On March 20, 2018, brentuximab vedotin (Adcetris) was approved for the treatment of adult patients with previously untreated stage III or IV classical Hodgkin lymphoma in combination with chemotherapy.1,2
Supporting Efficacy Data
Approval was based on the findings of the open-label phase III ECHELON-1 trial,3 in which 1,334 patients were randomized to receive brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD; n = 664) or bleomycin plus AVD (ABVD; n = 670). Patients received treatment on days 1 and 15 of 28-day cycles for up to 6 cycles. The primary endpoint was modified progression-free survival defined as time to disease progression, death, or noncomplete response and use of subsequent anticancer therapy.
Overall, the median age of patients was 36 years; 58% were male; 84% were white; 36% had stage III disease and 64% had stage IV disease; and 62% had extranodal involvement at diagnosis.
The median follow-up was 24.6 months. The estimated median modified progression-free survival was not reached in either group. In total, there were 117 events (18%) in the A+AVD group vs 146 events (22%) in the ABVD group (hazard ratio = 0.77, P = .035). At the time of the primary analysis, interim overall survival analysis did not show a significant difference between the groups. Complete response rates at the end of randomized treatment were 73% vs 70%, respectively.
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 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 monomethyl auristatin via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, inducing cell-cycle arrest and apoptosis. Additional findings in 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 this indication is 1.2 mg/kg via 30-minute intravenous infusion, up to a maximum of 120 mg in combination with chemotherapy given every 2 weeks until a maximum of 12 doses, disease progression, or unacceptable toxicity. Infusion should be interrupted if an infusion-related reaction occurs and immediately discontinued if anaphylaxis occurs.
The starting dose of brentuximab does not need to be changed in patients with mild or moderate renal impairment; treatment should be avoided in those with severe impairment. In patients with mild hepatic impairment, the starting dose should be 0.9 mg/kg up to 90 mg every 2 weeks; treatment should be avoided in those with moderate or severe hepatic impairment. Patients should receive prophylactic granulocyte colony-stimulating factor (G-CSF) beginning with cycle 1.
Treatment should be discontinued if Stevens-Johnson syndrome or toxic epidermal necrolysis occurs. Dose modification for peripheral neuropathy consists of dose reduction to 0.9 mg/kg up to a maximum of 90 mg every 2 weeks for grade 2 toxicity. For grade 3 peripheral neuropathy, treatment should be held until improvement to grade 2 or lower and restarted at 0.9 mg/kg up to 90 mg every 2 weeks; dose modification for other neurotoxic chemotherapy agents should be considered. Treatment should be discontinued for grade 4 toxicity. For grade 3 or 4 neutropenia, G-CSF prophylaxis should be given in subsequent cycles for patients not receiving primary G-CSF prophylaxis.
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, cyclosporine A, ritonavir, verapamil). Patients receiving concomitant treatment with either type of agent should be closely monitored for adverse reactions. Coadministration of brentuximab vedotin with the potent CYP3A4 inducer rifampin reduced MMAE exposure.
The most common adverse events occurring in at least 20% of patients receiving brentuximab vedotin across all clinical trials have been neutropenia, anemia, peripheral sensory neuropathy, nausea, fatigue, constipation, diarrhea, vomiting, and pyrexia.
In the ECHELON-1 trial, after 75% of patients had started study treatment, the use of prophylactic G-CSF was recommended with the initiation of treatment for all A+AVD patients, based on the observed rates of neutropenia and febrile neutropenia. Among 579 patients in this group who did not receive G-CSF primary prophylaxis beginning with cycle 1, 96% experienced any-grade neutropenia and 21% had febrile neutropenia, compared with rates of 61% and 11%, respectively, among those receiving primary prophylaxis.
In the trial, the most common adverse events of any grade in the A+AVD group were anemia (98% vs 92% in the ABVD group), neutropenia (91% vs 89%), peripheral sensory neuropathy (65% vs 41%), constipation (42% vs 37%), and vomiting (33% vs 28%). The most common grade 3 or 4 adverse events were neutropenia (82% vs 73%), febrile neutropenia (19% vs 8%), anemia (11% vs 6%), and peripheral sensory neuropathy (10% vs 2%).
Serious adverse events occurred in 43% vs 27% of patients, with the most common in the A+AVD group being febrile neutropenia (17%), pyrexia (7%), neutropenia, and pneumonia (3% each). Adverse events led to discontinuation of one or more drugs in 13% of the A+AVD group, with peripheral neuropathy leading to treatment discontinuation in 7%. There were nine on-study deaths in the A+AVD group; seven were associated with neutropenia, and none of the patients had received G-CSF prior to developing neutropenia.
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 and opportunistic infections, tumor-lysis syndrome, hepatotoxicity, pulmonary toxicity, serious dermatologic reactions, 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 while receiving brentuximab vedotin.
1. U.S. Food and Drug Administration: Brentuximab vedotin. Available at www.fda.gov. Accessed May 9, 2018.
2. Adcetris (brentuximab vedotin) for injection prescribing information, Seattle Genetics, March 2018. Available at www.seattlegenetics.com. Accessed May 9, 2018.
3. Connors JM, Jurczak W, Straus DJ, et al: Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med 378:331-344, 2018.