leading cause of tumor-related morbidity and mortality worldwide, with mortality most often attributable to metastatic disease. Bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor, has a significant role in the treatment of metastatic CRC (mCRC). However, patient access to bevacizumab may be limited in some regions or circumstances, owing to factors related to insurance coverage, reimbursement, patient out-of-pocket costs, or availability. As a result, outcomes for patients with mCRC may be worsened. Additionally, counterfeit bevacizumab has infiltrated legitimate supply chains, exposing patients to risk. Oncologists may also be affected detrimentally, since resolving access issues can be time-consuming and demoralizing. The imminent expiry of patents protecting bevacizumab provides other manufacturers with the opportunity to produce highly similar versions known as biosimilars. High-quality, safe, and effective biosimilars have the potential to expand access to bevacizumab. Most of the bevacizumab biosimilars currently in development are in clinical trials in patients with non-small-cell lung cancer, and future authorization for mCRC indications will, therefore, be based on extrapolation. This article reviews the current role of bevacizumab in the management of mCRC, the possible barriers associated with diminished access to bevacizumab, and the potential bevacizumab biosimilars in development. How biosimilars may impact the treatment of mCRC is also discussed.
Literature
1.
International Agency for Research on Cancer, World Health Organization. GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. World fact sheet. 2012 (last update 2012). http://​globocan.​iarc.​fr/​Pages/​fact_​sheets_​population.​aspx Accessed 8 Sept 2016
2.
Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet. 2014;383:1490–502. doi:10.​1016/​S0140-6736(13)61649-9.CrossRefPubMed
3.
National Cancer Institute. SEER cancer statistics factsheets: colon and rectum cancer. 2016 (last update 2016). http://​seer.​cancer.​gov/​statfacts/​html/​colorect.​html Accessed 23 Aug 2016.
4.
Van Cutsem E, Cervantes A, Nordlinger B, Arnold D. Metastatic colorectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25:iii1–9. doi:10.​1093/​annonc/​mdu260.CrossRefPubMed
5.
Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27:1386–422. doi:10.​1093/​annonc/​mdw235.CrossRefPubMed
6.
Kasi PM, Hubbard JM, Grothey A. Selection of biologics for patients with metastatic colorectal cancer: the role of predictive markers. Expert Rev Gastroenterol Hepatol. 2015;9:273–6. doi:10.​1586/​17474124.​2015.​1001743.CrossRefPubMed
7.
Roche Registration Limited. Avastin (bevacizumab) summary of product characteristics. 2009 (last update 10/19/2016). http://​www.​ema.​europa.​eu/​docs/​en_​GB/​document_​library/​EPAR_​-_​Product_​Information/​human/​000582/​WC500029271.​pdf Accessed 21 Oct 2016.
8.
Genentech Inc. Avastin® (bevacizumab) prescribing information. 2004 (last update 2016). https://​www.​accessdata.​fda.​gov/​drugsatfda_​docs/​label/​2016/​125085s317lbl.​pdf Accessed 16 May 2017.
9.
Cherny N, Sullivan R, Torode J, Saar M, Eniu A. ESMO European consortium study on the availability, out-of-pocket costs and accessibility of antineoplastic medicines in Europe. Ann Oncol. 2016;27:1423–43. doi:10.​1093/​annonc/​mdw213.CrossRefPubMed
10.
Baer WH, Maini A, Jacobs I. Barriers to the access and use of rituximab in patients with non-Hodgkin’s lymphoma and chronic lymphocytic leukemia: a physician survey. Pharmaceuticals (Basel). 2014;7:530–44. doi:10.​3390/​ph7050530.CrossRef
11.
Lammers P, Criscitiello C, Curigliano G, Jacobs I. Barriers to the use of trastuzumab for HER2+ breast cancer and the potential impact of biosimilars: a physician survey in the United States and emerging markets. Pharmaceuticals (Basel). 2014;7:943–53. doi:10.​3390/​ph7090943.CrossRef
12.
Monk BJ, Lammers PE, Cartwright T, Jacobs I. Barriers to the access of bevacizumab in patients with solid tumors and the potential impact of biosimilars: a physician survey. Pharmaceuticals (Basel). 2017. doi:10.​3390/​ph10010019.
13.
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42. doi:10.​1056/​NEJMoa032691.CrossRefPubMed
14.
Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25:1539–44. doi:10.​1200/​JCO.​2006.​09.​6305.CrossRefPubMed
15.
Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14:29–37. doi:10.​1016/​S1470-2045(12)70477-1.CrossRefPubMed
16.
Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol. 2013;14:1077–85. doi:10.​1016/​S1470-2045(13)70154-2.CrossRefPubMed
17.
Guan ZZ, Xu JM, Luo RC, Feng FY, Wang LW, Shen L, et al. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. Chin J Cancer Res. 2011;30:682–9. doi:10.​5732/​cjc.​011.​10188.CrossRef
18.
Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21:60–5. doi:10.​1200/​JCO.​2003.​10.​066.CrossRefPubMed
19.
Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Hecht JR, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005;23:3697–705. doi:10.​1200/​JCO.​2005.​05.​112.CrossRefPubMed
20.
Passardi A, Nanni O, Tassinari D, Turci D, Cavanna L, Fontana A, et al. Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann Oncol. 2015;26:1201–7. doi:10.​1093/​annonc/​mdv130.CrossRefPubMed
21.
Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–9. doi:10.​1200/​JCO.​2007.​14.​9930.CrossRefPubMed
22.
Stathopoulos GP, Batziou C, Trafalis D, Koutantos J, Batzios S, Stathopoulos J, et al. Treatment of colorectal cancer with and without bevacizumab: a phase III study. Oncology. 2010;78:376–81. doi:10.​1159/​000320520.CrossRefPubMed
23.
Tebbutt NC, Wilson K, Gebski VJ, Cummins MM, Zannino D, van Hazel GA, et al. Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group Randomized Phase III MAX Study. J Clin Oncol. 2010;28:3191–8. doi:10.​1200/​JCO.​2009.​27.​7723.CrossRefPubMed
24.
Botrel TE, Clark LG, Paladini L, Clark OA. Efficacy and safety of bevacizumab plus chemotherapy compared to chemotherapy alone in previously untreated advanced or metastatic colorectal cancer: a systematic review and meta-analysis. BMC Cancer. 2016;16:677. doi:10.​1186/​s12885-016-2734-y.CrossRefPubMedPubMedCentral
25.
Qu CY, Zheng Y, Zhou M, Zhang Y, Shen F, Cao J, et al. Value of bevacizumab in treatment of colorectal cancer: a meta-analysis. World J Gastroenterol. 2015;21:5072–80. doi:10.​3748/​wjg.​v21.​i16.​5072.CrossRefPubMedPubMedCentral
26.
Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, et al. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015;26:724–30. doi:10.​1093/​annonc/​mdv012.CrossRefPubMed
27.
Strickler JH, Hurwitz HI. Bevacizumab-based therapies in the first-line treatment of metastatic colorectal cancer. Oncologist. 2012;17:513–24. doi:10.​1634/​theoncologist.​2012-0003.CrossRefPubMedPubMedCentral
28.
Sclafani F, Cunningham D. Bevacizumab in elderly patients with metastatic colorectal cancer. J Geriatr Oncol. 2014;5:78–88. doi:10.​1016/​j.​jgo.​2013.​08.​006.CrossRefPubMed
29.
Ciardiello F. Maintenance therapy for metastatic colorectal cancer. Lancet Oncol. 2015;16:1444–5. doi:10.​1016/​S1470-2045(15)00308-3.CrossRefPubMed
30.
Renouf DJ, Lim HJ, Speers C, Villa D, Gill S, Blanke CD, et al. Survival for metastatic colorectal cancer in the bevacizumab era: a population-based analysis. Clin Colorectal Cancer. 2011;10:97–101. doi:10.​1016/​j.​clcc.​2011.​03.​004.CrossRefPubMed
31.
Tomita Y, Karapetis CS, Ullah S, Townsend AR, Roder D, Beeke C, et al. Survival improvements associated with access to biological agents: results from the south Australian (SA) metastatic colorectal cancer (mCRC) registry. Acta Oncol. 2016;55:480–5. doi:10.​3109/​0284186X.​2015.​1117135.CrossRefPubMed
32.
Chan KK, Wong B, Siu LL, Straus SE, Chang J, Berry SR. Less than ideal: how oncologists practice with limited drug access. J Oncol Pract. 2012;8:190–5. doi:10.​1200/​JOP.​2011.​000337.CrossRefPubMedPubMedCentral
33.
