Bevacizumab

from Wikipedia, the free encyclopedia
Bevacizumab
Mass / length primary structure 149  kDa
Identifier
External IDs
Drug information
ATC code L01 XC07
DrugBank DB00112
Drug class Cytostatic , monoclonal antibody

Bevacizumab (trade name Avastin ® ; manufacturer Roche ) is a humanized monoclonal antibody (subtype IgG 1 ). In the European Union, bevacizumab is approved for the treatment of six advanced cancers (colon, lung, breast, kidney, ovarian and cervical cancer).

Mode of action

Bevacizumab is what is known as an angiogenesis inhibitor . The angiogenesis , the formation of new blood vessels in the human body, for the progression of many cancers is of great importance and is considered a key target of the modern cancer therapy.

Like all other cells in the human body, cancer cells are dependent on a supply of nutrients and oxygen. In the case of small tumors, this supply takes place via diffusion . From a diameter of 1–2 mm, the tumor can only supply itself adequately through its own vascular system. An angiogenic switch occurs: the tumor releases growth factors that stimulate the formation of blood vessels in the direction of the tumor. The vascular growth factor VEGF (Vascular Endothelial Growth Factor) plays a key role in this process of tumor angiogenesis .

Bevacizumab is an angiogenesis inhibitor that specifically binds to the growth factor VEGF so that it can no longer dock on its receptors and the growth signals are suppressed. Through this targeted blockade of the VEGF, newly formed, but still immature blood vessels recede and the formation of new vessels is prevented. This reduces the supply of oxygen and nutrients to the tumor and inhibits its growth. In addition, the therapy with the antibody brings about a normalization of the vascular permeability.

Indications in cancer therapy

Bevacizumab is approved as a drug for the treatment of six advanced-stage cancers in the European Union.

Tabular overview of the approval status of bevacizumab (2017)
illness Admission
Colon cancer
(colorectal cancer, CRC)		 for metastatic CRC in combination with fluoropyrimidine-containing chemotherapy (e.g. 5-FU , capecitabine )
Breast cancer
(breast cancer, BC)		 in metastatic BC in first-line therapy in combination with paclitaxel
or:
in metastatic BC in first-line therapy in combination with capecitabine , if other therapy options, including taxanes or anthracyclines, are considered unsuitable
Lung cancer
(non-small cell lung cancer, NSCLC)		 in locally advanced, metastatic or recurrent NSCLC ( exception: squamous epithelial histology ), in combination with platinum-based chemotherapy in first-line or subsequent therapies, in NSCLC patients with EGFR mutation in combination with erlotinib
Kidney cancer
(renal cell carcinoma)		 in combination with interferon alpha in first-line therapy
Ovarian cancer
(ovarian cancer , OC)		 with advanced OC in FIGO stages IIIB, IIIC and IV, in combination with carboplatin and paclitaxel
or
with relapse of an OC that had responded to a platinum-containing therapy and has not yet been treated with VEGF inhibitors, in combination with carboplatin and gemcitabine
or :
in the recurrence of an OC that had not responded to a platinum-containing therapy in combination with paclitaxel, topotecan or pegylated liposomal doxorubicin
Cervical cancer (CC) in therapy-refractory, relapsed or metastatic CC in combination with paclitaxel and cisplatin - or alternatively in patients who cannot receive platinum-containing therapy, with paclitaxel and topotecan

Colon cancer

Approved since 2005 in combination with all fluoropyrimidine-based chemotherapies for the treatment of patients with metastatic colon cancer (colorectal or rectal cancer ). Clinical studies show that the additional treatment with bevacizumab offers patients a statistically significant survival advantage of four and two months, respectively, in first- and second-line therapy.

Lung cancer

Since 2007 for the first-line treatment of inoperable, advanced, metastatic or relapsed lung cancer (non-small-cell lung cancer NSCLC, except squamous cell carcinoma) in combination with platinum-containing chemotherapeutic agents. In the US registration study, the antibody extended the patient's mean overall survival to more than one year for the first time. The joint guidelines of the German Society for Pneumology and Respiratory Medicine and the German Cancer Society recommend the administration of the angiogenesis inhibitor to patients in stage IIIB / IV (recommendation grade B). In 2014, a scientific study was published in which patients with NSCLC who had mutations in the EGFR (epithelial growth factor receptor) were treated either with erlotinib (the previous standard treatment for this group of patients) or with erlotinib in combination with bevacizumab. The second-named patient group showed a significantly improved progression-free survival (16.0 months versus 9.7 months). On June 8, 2016, the drug was then approved for the first-line treatment of lung cancer patients with EGFR mutations in combination with erlotinib.

