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FDA approves Adcetris for first-line treatment of peripheral T-cell lymphoma
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The FDA expanded the approval of brentuximab vedotin to include its use with chemotherapy as first-line treatment for adults with certain types of peripheral T-cell lymphoma.
The approval applies to use of brentuximab vedotin (Adcetris, Seattle Genetics) — a monoclonal antibody that binds to CD30 — with CHP chemotherapy, which consists of cyclophosphamide, doxorubicin and prednisone.
The regimen is indicated for adults with previously untreated systemic anaplastic large cell lymphoma or other CD30-expressing peripheral T-cell lymphomas, including angioimmunoblastic T-cell lymphoma.
This is the first treatment approved for newly diagnosed peripheral T-cell lymphoma.
The FDA based the approval on results of the phase 3 ECHELON-2 trial, which included 452 patients with peripheral T-cell lymphoma.
Researchers randomly assigned patients to brentuximab plus CHP chemotherapy, or to CHOP chemotherapy. CHOP — which consists of cyclophosphamide, doxorubicin, vincristine and prednisone — is a standard frontline treatment for peripheral T-cell lymphoma.
Results showed the brentuximab vedotin regimen significantly extended PFS as assessed by blinded independent review (median, 48 months vs. 21 months; HR = 0.71; 95% CI, 0.54-0.93).
The brentuximab vedotin regimen also appeared superior with regard to secondary endpoints, including OS (HR = 0.66; 95% CI, 0.46-0.95), complete remission rate (68% vs. 56%; P = .007), objective response rate (83% vs. 72%; P = .003), and PFS among a subgroup of patients with systemic anaplastic large cell lymphoma (HR = 0.59; 95% CI, 0.42-0.84).
Complete data from ECHELON-2 will be presented at the ASH Annual Meeting and Exposition, scheduled for Dec. 1-4 in San Diego.
“The current standard of care for initial treatment of peripheral T-cell lymphoma is multi-agent chemotherapy. That treatment has not significantly changed in decades and is too often unsuccessful in leading to long-term remissions, underscoring the need for new treatments,” Steven M. Horwitz, MD, medical oncologist on the lymphoma service at Memorial Sloan Kettering Cancer Center, said in a Seattle Genetics-issued press release. “With this approval, clinicians have the opportunity to transform the way newly diagnosed [patients with CD30-expressing peripheral T-cell lymphoma] are treated.”
The safety profile of brentuximab vedotin plus CHP appeared comparable to that of CHOP. It also was consistent with the established safety profile of brentuximab vedotin in combination with doxorubicin, vinblastine and dacarbazine, an FDA-approved regimen for patients with treatment-naive stage III or stage IV classical Hodgkin lymphoma.
The most common any-grade adverse events that occurred among at least 20% of patients assigned brentuximab vedotin plus CHP included peripheral neuropathy, nausea, diarrhea, neutropenia, lymphopenia, fatigue, mucositis, constipation, alopecia, pyrexia, vomiting and anemia.
Serious adverse events that occurred among at least 2% of patients assigned the combination included febrile neutropenia, pneumonia, pyrexia and sepsis.
The FDA granted the approval under its Real-Time Oncology Review Pilot Program. The approval came less than 2 weeks after submission of the complete application.
“The Real-Time Oncology Review program allows the FDA to access key data prior to the official submission of the application, allowing the review team to begin their review earlier and communicate with the sponsor prior to the application’s actual submission,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products, said in an FDA-issued press release. “When the sponsor submits the completed application, the review team will already be familiar with the data and be able to conduct a more efficient, timely and thorough review.”
The FDA previously approved brentuximab vedotin for treatment of three specific subgroups of patients with classical Hodgkin lymphoma, as well as for treatment of certain patients with anaplastic large cell lymphoma or CD30-expressing mycosis fungoides.
Perspective
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Joshua Brody, MD
There have been unbelievable advances for B-cell lymphoma. However, treatments for T-cell lymphomas have languished.There are two primary reasons. First, T-cell lymphomas are less common. Second, when you are treating B-cell lymphomas, you can accidentally kill healthy B cells. We used to think that these individuals would become so immunosuppressed that they could die of infections, but it turns out people can live pretty well without healthy B cells and only have a minor increased risk for infections.
If you go after T-cell cancers and accidentally get rid of healthy T cells, that is a big problem. If people with HIV lose even part of their CD4 T cells, they tend to die of infections. So biologically, it is harder to go after T-cell lymphomas because it is harder to target them without hurting healthy immune cells.
Brentuximab vedotin is part of an elegant class of therapy known as antibody-drug conjugates. The tail end of the antibody is conjugated to some type of chemotherapy. Instead of infusing chemotherapy, the chemotherapy gets targeted right to the cancer cell, hopefully sparing healthy cells.
T-cell lymphoma is more aggressive than other types of lymphomas. On average, people live for a few years.
The study on which this approval was based showed an OS benefit, but the caveat is that T-cell lymphomas are heterogeneous. We already knew that some types of T-cell lymphomas respond to this antibody-drug conjugate. There is a specific type of T-cell lymphoma called anaplastic large cell lymphoma (ALCL). It responds best to this therapy because it has the highest expression of CD30, the target this antibody goes after. For that subgroup, we are even more confident that this agent will have a huge impact.
Other T-cell lymphomas have less amounts of CD30, so it works on them but not as well.
The tricky part is that many of the people in the trial had the ALCL subtype. There were fewer patients with other types that make up the majority of T-cell lymphomas. We are still optimistic that this therapy will prolong their survival, but it’s not as clear whether it will help all patients to the same extent.
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