Li E, Schleif R, Edelen B. Hospital management of outpatient oncology treatment decisions: a survey to identify strategies and concerns. J Oncol Pract. 2013;9:e248–54. doi:10.​1200/​JOP.​2012.​000814.CrossRefPubMed
34.
Nadler E, Eckert B, Neumann PJ. Do oncologists believe new cancer drugs offer good value? Oncologist. 2006;11:90–5. doi:10.​1634/​theoncologist.​11-2-90.CrossRefPubMed
35.
Skopec L. ACS CAN examination of cancer drug coverage and transparency in the health insurance marketplaces. 2015 (last update 11/18/2015). https://​www.​acscan.​org/​sites/​default/​files/​ACS%20​CAN%20​Drug%20​Formulary%20​Paper%20​2015.​pdf Accessed 1 Feb 2017.
36.
Chamberlain C, Collin SM, Stephens P, Donovan J, Bahl A, Hollingworth W. Does the cancer drugs fund lead to faster uptake of cost-effective drugs? A time-trend analysis comparing England and Wales. Br J Cancer. 2014;111:1693–702. doi:10.​1038/​bjc.​2014.​86.
38.
Whyte S, Pandor A, Stevenson M. Bevacizumab for metastatic colorectal cancer: a NICE single technology appraisal. Pharmacoeconomics. 2012;30:1119–32. doi:10.​2165/​11597210-000000000-00000.CrossRefPubMed
39.
National Institute for Health and Care Excellence. Bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine for the treatment of metastatic colorectal cancer. 2010 (last update 12/5/2010). https://​www.​nice.​org.​uk/​guidance/​ta212 Accessed 2 May 2017.
40.
Li E, Subramanian J, Anderson S, Thomas D, McKinley J, Jacobs IA. Development of biosimilars in an era of oncologic drug shortages. Drug Des Devel Ther. 2015;9:3247–55. doi:10.​2147/​DDDT.​S75219.CrossRefPubMedPubMedCentral
41.
Mackey TK, Cuomo R, Guerra C, Liang BA. After counterfeit Avastin®--what have we learned and what can be done? Nat Rev Clin Oncol. 2015;12:302–8. doi:10.​1038/​nrclinonc.​2015.​35.CrossRefPubMed
42.
Bikov KA, Mullins CD, Hung A, Seal B, Onukwugha E, Hanna N. Patterns of biologics use across treatment lines in elderly (age >65) Medicare patients with metastatic colon cancer. Oncologist. 2016;21:676–83. doi:10.​1634/​theoncologist.​2015-0199.CrossRefPubMedPubMedCentral
43.
Blackstone EA, Fuhr Jr JP, Pociask S. The health and economic effects of counterfeit drugs. Am Health Drug Benefits. 2014;7:216–24.PubMedPubMedCentral
44.
Cuomo RE, Mackey TK, Stigler P. The economics of counterfeit Avastin: a geospatial and statistical analysis of demographic correlates to FDA warning letters. Pharmacoepidemiol Drug Saf. 2015;24:748–56. doi:10.​1002/​pds.​3796.CrossRefPubMed
45.
US Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. 2015 (last update 4/2015). http://​www.​fda.​gov/​downloads/​DrugsGuidanceCom​plianceRegulator​yInformation/​Guidances/​UCM291128.​pdf Accessed 10 June 2016.
46.
IMS Health. The impact of biosimilar competition. 2016 (last update 6/2016). http://​ec.​europa.​eu/​DocsRoom/​documents/​17325/​attachments/​1/​translations/​en/​renditions/​native Accessed 19 Sept 2016.
47.
Pettengell R, Bias P, Mueller U, Lang N. Clinical safety of tbo-filgrastim, a short-acting human granulocyte colony-stimulating factor. Support Care Cancer. 2016;24:2677–84. doi:10.​1007/​s00520-015-3057-2.CrossRefPubMed
48.
Gascón P, Tesch H, Verpoort K, Rosati MS, Salesi N, Agrawal S, et al. Clinical experience with Zarzio(R) in Europe: what have we learned? Support Care Cancer. 2013;21:2925–32. doi:10.​1007/​s00520-013-1911-7.CrossRefPubMedPubMedCentral
49.