Breast cancer

Approved in combination with paclitaxel for the first-line therapy of patients with metastatic HER2-negative breast cancer (breast cancer) since 2007 . Since 2011 also in combination with the oral fluoropyrimidine capecitabine. In both combinations, additional treatment with bevacizumab results in a statistically significant increase in progression-free survival compared to chemotherapy alone. In the therapy guidelines of the Working Group for Gynecological Oncology (AGO), bevacizumab is recommended in this therapy situation with both combination partners (+).

Renal cell cancer

Since the end of 2007 in combination with interferon-alpha2a for first-line treatment of advanced or metastatic renal cell carcinoma . In the approval study, the combination with the angiogenesis inhibitor almost doubled progression-free survival compared to interferon monotherapy. In the current guidelines of the European Society of Urology (EAU), combination therapy is recommended for patients with advanced kidney cancer and a low to medium risk.

Ovarian cancer

Approved in combination with carboplatin plus paclitaxel for the first-line therapy of women with advanced ovarian cancer in FIGO stages IIIB-IV since the end of 2011 . In the registration study, the combination of antibodies plus chemotherapy with subsequent bevacizumab monotherapy resulted in a statistically significant increase in progression-free survival.

Study situation

With over 40,000 patients, bevacizumab has by far the most comprehensive development program in oncology. In total, more than 1000 studies in around 50 different cancers have been carried out with the angiogenesis inhibitor and over a million patients have been treated worldwide. The efficacy of bevacizumab is currently being investigated in extensive studies on adjuvant therapy for lung and breast cancer, for relapse therapy for ovarian cancer and for the treatment of newly diagnosed glioblastoma . In May 2009 the FDA accelerated approval of bevacizumab ( iv .) As a single agent for the treatment of advanced glioblastoma in patients who had previously undergone radiation therapy and chemotherapy with temozolomide . The most commonly observed side effects were infection, tiredness, headache, increased blood pressure, nosebleeds (epistaxis) and diarrhea (diarrhea). Bevacizumab increases progression-free survival in patients with glioblastoma, but has no effect on overall survival.

However, the use of bevacizumab is not undisputed. In late 2011, the US FDA withdrew its approval for the treatment of metastatic breast cancer. According to the FDA, life-threatening side effects can occur with no evidence of an increase in lifespan or quality. Other types of cancer could still be treated with it. Subsequent studies confirm the FDA's decision. The English NICE made a similar statement. The institute criticized the effectiveness and treatment costs. Roche, the company that makes Avastin, has now announced new phase III studies.

Side effects

The safety profile of bevacizumab is based on data from around 3500 patients with various cancers, most of whom were treated with the angiogenesis inhibitor in combination with chemotherapy in clinical studies.

The most common side effects, some serious, with bevacizumab included:

  • Hypertension (high blood pressure)
  • Fatigue (exhaustion, tiredness)
  • Diarrhea (diarrhea) and abdominal pain
  • Protein excretion in the urine (proteinuria)
  • Wound healing disorders

Off-label use in ophthalmology

Bevacizumab is used in ophthalmology in some cases without approval ( off-label use ) for the wet form of age-related macular degeneration (AMD). Ranibizumab is an approved therapy option for the treatment of this disease . Compared to the more expensive ranibizumab (Lucentis ® ), bevacizumab (Avastin ® ) is equally effective and shows no increased risk of death or serious side effects. This is the result of nine evaluated studies in which the safety of both active substances was compared. It has been on the WHO list of essential drugs for this application since 2013 .

After glaucoma surgery (i.e. trabeculectomy), bevacizumab is given to dampen the formation of blood vessels and thus prevent the seepage pad from becoming encapsulated. For this purpose, bevacizumab is made available as eye drops by hospital pharmacies.

