Brentuximab vedotin

Compound Name:Brentuximab vedotinMolecular Target:CD30Molecular Structure:Chimeric IgG1k monoclonal antibody conjugated to a microtubule disrupting agent MMAE by a protease-cleavable linkerLicensed Indication:Hodgkin's lymphoma, Systemic anaplastic large cell lymphomaManufacturer and/or Distributor:SeattleGeneticsInitial FDA Approval2011SummaryBrentuximab vedotin (Adcetris) is an antibody-drug conjugate consisting of a chimeric IgG1k monoclonal antibody covalently attached by a dipeptide protease-sensitive linker to a microtubule toxin, monomethyl auristatin E (MMAE or vedotin). The antibody moiety targets CD30, which is a membrane glycoprotein member of the TNFR superfamily normally expressed on only a small percentage of lymphocytes, particularly activated T cells and B cells, as well as in thymocytes during thymus development. CD30 is also found on certain lymphoid malignancies, including Hodgkin’s lymphoma and anaplastic large cell lymphoma. Its ligand, CD30L, is expressed normally on several cell types. CD30L/CD30 interaction can result in cell proliferation and in cell death, depending on the cell type receiving the signal and the environment in which the signal is delivered. Brentuximab vedotin binds to CD30 on the surface of tumor cells, and is then endocytosed into lysosomes, where the dipeptide bridge is cleaved by protease to release the toxic MMAE moiety that kills the cell by inhibiting the polymerization of microtubule Brentuximab vedotin is typically administered as outpatient therapy intravenously every 3 weeks. Single arm (uncontrolled) trials of brentuximab vedontin in patients with resistant Hodgkin’s (N = 102) and anaplastic large cell (N = 58) lymphomas showed response rates of 73% and 86%, respectively. These results led to accelerated FDA approval in 2011 for (1) Hodgkin’s patients who had failed autologous stem cell transplant or who had failed >2 multi-agent chemotherapy agents and were not candidates for autologous stem cell transplantation; and (2) systemic anaplastic large cell lymphoma patients who had failed >1 multi-agent chemotherapy regimen. Significant safety concerns include: (1) peripheral neuropathy (sensory > motor); (2) neutropenia, including grade 3 (14%) and grade 4 (6%); risk increased if used with multi-agent chemotherapy regimens; (3) progressive multifocal leukoencephalopathy from JC virus; (4) pulmonary toxicity (especially in combination with bleomycin); (5) pancreatitis; (6) Others (e.g. infusion reactions, diarrhea, tumor lysis syndrome, Stevens-Johnson syndrome); (7) Bergdorf reaction (hand-foot maculo-papular rash with fissuring). Dose adjustments may be required, including use in patients with renal insufficiency.References

Package Insert: http://www.adcetris.com/_pdf/Final_Adcetris_USPI_Jan12_2012.pdf

1. Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, et al. Brentuximab Vedotin (SGN-35) in Patients With Relapsed or Refractory Systemic Anaplastic Large-Cell Lymphoma: Results of a Phase II Study. J Clin Oncol. 2012 May 21 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22614995

2. Jalan P, Mahajan A, Pandav V, Bekker S, Koirala J. Brentuximab associated progressive multifocal leukoencephalopathy. Clin Neurol Neurosurg. 2012 Apr 1
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22472351

3. Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, et al. Results of a Pivotal Phase II Study of Brentuximab Vedotin for Patients With Relapsed or Refractory Hodgkin's Lymphoma. J Clin Oncol. 2012 May 29
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22454421

4. Minich SS. Brentuximab vedotin: a new age in the treatment of Hodgkin lymphoma and anaplastic large cell lymphoma. Ann Pharmacother. 2012 Mar;46(3):377-383.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22395252

5. Younes A, Yasothan U, Kirkpatrick P. Brentuximab vedotin. Nat Rev Drug Discov. 2012 Jan;11(1):19-20.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22212672

6. Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010 Nov 4;363(19):1812-1821.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21047225

7. Younes A. CD30-targeted antibody therapy. Curr Opin Oncol. 2011 Nov;23(6):587-593.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21986847

8. Horie R, Watanabe T. CD30: expression and function in health and disease. Semin Immunol. 1998 Dec;10(6):457-470.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9826579

9. Moskowitz A. New frontiers for brentuximab vedotin for lymphomas. Leuk Lymphoma 2014 (ahead of print: PMID: PMID: 25315080)

10. Ansell sm. Brentuximab vedotin. Blood 2014 (ahead of print: PMID: PMID: 25293772)

11. Gravanis I, Tzogani K, van Hennik P, de Graeff P, Schmitt P, Mueller-Berghaus J, Salmonson T, Gisselbrecht C, Laane E, Bergmann L, Pignatti F. The European Medicines Agency Review of Brentuximab Vedotin (Adcetris) for the Treatment of Adult Patients With Relapsed or Refractory CD30+ Hodgkin Lymphoma or Systemic Anaplastic Large Cell Lymphoma: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use. Oncologist. 2015 Nov 30. pii: theoncologist.2015-0276.

12. Rehman JU, Kelta M, AlBeirouti B, Rashidhaider RG, Mohamed B. Brentuximab-induced hand-foot syndrome in a Hodgkin lymphoma patient. Ann Hematol. 2015 Nov 18.

13. Oak E, Bartlett NL. A safety evaluation of brentuximab vedotin for the treatment of Hodgkin lymphoma. Expert Opin Drug Saf. 2016 Jun;15(6):875-8

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