Brentuximab vedotin: A breakthrough for refractory CD30+ lymphomas

The introduction of rituximab in the 1990s revolutionized the treatment of CD20+ B-cell lymphomas.

Unfortunately, no drugs have had the same effect for lymphomas that do not carry the CD20 marker.

CD30, a marker fairly specific to Reed–Sternberg and malignant T cells, has long been considered a desirable drug target due to its restricted expression. When unconjugated antibodies targeting CD30 were studied, they were found to have minimal clinical efficacy. More recent efforts have focused on using these antibodies to deliver cytotoxic agents directly to malignant cells.

Brentuximab vedotin (Adcetris, Seattle Genetics) is a chimeric CD30 antibody conjugated to approximately four molecules of monomethyl auristatin E (MMAE) with a cleavable dipeptide linker. The antibody portion of the molecule binds to CD30 and is internalized by the cell. Once inside, lysosomes act on the linker portion, cleave the peptide and release the attached MMAE molecules.

Sarah Rodriguez

MMAE is responsible for binding tubulin and arresting the cell cycle, resulting in cell death. There is some information to suggest that MMAE also may diffuse out of the tumor cell to surrounding inflammatory cells in the tumor microenvironment. These inflammatory cells may enhance growth of the tumor and provide protection from the host’s immune system, especially in Hodgkin’s lymphoma. The effects of MMAE on these surrounding cells may enhance the efficacy of brentuximab vedotin.

CD30+ lymphomas primarily include Hodgkin’s lymphomas, but they also encompass anaplastic large cell lymphomas (ALCL) and some other T-cell lymphomas. After front-line combination chemotherapy, recurrent or refractory Hodgkin’s lymphoma may be treated with second-line chemotherapy followed by autologous stem cell transplant (ASCT).

Despite these efforts, approximately 50% of patients with Hodgkin’s lymphoma relapse after ASCT and survival is limited in these young adults. In this refractory population, combination chemotherapy generally confers clinical benefits over single-agent chemotherapy, but it does so with substantial toxicities.

There remains a lack of consensus among experts in this field regarding the best treatment options for patients in this refractory/recurrent setting, making brentuximab vedotin a unique entity with potential to change the course of this deadly disease.

Clinical activity

Brentuximab vedotin received FDA approval in August through the accelerated process for two indications.

The first approval is for patients with Hodgkin’s lymphoma relapsed after ASCT or in those patients not eligible for transplant after failure of at least two multi-agent chemotherapy regimens. This indication was based on a phase 2 trial of 102 patients with Hodgkin’s lymphoma with progressive disease after ASCT, 71% of whom were considered to have primary refractory disease.

The investigators used a dose of 1.8 mg/kg of brentuximab vedotin given by IV infusion once every 3 weeks for up to 16 cycles. Objective responses were seen in 75% of patients, with 34% achieving complete remission. These results are unprecedented, especially given that this drug was administered as a single agent and toxicities were manageable (see Table 1).

The FDA also approved brentuximab vedotin for the treatment of systemic ALCL after failure of at least one prior multi-agent chemotherapy regimen. A phase 2 trial included 58 patients with relapsed or refractory ALCL, many of whom had poor prognostic factors. Objective responses were seen in 86% of patients, with 53% achieving complete remission. This also appears to be a significant advancement over what was historically achieved with combination chemotherapy regimens administered in this setting.

Toxicity

The most common adverse reactions seen with the use of brentuximab vedotin — occurring in more than 20% of patients — were neutropenia, peripheral neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, fever, rash, thrombocytopenia, cough and vomiting.

As with other targeted agents, patients with rapidly proliferating or bulky disease may be at risk for tumor lysis syndrome, especially during the first infusion of brentuximab vedotin. Other serious adverse effects include Stevens-Johnson syndrome and progressive multifocal leukoencephalopathy, with one case of each occurring in clinical trials.

Similarly to other agents that act through inhibition of microtubules, brentuximab vedotin has been associated with peripheral neuropathy. This neuropathy is predominately sensory, but motor neuropathy also has been reported.