See also

Web links

Individual evidence

  1. ↑ a b c d e f g h i Technical information Avastin®, June 2017.
  2. ^ Judah Folkman : Tumor Angiogenesis. In: Robert C. Bast, Jr., Donald W. Kufe, Raphael E Pollock, Ralph R. Weichselbaum, James F Holland, Emil Frei, III: Cancer Medicine. 5th edition. Dekker, Hamilton et al. a. 2000, ISBN 1-55009-113-1 , pp. 132–152, (online)
  3. ^ Gabriele Bergers, Laura E. Benjamin: Angiogenesis: Tumorigenesis and the angiogenic switch . (PDF; 2.4 MB). In: Nature Reviews Cancer . Volume 3, pp. 401-410, doi: 10.1038 / nrc1093 .
  4. ↑ Masahiro Inoue, Jeffrey H. Hager, Napoleone Ferrara, Hans-Peter Gerber, Douglas Hanahan : VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic β cell carcinogenesis. In: Cancer Cell . Volume 1, No. 2, March 2002, pp. 193-202, doi: 10.1016 / S1535-6108 (02) 00031-4 . PMID 12086877 .
  5. ↑ Peter Baluk, Hiroya Hashizume, Donald M. McDonald: Cellular abnormalities of blood vessels as targets in cancer. In: Current opinion in genetics & development. Volume 15, No. 1, February 2005, pp. 102-111, doi: 10.1016 / j.gde 2004.12.005 . PMID 15661540 . (Review).
  6. ↑ James PB O'Connor, Richard AD Carano, Andrew R. Clamp, Jed Ross, Calvin CK Ho, Alan Jackson, Geoff JM Parker, Chris J. Rose, Franklin V. Peale, Michel Friesenhahn, Claire L. Mitchell, Yvonne Watson , Caleb Roberts, Lynn Hope, Sue Cheung, Hani Bou Reslan, Mary Ann T. Go, Glenn J. Pacheco, Xiumin Wu, Tim C. Cao, Sarajane Ross, Giovanni A. Buonaccorsi, Karen Davies, Jurjees Hasan, Paula Thornton, Olivia del Puerto, Napoleone Ferrara, Nicholas van Bruggen, Gordon C. Jayson: Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor: insights from imaging. In: Clinical Cancer Research . Volume 15, No. 21, November 2009, pp. 6674-6682, doi: 10.1158 / 1078-0432.CCR-09-0731 . PMID 19861458 .
  7. ↑ a b Christopher G. Willett, Yves Boucher, Emmanuelle di Tomaso, Dan G Duda, Lance L. Munn, Ricky T. Tong, Daniel C. Chung, Dushyant V. Sahani, Sanjeeva P. Kalva, Sergey V. Kozin, Mari Mino, Kenneth S. Cohen, David T. Scadden, Alan C. Hartford, Alan J. Fischman, Jeffrey W. Clark, David P. Ryan, Andrew X. Zhu, Lawrence S. Blaszkowsky, Helen X. Chen, Paul C. Shellito, Gregory Y. Lauwers, Rakesh K. Jain: Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. In: Nature medicine . Volume 10, No. 2, February 2004, pp. 145-147, doi: 10.1038 / nm988 . PMID 14745444 , PMC 2693485 (free full text).
  8. ↑ Seiji Mabuchi, Yoshito Terai, Kenichiro Morishige, Akiko Tanabe-Kimura, Hiroshi Sasaki, Masanori Kanemura, Satoshi Tsunetoh, Yoshimichi Tanaka, Masahiro Sakata, Robert A. Burger, Tadashi Kimura, Masahide Ohmichi: Maintenance treatment with bevacizumab in prolongs survival vivo ovarian cancer model. In: Clinical cancer research. Volume 14, No. 23, December 2008, pp. 7781-7789, doi: 10.1158 / 1078-0432.CCR-08-0243 . PMID 19047105 .
  9. ↑ Gerald W. Prager, Eva-Maria Lackner, Maria-Theresa Krauth, Matthias Unseld, Marina Poettler, Sylvia Laffer, Sabine Cerny-Reiterer, Wolfgang Lamm, Gabriela V. Kornek, Bernd R. Binder, Christoph C. Zielinski, Peter Valent : Targeting of VEGF-dependent transendothelial migration of cancer cells by bevacizumab. In: Molecular Oncology . Volume 4, No. 2, April 2010, pp. 150-160, doi: 10.1016 / j.molonc.2010.01.002 . PMID 20106729 .
  10. ↑ Bruce J. Giantonio, Paul J. Catalano, Neal J. Meropol, Peter J. O'Dwyer, Edith P. Mitchell, Steven R. Alberts, Michael A. Schwartz, Al B. Benson III: Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. In: Clinical cancer research. Volume 13, No. 13, July 2007, pp. 3942-3950, doi: 10.1158 / 1078-0432.CCR-07-0278 . PMID 17606728 .
  11. ↑ Rakesh K. Jain: Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. In: Science . Volume 307, No. 5706, January 2005, pp. 58-62, doi: 10.1126 / science.1104819 . PMID 15637262 . (Review).
