Brentuximab 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:
- Peripheral neuropathy (sensory > motor);
- Neutropenia, including grade 3 (14%) and grade 4 (6%); risk increased if used with multi-agent chemotherapy regimens;
- Progressive multifocal leukoencephalopathy from JC virus;
- Pulmonary toxicity (especially in combination with bleomycin);
- Others (e.g. infusion reactions, diarrhea, tumor lysis syndrome, Stevens-Johnson syndrome);
- Bergdorf reaction (hand-foot maculo-papular rash with fissuring). Dose adjustments may be required, including use in patients with renal insufficiency.