Celltrion Healthcare Hungary Kft. Truxima. Summary of product characteristics. 2017 (last update 3/8/2017). http://​www.​ema.​europa.​eu/​docs/​en_​GB/​document_​library/​EPAR_​-_​Product_​Information/​human/​004112/​WC500222694.​pdf Accessed 15 Mar 2017.
50.
Health Canada. Guidance document: information and submission requirements for biosimilar biologic drugs. 2016 (last update 11/14/2016). http://​www.​hc-sc.​gc.​ca/​dhp-mps/​alt_​formats/​pdf/​brgtherap/​applic-demande/​guides/​seb-pbu/​seb-pbu-2016-eng.​pdf Accessed 16 Dec 2016.
51.
European Medicines Agency. Guideline on similar biological medicinal products. 2014 (last update 4/30/2015). http://​www.​ema.​europa.​eu/​docs/​en_​GB/​document_​library/​Scientific_​guideline/​2014/​10/​WC500176768.​pdf Accessed 9 June 2016.
52.
European Medicines Agency. Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues. 2012 (last update 12/1/2012). http://​www.​ema.​europa.​eu/​docs/​en_​GB/​document_​library/​Scientific_​guideline/​2012/​06/​WC500128686.​pdf Accessed 20 July 2016.
53.
Weise M, Kurki P, Wolff-Holz E, Bielsky MC, Schneider CK. Biosimilars: the science of extrapolation. Blood. 2014;124:3191–6. doi:10.​1182/​blood-2014-06-583617.CrossRefPubMed
54.
Rugo HS, Linton KM, Cervi P, Rosenberg JA, Jacobs I. A clinician’s guide to biosimilars in oncology. Cancer Treat Rev. 2016;46:73–9. doi:10.​1016/​j.​ctrv.​2016.​04.​003.CrossRefPubMed
55.
Amgen. Amgen and Allergan submit biosimilar Biologics License Application for ABP 215 to U.S. Food and Drug Administration. 2016 (last update 11/15/2016). http://​wwwext.​amgen.​com/​media/​news-releases/​2016/​11/​amgen-and-allergan-submit-biosimilar-biologics-license-application-for-abp-215-to-u-s--food-and-drug-administration/​ Accessed 19 Jan 2017.
56.
Amgen. Amgen and Allergan submit biosimilar Marketing Authorization Application to European Medicines Agency for ABP 215, a biosimilar candidate to bevacizumab. 2016 (last update 12/2/16). http://​wwwext.​amgen.​com/​media/​news-releases/​2016/​12/​amgen-and-allergan-submit-biosimilar-marketing-authorization-application-to-european-medicines-agency-for-abp-215-a-biosimilar-candidate-to-bevacizumab/​ Accessed 19 Jan 2017.
57.
Wang Y, Fei D, Vanderlaan M, Song A. Biological activity of bevacizumab, a humanized anti-VEGF antibody in vitro. Angiogenesis. 2004;7:335–45. doi:10.​1007/​s10456-004-8272-2.CrossRefPubMed
58.
Muller YA, Chen Y, Christinger HW, Li B, Cunningham BC, Lowman HB, et al. VEGF and the Fab fragment of a humanized neutralizing antibody: crystal structure of the complex at 2.4 a resolution and mutational analysis of the interface. Structure. 1998;6:1153–67.CrossRefPubMed
59.
Born TL, Huynh Q, Mathur A, Velayudhan J, Canon J, Reynhardt K, et al. 489P Functional similarity assessment results comparing bevacizumab to biosimilar candidate ABP 215. Presented at the 39th European Society for Medical Oncology Congress, Madrid, Spain, 26–30 Sep, 2014.
60.
Rule K, Peraza M, Shiue M, Finch G, Thibault S, Rosenberg JA, et al. Nonclinical development of PF-06439535, a potential biosimilar to bevacizumab. J Thorac Oncol. 2015;10 suppl 2:S485.
61.
Markus R, Born T, Chow V, Zhang N, Huynh Q, Maher G, et al. Functional similarity and human pharmacokinetic (PK) equivalence of ABP 215 and bevacizumab. J Clin Oncol. 2015;33:(Suppl.) [abstract e14659].
62.
Thatcher N, Thomas M, Paz-Ares L, Ostoros G, Pan Z, Goldschmidt JH, et al. Randomized, double-blind, phase 3 study evaluating efficacy and safety of ABP 215 compared with bevacizumab in patients with non-squamous NSCLC. J Clin Oncol. 2016;34:(Suppl.) [abstract 9095].
