On November 16, 2018, brentuximab vedotin was approved for use in combination with chemotherapy for previously untreated systemic anaplastic large-cell lymphoma or other CD30-expressing peripheral T-cell lymphomas (PTCLs), including angioimmunoblastic T-cell lymphoma and PTCL–not otherwise specified.1,2 Brentuximab vedotin is an antibody-drug conjugate directed to CD30. This is the first U.S. Food and Drug Administration (FDA) approval for previously untreated PTCL including systemic anaplastic large-cell lymphoma.
Supporting Efficacy Data
Approval was based on the phase III double-blind ECHELON-2 trial (NCT01777152) in patients with previously untreated CD30-expressing PTCL.3,4 Investigators evaluated the combination of brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (CHP) vs the control arm, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). The study met its primary endpoint, demonstrating a statistically significant improvement in progression-free survival of brentuximab vedotin in
Brentuximab vedotin is marketed under the brand name Adcetris by Seattle Genetics. See the full prescribing information for more on drug indications, dosage, and safety, including a boxed warning for progressive multifocal leukoencephalopathy. For further information, visit FDA.gov.
combination with CHP vs CHOP, as assessed by an independent review facility (hazard ratio [HR] = 0.71; P = .01). The brentuximab vedotin plus CHP arm also demonstrated superior overall survival compared with CHOP (HR = 0.66; P = .02).
All other key secondary endpoints, including progression-free survival in patients with systemic anaplastic large-cell lymphoma, complete remission rate, and objective response rate were statistically significantly in favor of the brentuximab vedotin plus CHP arm. The safety profile of brentuximab vedotin plus CHP in the ECHELON-2 trial was comparable to that of CHOP and consistent with the established safety profile of brentuximab vedotin in combination with chemotherapy.
How It Works
Brentuximab vedotin is an antibody-drug conjugate consisting of a chimeric IgG1 antibody directed against CD30 and the small-molecule microtubule disrupting agent monomethyl auristatin E (MMAE), which is covalently attached to the antibody via a linker. Preclinical findings indicate that binding of the conjugate to CD30-expressing cells is followed by internalization of the conjugate-CD30 complex and release of MMAE via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, inducing cell cycle arrest and apoptosis. Additional findings from in vitro data provide evidence of antibody-dependent cellular phagocytosis.
CD30 is a member of the tumor necrosis factor receptor family. It is expressed on the surface of systemic anaplastic large cell lymphoma cells and on Hodgkin Reed-Sternberg cells in classical Hodgkin lymphoma, and has limited expression on healthy tissue and cells. In vitro data indicate that signaling through CD30-CD30L binding affects cell survival and proliferation.
How It Is Used
The recommended dose of brentuximab vedotin in the current indication is 1.8 mg/kg up to a maximum of 180 mg in combination with chemotherapy given every 3 weeks with each cycle of chemotherapy for 6 to 8 doses. In patients with previously untreated PTCL who are treated with brentuximab vedotin and chemotherapy, prophylactic granulocyte colony-stimulating factor (G-CSF) should be given beginning with cycle 1. Treatment should be avoided in those with severe renal impairment or moderate or severe hepatic impairment.
Product labeling provides recommended dose modifications for specific populations, including those with mild hepatic impairment or other special concerns, such as peripheral neuropathy and neutropenia.
The most common adverse events observed with brentuximab vedotin (≥ 20%) in any study have been peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, pyrexia, constipation, vomiting,
alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia, and mucositis.
In the ECHELON-2 study, serious adverse events occurred in 38% vs 35% of patients in the control arm, with the most common in the brentuximab vedotin group being febrile neutropenia (14%), pneumonia (5%), pyrexia (4%), and sepsis (3%). Adverse events led to dose delays in 25% of patients in the brentuximab vedotin group, dose reduction in 9% (mostly for peripheral neuropathy), and discontinuation of brentuximab vedotin in 7% (mostly for peripheral neuropathy and infection).
Brentuximab vedotin carries a boxed warning for progressive multifocal leukoencephalopathy.
For more information about brentuximab vedotin, including dosage, indications, and safety, visit FDA.gov. ■
1. United States Food and Drug Administration: Approved drugs. FDA approves brentuximab vedotin for previously untreated sALCL and CD30-expressing PTCL. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm626116.htm. Accessed November 29, 2018.
2. ADCETRIS® (brentuximab vedotin) for injection prescribing information, Seattle Genetics, Inc, November 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/125388s099lbl.pdf. Accessed November 29, 2018.
3. Horwitz SM, O’Connor OA, Pro B, et al: The ECHELON-2 Trial: Results of a randomized, double-blind, active-controlled phase 3 study of brentuximab vedotin and CHP vs CHOP in the frontline treatment of patients with CD30+ peripheral T-cell lymphomas. 2018 ASH Annual Meeting & Exposition. Abstract 997. Presented December 3, 2018.
4. Horwitz SM, O’Connor OA, Pro B, et al: Brentuximab vedotin with chemotherapy for CD-30 positive peripheral T-cell lymphoma (ECHELON-2): A global, double-blind, randomized, phase 3 trial. Lancet 393:229-240, 2019.