Brentuximab Vedotin for Consolidation Therapy in High-Risk Hodgkin Lymphoma


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Brentuximab Vedotin in High-Risk Hodgkin Lymphoma

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

 

On August 17, 2015, brentuximab vedotin (Adcetris) was approved for consolidation treatment post autologous hematopoietic stem cell transplantation in patients with classic Hodgkin lymphoma who are at high risk of relapse or progression.1,2

Supporting Efficacy Data

Approval was based on a double-blind phase III trial (AETHERA) showing prolonged progression-free survival with brentuximab vedotin vs placebo on independent review.2,3 A total of 327 evaluable patients defined as high risk (response to front-line therapy defined as refractory, relapsed disease occurring within 12 months or relapsed disease with extranodal involvement) were randomized to receive brentuximab vedotin 1.8 mg/kg given IV over 30 minutes (n = 167) or placebo (n = 160) every 3 weeks for up to 16 cycles. All patients received best supportive care.

Patients were required to have had complete or partial response or stable disease during the most recent salvage therapy. Patients had a median age of 32 years (range = 18–76 years), most were male (53%) and white (94%), and the median number of prior systemic therapies (excluding autologous hematopoietic stem cell transplantation) was 2 (range = 2–8).

Median follow-up for progression-free survival was 22 months (range = 0–49 months). Median progression-free survival was 42.9+ months (95% confidence interval [CI] = 30.4–42.9+ months) in the brentuximab vedotin group vs 24.1 months (95% CI = 11.5 to not estimable) in the placebo group (stratified hazard ratio = 0.57, P = .001). At the time of the progression-free survival analysis, interim analysis of overall survival showed no significant difference between the groups. Patients in the placebo group could receive brentuximab vedotin in a separate trial after disease progression.

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 MMAE (monomethyl auristatin E), which is covalently attached to the antibody via a linker. Preclinical findings indicated 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.

How It Is Given

The recommended dosage for brentuximab vedotin as consolidation therapy post autologous hematopoietic stem cell transplantation is 1.8 mg/kg up to 180 mg given IV over 30 minutes every 3 weeks. Treatment should be initiated within 4 to 6 weeks after autologous hematopoietic stem cell transplantation or upon recovery from transplantation and should be continued until a maximum of 16 cycles, disease progression, or unacceptable toxicity. Infusion should be interrupted for infusion reaction and discontinued for anaphylaxis.

The starting dose of brentuximab does not need to be changed in patients with mild or moderate renal impairment, but the drug should be avoided in patients with severe renal impairment. The recommended starting dose is 1.2 mg/kg up to 120 mg in patients with mild hepatic impairment; the drug should be avoided in patients with moderate or severe hepatic impairment.

Treatment should be held for new or worsening grade 2 or 3 neuropathy until recovery to grade 1 or baseline and then restarted at 1.2 mg/kg; 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, treatment discontinuation or dose reduction to 1.2 mg/kg should be considered.

MMAE is primarily metabolized by CYP3A. Coadministration of brentuximab vedotin with the strong CYP3A4 inhibitor ketoconazole increased exposure to MMAE by approximately 34%; patients who are receiving strong CYP3A4 inhibitors (eg, ketoconazole, clarithromycin, indinavir [Crixivan], ritonavir [Norvir], boceprevir [Victrelis]) concomitantly with brentuximab vedotin should be closely monitored for adverse reactions.

Coadministration of brentuximab with the strong CYP3A4 inducer rifampin reduced exposure to MMAE by approximately 46%. Coadministration with P-glycoprotein inhibitors (eg, ketoconazole, cyclosporin A, ritonavir, verapamil) may increase exposure to MMAE, and patients receiving concomitant treatment should be closely monitored for adverse reactions.

Safety Profile

In the phase III trial, the most common adverse events of any grade in the brentuximab vedotin group were neutropenia (78% vs 34% in the placebo group), peripheral sensory neuropathy (56% vs 16%), thrombocytopenia (41% vs 20%), anemia (27% vs 19%), and upper respiratory tract infection (26% vs 23%). The most common grade 3 or 4 adverse events were neutropenia (39% vs 10%), peripheral sensory neuropathy (10% vs 1%), and peripheral motor neuropathy (6% vs 1%). Infusion-related reactions occurred in 15% (grade 3 in 1.7%) vs 2% of patients. Pulmonary toxicity occurred in 5% vs 3%.

Overall, 67% of patients receiving brentuximab vedotin had neuropathy of any grade. The median time to first onset was 14 weeks for any grade neuropathy, 27 weeks for grade 2 neuropathy, and 34 weeks for grade 3 neuropathy. The median time from onset to resolution or improvement was 23 weeks for any grade, 24 weeks for grade 2, and 25 weeks for grade 3. Complete resolution occurred in 59% of patients; of 41% with residual neuropathy, 26% had partial improvement at last evaluation.

Serious adverse events occurred in 25% of the brentuximab vedotin group, with the most common being pneumonia (4%), pyrexia (4%), vomiting (3%), nausea (2%), hepatotoxicity (2%), and peripheral sensory neuropathy (2%). The most common adverse events leading to dose delays were neutropenia (22%), peripheral sensory neuropathy (16%), upper respiratory tract infection (6%), and peripheral motor neuropathy (6%). Adverse events led to treatment discontinuation in 32% of patients, with the most common causes being peripheral sensory neuropathy (14%), peripheral motor neuropathy (7%), acute respiratory distress syndrome (1%), paresthesia (1%), and vomiting (1%).

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, and embryo-fetal 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 pulmonary toxicity. ■

References

1. U.S. Food and Drug Administration: Brentuximab vedotin. Available at www.fda.gov. Accessed August 27, 2015.

2. Adcetris (brentuximab vedotin) for injection prescribing information, Seattle Genetics, Inc, August 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125388s080lbl.pdf. Accessed August 27, 2015.

3. Moskowitz CH, et al: Lancet 385:1853-1862, 2015.



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