  12. ↑ APPENDIX I SUMMARY OF MEDICINAL PRODUCT CHARACTERISTICS. (PDF) European Medicines Agency, accessed on August 17, 2017 .
  13. ↑ Herbert Hurwitz, Louis Fehrenbacher, William Novotny, Thomas Cartwright, John Hainsworth, William Heim, Jordan Berlin, Ari Baron, Susan Griffing, Eric Holmgren, Napoleone Ferrara, Gwen Fyfe, Beth Rogers, Robert Ross, Fairooz Kabbinavar: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. In: The New England journal of medicine . Volume 350, No. 23, June 2004, pp. 2335-2342, doi: 10.1056 / NEJMoa032691 . PMID 15175435 .
  14. ↑ Bruce J. Giantonio, Paul J. Catalano, Neal J. Meropol, Peter J. O'Dwyer, Edith P. Mitchell, Steven R. Alberts, Michael A. Schwartz, Al B. Benson III: Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. In: Journal of clinical oncology . Official journal of the American Society of Clinical Oncology. Volume 25, No. 12, April 2007, pp. 1539-1544, doi: 10.1200 / JCO.2006.09.6305 . PMID 17442997 .
  15. ^ Alan Sandler, Robert Gray, Michael C. Perry, Julie Brahmer, Joan H. Schiller, Afshin Dowlati, Rogerio Lilenbaum, David H. Johnson: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. In: The New England Journal of Medicine . Volume 355, No. 24, December 2006, pp. 2542-2550, doi: 10.1056 / NEJMoa061884 . PMID 17167137 .
  16. ↑ G. Goeckenjan, H. Sitter, M. Thomas, D. Branscheid, M. Flentje, F. Griesinger, N. Niederle, M. Stuschke, T. Blum, K.-M. Deppermann, JH Ficker, L. Freitag, AS Lübbe, T. Reinhold, E. Späth-Schwalbe, D. Ukena, M. Wickert, M. Wolf, S. Andreas, T. Auberger, RP Baum, B. Baysal, J . Beuth, H. Bickeböller, A. Böcking, RM Bohle, I. Brüske, O. Burghuber, N. Dickgreber, S. Diederich, H. Dienemann, W. Eberhardt, S. Eggeling, T. Fink, B. Fischer, M. Franke, G. Friedel, T. Gauler, S. Gütz, H. Hautmann, A. Hellmann, D. Hellwig, F. Herth, CP Heussel, W. Hilbe, F. Hoffmeyer, M. Horneber, RM Huber, J. Huebner, H.-U. Kauczor, K. Kirchbacher, D. Kirsten, T. Kraus, SM Lang, U. Martens, A. Mohn-Staudner, K.-M. Müller, J. Müller-Nordhorn, D. Nowak, U. Ochmann, B. Passlick, I. Petersen, R. Pirker, B. Pokrajac, M. Reck, S. Riha, C. Rübe, A. Schmittel, N. Schönfeld, W. Schütte, M. Serke, G. Stamatis, M. Steingräber, M. Steins, Erich Stoelbe, L. Swoboda, H. Teschler, HW Tessen, M. Weber, A. Werner, H.-E. Wichmann, E. Irlinger Wimmer, C. Witt, H. Worth: Prevention, diagnostics, therapy and aftercare of lung cancer. Interdisciplinary S3 guideline of the German Society for Pneumology and Respiratory Medicine and the German Cancer Society. In: Pneumology. Volume 64, 2010, pp. E1-e164, doi: 10.1055 / s-0029-1243837 .
  17. ↑ T. Seto, T. Kato, M. Nishio, K. Goto, S. Atagi, Y. Hosomi, N. Yamamoto, T. Hida, M. Maemondo, K. Nakagawa, S. Nagase, I. Okamoto, T. . Yamanaka, K. Tajima, R. Harada, M. Fukuoka, N. Yamamoto: Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harboring EGFR mutations (JO25567): an open-label, randomized, multicentre, phase 2 study. In: Lancet Oncol. 15 (11), 2014, pp. 1236-1244. doi: 10.1016 / S1470-2045 (14) 70381-X
  18. ↑ Media release: Roche receives EU approval for Avastin in combination with Tarceva in patients with a certain form of advanced lung cancer. June 8, 2016, accessed July 30, 2017 .
  19. ^ Robert Gray, Suman Bhattacharya, Christopher Bowden, Kathy Miller, Robert L. Comis: Independent review of E2100: a phase III trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer. In: Journal of clinical oncology. Official journal of the American Society of Clinical Oncology. Volume 27, No. 30, October 2009, pp. 4966-4972, doi: 10.1200 / JCO.2008.21.6630 . PMID 19720913 , PMC 2799052 (free full text).