63.
Thatcher N, Thomas M, Ostoros G, Pan Z, Goldschmidt JH, Hanes V. Secondary efficacy results from a phase 3 study comparing efficacy and safety of biosimilar candidate ABP 215 with bevacizumab in patients with non-squamous non-small cell lung cancer (NSCLC). Ann Oncol. 2016;27:vi411–5. doi:10.​1093/​annonc/​mdw382.​10.CrossRef
64.
Orlov SV, Burdaeva ON, Nachaeva MP, Kopp MV, Kotiv BN, Sheveleva LP, et al. Pharmacokinetics and safety of BCD-021, bevacizumab biosimilar candidate, compared to Avastin in patients. J Clin Oncol. 2014;32:(Suppl.) [abstract e13500].
65.
Filon O, Orlov S, Burdaeva O, Kopp MV, Kotiv B, Alekseev S, et al. Efficacy and safety of BCD-021, bevacizumab biosimilar candidate, compared to Avastin: Results of international multicenter randomized double blind phase III study in patients with advanced non-squamous NSCLC. J Clin Oncol. 2015;33:(Suppl.) [abstract 8057].
66.
Hettema W, Wynne C, Schliephake D, Lang B, Altendorfer M, Czeloth N. A randomized, single-blind, phase I trial (INVICTAN®-1) assessing the pharmacokinetic bioequivalence and safety of BI 695502, a bevacizumab biosimilar candidate, in healthy subjects. 2016 (last update 11/2016). http://​abstracts.​aaps.​org/​Verify/​AAPS2016/​PosterSubmission​s/​08W1230.​pdf Accessed 18 Jan 2017.
67.
Knight B, Rassam D, Liao S, Ewesuedo R. A phase I pharmacokinetics study comparing PF-06439535 (a potential biosimilar) with bevacizumab in healthy male volunteers. Cancer Chemother Pharmacol. 2016;77:839–46. doi:10.​1007/​s00280-016-3001-2.CrossRefPubMedPubMedCentral
68.
US Food and Drug Administration. Clinical pharmacology data to support a demonstration of biosimilarity to a reference product. Guidance for industry. 2016 (last update 12/2016). http://​www.​fda.​gov/​downloads/​drugs/​guidancecomplian​ceregulatoryinfo​rmation/​guidances/​ucm397017.​pdf Accessed 30 Jan 2017.
69.
World Health Organization. Guidelines on evaluation of monoclonal antibodies as similar biotherapeutic products (SBPs). 2016 (last update 10/2016). http://​www.​who.​int/​biologicals/​expert_​committee/​mAb_​SBP_​GL-ECBS_​review_​adoption-2016.​10.​26-11.​7post_​ECBS-Clean_​Version.​pdf?​ua=​1 Accessed 12 Apr 2017.
70.
Isakov L, Jin B, Jacobs IA. Statistical primer on biosimilar clinical development. Am J Ther. 2016;23:e1903–e10. doi:10.​1097/​MJT.​0000000000000391​.CrossRefPubMedPubMedCentral
71.
Feagan BG, Choquette D, Ghosh S, Gladman DD, Ho V, Meibohm B, et al. The challenge of indication extrapolation for infliximab biosimilars. Biologicals. 2014;42:177–83. doi:10.​1016/​j.​biologicals.​2014.​05.​005.CrossRefPubMed
72.
Christl LA, Woodcock J, Kozlowski S. Biosimilars: the US regulatory framework. Annu Rev Med. 2017;68:243–54. doi:10.​1146/​annurev-med-051215-031022.CrossRefPubMed
73.
Han K, Peyret T, Marchand M, Quartino A, Gosselin NH, Girish S, et al. Population pharmacokinetics of bevacizumab in cancer patients with external validation. Cancer Chemother Pharmacol. 2016;78:341–51. doi:10.​1007/​s00280-016-3079-6.CrossRefPubMedPubMedCentral
74.
Declerck P, Danesi R, Petersel D, Jacobs I. The language of biosimilars: clarification, definitions, and regulatory aspects. Drugs. 2017;77:671–7. doi:10.​1007/​s40265-017-0717-1.CrossRefPubMedPubMedCentral