On November 9, 2017, brentuximab vedotin (Adcetris) received regular approval for the treatment of adult patients with primary cutaneous anaplastic large cell lymphoma or CD30-expressing mycosis fungoides who have received prior systemic therapy.1,2
Supporting Efficacy Data
Approval was based on findings in the open-label phase III ALCANZA trial, in which 131 patients with mycosis fungoides or primary cutaneous anaplastic large cell lymphoma who had previously received systemic therapy and required systemic treatment were randomized to receive brentuximab vedotin (1.8 mg/kg intravenously over 30 minutes every 3 weeks) or physician’s choice of methotrexate (5–50 mg orally weekly) or bexarotene (300 mg/m2 orally daily).2,3 Randomization was stratified by the diagnosis of mycosis fungoides or primary cutaneous anaplastic large cell lymphoma.
Brentuximab vedotin carries a boxed warning for progressive multifocal leukoencephalopathy, including fatality.
Efficacy results were based on 128 patients, consisting of 64 patients in each group with CD30 expression ≥ 10% in at least 1 biopsy. Among these 128 patients: median age was 60 years (range = 22–83 years); 55% were male; 85% were white; median number of prior systemic therapies was 4 (range = 0–15), including a median of 1 prior skin-directed therapy (range = 0–9) and 2 systemic therapies (range = 0–11); and disease stage was I in 25%, II in 38%, III in 5%, and IV in 13%.
On independent review, objective response lasting ≥ 4 months was observed in 56% of the brentuximab vedotin group vs 12% of the control group (P < .001). Complete response was observed in 16% vs 2% (P = .007). Median progression-free survival was 17 vs 4 months (hazard ratio = 0.27, P < .001).
How It Works
Brentuximab vedotin is an antibody-drug conjugate consisting of a chimeric immunoglobulin G1 antibody directed against CD30 and the small-molecule microtubule disrupting agent 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 starting dose of brentuximab vedotin for this indication is 1.8 mg/kg, up to a maximum of 180 mg as an intravenous infusion over 30 minutes every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity. Infusion should be interrupted if an infusion reaction occurs and discontinued if anaphylaxis occurs.
The recommended starting dose of brentuximab does not need to be changed in patients with mild or moderate renal impairment. In patients with mild hepatic impairment, the starting dose should be 1.2 mg/kg, up to 120 mg. Use of the agent should be avoided in patients with severe renal impairment and those with moderate or severe hepatic impairment.
Treatment should be held for new or worsening grade 2 or 3 peripheral neuropathy until recovery to grade 1 or baseline and then restarted at 1.2 mg/kg to a maximum of 120 mg; treatment should be discontinued for grade 4 peripheral neuropathy. Treatment should be held for grade 3 or 4 neutropenia until resolution to baseline or grade ≤ 2.
Granulocyte colony-stimulating factor (G-CSF) prophylaxis should be considered for subsequent cycles. If grade 4 neutropenia recurs despite G-CSF prophylaxis, discontinuation of treatment or dose reduction to 1.2 mg/kg up to a maximum of 120 mg should be considered. Treatment should be discontinued for Stevens-Johnson syndrome or toxic epidermal necrolysis.
MMAE exposure may be increased by concomitant administration of brentuximab vedotin with strong CYP3A4 inhibitors (eg, ketoconazole, clarithromycin, indinavir [Crixivan], ritonavir, boceprevir [Victrelis]) and P-glycoprotein inhibitors (eg, ketoconazole, ritonavir, verapamil). Patients receiving concomitant treatment with either type of agent should be closely monitored for adverse reactions.
In the ALCANZA trial, the most common adverse events of any grade in the brentuximab vedotin group were anemia (62%), peripheral sensory neuropathy (45%), nausea (36%), diarrhea (29%), fatigue (29%), and neutropenia (21%). The most common grade ≥ 3 adverse events were neutropenia, peripheral sensory neuropathy, and fatigue (5% each).
Serious adverse events occurred in 29% of patients, with the most common being cellulitis (3%) and pyrexia (3%). Adverse events that led to dose delays in > 5% of patients were peripheral sensory neuropathy (15%) and neutropenia (6%). Adverse events led to treatment discontinuation in 24%, with the most common cause being peripheral neuropathy (12%).
Brentuximab vedotin carries a boxed warning for progressive multifocal leukoencephalopathy, including fatality. It also carries warnings/precautions for peripheral neuropathy; anaphylaxis and infusion reactions; hematologic toxicities; serious infections and opportunistic infections; tumor-lysis syndrome; hepatotoxicity; pulmonary toxicity; serious dermatologic reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis); gastrointestinal complications; and embryofetal toxicity. Complete blood cell counts should be monitored before each dose. Liver enzymes and bilirubin should be routinely monitored. The drug is contraindicated with concomitant bleomycin due to the risk of pulmonary toxicity. Women should be advised not to breastfeed during brentuximab vedotin therapy.
1. U.S. Food and Drug Administration: FDA approves brentuximab vedotin for the treatment of adult patients with primary cutaneous anaplastic large cell lymphoma. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm584543.htm. Accessed November 21, 2017.
2. Adcetris (brentuximab vedotin) for injection prescribing information, Seattle Genetics, Inc, November 2017. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2017/125388s094lbl.pdf. Accessed November 21, 2017.
3. Prince HM, Kim YH, Horwitz SM, et al: Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): An international, open-label, randomised, phase 3, multicentre trial. Lancet 390:555-566, 2017.