  20. ↑ Nicholas J. Robert, Véronique Diéras, John Glaspy, Adam M. Brufsky, Igor Bondarenko, Oleg N. Lipatov, Edith A. Perez, Denise A. Yardley, Stephen YT Chan, Xian Zhou, See-Chun Phan, Joyce O ' Shaughnessy: RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. In: Journal of clinical oncology. Official journal of the American Society of Clinical Oncology. Volume 29, No. 10, April 2011, pp. 1252-1260, doi: 10.1200 / JCO.2010.28.0982 . PMID 21383283 .
  21. ↑ Diagnosis and therapy of primary and metastatic breast cancer. Version 2012.1D (PDF; 4.1 MB) Working Group for Gynecological Oncology (AGO) e. V.
  22. ↑ Bernard Escudier, Anna Pluzanska, Piotr Koralewski, Alain Ravaud, Sergio Bracarda, Cezary Szczylik, Christine Chevreau, Marek Filipek, Bohuslav Melichar, Emilio Bajetta: Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomized, double- blind phase III trial. In: The Lancet . Volume 370, 2007, pp. 2103-2111, doi: 10.1016 / S0140-6736 (07) 61904-7 . PMID 18156031 .
  23. ↑ Börje Ljungberg, Nigel C. Cowan, Damian C. Hanbury, Milan Hora, Markus A. Kuczyk, Axel S. Merseburger, Jean-Jacques Patard, Peter FA Mulders, Ioanel C. Sinescu: EAU guidelines on renal cell carcinoma: the 2010 update. In: European Urology . Volume 58, 2010, pp. 398-406, doi: 10.1016 / j.eururo.2010.06.032 . PMID 20633979 .
  24. ^ Robert A. Burger, Mark F. Brady, Michael A. Bookman, Gini F. Fleming, Bradley J. Monk, Helen Huang, Robert S. Mannel, Howard D. Homesley, Jeffrey Fowler, Benjamin E. Greer, Matthew Boente, Michael J. Birrer, Sharon X. Liang: Incorporation of bevacizumab in the primary treatment of ovarian cancer. In: The New England Journal of Medicine . Volume 365, No. 26, December 2011, pp. 2473-2483, doi: 10.1056 / NEJMoa1104390 . PMID 22204724 .
  25. ↑ Summary Bridging Report to EMA, April 2011.
  26. ^ ClinicalTrials.gov
  27. ↑ FDA Approval for Bevacizumab . National Cancer Institute at the NIH. Cancer Drug Information. May 5, 2009.
  28. ↑ Mustafa Khasraw et al. a .: Antiangiogenic therapy for high-grade glioma . In: The Cochrane Database of Systematic Reviews . No. 9 , September 22, 2014, p. CD008218 , doi : 10.1002 / 14651858.CD008218.pub3 , PMID 25242542 .
  29. ↑ FDA Commissioner Removes Breast Cancer Indication from Avastin Label , FDA press release , November 18, 2011.
  30. ↑ FDA revokes the Avastin indication in breast cancer ( memo of November 22, 2011 in the Internet Archive ) in Deutsches Ärzteblatt, November 21, 2011.
  31. ↑ Anna Dorothea Wagner, Christoph Thomssen, Johannes Haerting, Susanne Unverzagt: Vascular-endothelial-growth-factor (VEGF) targeting therapies for endocrine refractory or resistant metastatic breast cancer. In: The Cochrane Database of Systematic Reviews. Volume 11, No. 7, 2012, doi: 10.1002 / 14651858.CD008941.pub2
  32. ↑ NICE draft guidance continues not to recommend bevacizumab (Avastin) for metastatic breast cancer , July 4, 2012, National Institute for Health and Clinical Excellence
  33. ^ Roche press release ( Memento of May 2, 2012 in the Internet Archive ), November 18, 2011.
  34. ↑ Christoph Baumgärtel: Label against off-label use. AMD update. In: Österreichische Apotheker-Zeitung. Volume 64, No. 7, 2010, pp. 388–390, apoverlag.at ( Memento from December 18, 2015 in the Internet Archive ) (PDF; 11 MB)
  35. ↑ Juliane Ziegler, Doris Uhl: Avastin ® not riskier than Lucentis ® . In: Deutsche Apothekerzeitung . 154, 39, Stuttgart, September 25, 2014, p. 28.
  36. ↑ L. Moja et al. a .: Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration. In: Cochrane Database Syst Rev. 9, 2014, CD011230. PMID 25220133 ; doi: 10.1002 / 14651858.CD011230.pub2
  37. ↑ Franz Grehn, Thomas Klink: Aftercare after glaucoma operations. In: Journal for practical ophthalmology & advanced training in ophthalmology. Volume 30, 2009, pp. 235–243, kaden-verlag.de (PDF; 771 kB)