In the two phase 2 clinical trials, approximately 52% of patients experienced peripheral neuropathy of any grade, with grade-3 or grade-4 symptoms occurring in 9% of patients. This effect is cumulative and can be irreversible. Patients receiving brentuximab vedotin should be carefully monitored for neuropathy throughout treatment. Dosing modifications or discontinuation of therapy should be considered for worsening symptoms (see Table 2).

Neutropenia and thrombocytopenia both were commonly reported in clinical trials, with grade-3 or grade-4 neutropenia occurring in an average of 21% of patients. This is not unexpected, given the fact that many of these patients are post-transplant and their bone marrow reserve is compromised. Growth factors are not currently recommended for primary prevention but should be added for patients who experience a neutropenic event (see Table 2).

Infusion-related reactions have been reported with the use of brentuximab vedotin in 12% of patients in phase 2 clinical trials. Symptoms were usually grade 1 or grade 2 and included chills, nausea, dyspnea, fever and cough. Anaphylactic reactions were seen in two patients during phase 1 studies. Although there are no recommendations for using premedications before the first infusion of brentuximab vedotin, they should be added to subsequent cycles in patients who experience a reaction. A combination of corticosteroids, antihistamines and acetaminophen is recommended. If anaphylaxis occurs, treatment should be discontinued permanently.

Since brentuximab vedotin received accelerated approval by the FDA, additional adverse events may arise because its use is expanded to more patients. It is important to inform the FDA of serious events involving the drug through postmarket reporting mechanisms.

Dosing and administration

The recommended dose of brentuximab vedotin is 1.8 mg/kg IV for 30 minutes every 3 weeks, with a maximum dose of 180 mg per cycle for up to 16 cycles or until disease progression. After reconstitution, the drug should be diluted in normal saline, a solution of 5% dextrose in water, or Lactated Ringer’s solution to a final concentration of 0.4 mg/mL to 1.8 mg/mL.

The final solution can be refrigerated for up to 24 hours. Brentuximab vedotin should not be mixed or administered as an infusion with other drugs.

Pharmacokinetic data suggest that MMAE is eliminated primarily renally and to a lesser extent through hepatic CYP450 3A4 metabolism. Caution should be used when administering brentuximab vedotin with strong CYP 3A4 inhibitors or inducers such as ketoconazole or rifampin. Also, patients with severe renal and hepatic impairment were not included in clinical trials. Further investigation will be needed to determine the tolerability and dosing of brentuximab vedotin in these populations.

Conclusion

Brentuximab vedotin is a novel agent with impressive response rates in treatment-experienced patients with CD30+ lymphomas. It is approved for the treatment of patients with relapsed Hodgkin’s lymphoma after ASCT or in patients who are not stem cell transplant candidates who have relapsed after at least two prior multi-agent chemotherapy regimens. It also is indicated for patients with ALCL after failure of at least one multi-agent chemotherapy regimen.

The average wholesale price of a 50-mg vial of brentuximab vedotin is $5,400, making the cost of each course of therapy approximately $16,000 for a 75-kg patient. Although patient assistance programs have been established by Seattle Genetics to assist with the cost of treatment, care should be taken by prescribers to adhere to labeled product indications to avoid issues with insurance company reimbursement.

Brentuximab vedotin is an exciting breakthrough in the treatment of relapsed or refractory Hodgkin’s and ALCL. Further studies will be needed to fully define its role in the management of Hodgkin’s lymphoma and ALCL, including its role in upfront treatment or combined with chemotherapy.

Sarah Rodriguez, PharmD, BCPS, is a clinical pharmacist at The University of Texas MD Anderson Cancer Center in Houston. Disclosure: Dr. Rodriguez reports no relevant financial disclosures.

For more information:

• Adcetris [package insert]. Bothell, WA: Seattle Genetics; 2011.
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• Katz J. Clin Cancer Res. 2011;17:6428-6436.
• Pro B. Abstract #8032. Presented at: the Annual Meeting of the American Society of Clinical Oncology; June 3-7, 2011; Chicago.
• Younes A. Curr Opin Oncol. 2011;23:587-593.
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