FDA Approval Tweaks Decades-Old Treatment of Hodgkin's Lymphoma

Nick Mulcahy

Disclosures

March 20, 2018

The US Food and Drug Administration (FDA) today approved brentuximab vedotin (Adcetris, Seattle Genetics) in combination with chemotherapy for adult patients with previously untreated stage III or IV classic Hodgkin's lymphoma.

The approval was based on results from the ECHELON-1 clinical trial, which compared brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline therapy in these patients.

The results were first presented at the 2017 American Society of Hematology (ASH) annual meeting, as reported by Medscape Medical News, and were simultaneously published in the New England Journal of Medicine.

The brentuximab plus AVD combination represents the first clinically feasible improvement in the initial treatment of these patients in decades, said a study investigator at the ASH annual meeting.

"The study results represent the first successful effort in more than 30 years to improve outcomes of first-line treatment in patients with advanced HL [Hodgkin's lymphoma] without escalating the toxicity of the chemotherapy to unacceptable levels," said lead study author Joseph M. Connors, MD, clinical director of the British Columbia Cancer Agency Center for Lymphoid Cancer in Vancouver, Canada, in an ASH news release.

Change has been a long time coming, suggested Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, in a press statement.

"Today's approval represents an improvement in the initial treatment regimens of advanced Hodgkin lymphoma that were introduced into clinical practice more than 40 years ago," Pazdur commented.

ECHELON-1

In the pivotal randomized phase 3 trial, patients with previously untreated stage III or IV classic Hodgkin's lymphoma were assigned to receive A+AVD (n = 664) or the standard-of-care ABVD (n = 670).

The primary endpoint was modified progression-free survival (mPFS), defined as the time to progression, death, or noncomplete response and use of subsequent anticancer therapy.

At a median follow-up of 24.6 months, the 2-year mPFS rates in the A+AVD and ABVD groups were 82.1% and 77.2%, respectively, representing an absolute difference of 4.9% (hazard ratio, 0.77; P = .04).

With regard to adverse events, neutropenia occurred more commonly in the A+AVD group vs the ABVD group (58% vs 45%). Peripheral neuropathy also occurred more commonly in the A+AVD group vs the ABVD group (67% vs 43%).

Pulmonary toxicity of grade 3 or higher was seen in fewer than 1% of patients receiving A+AVD and in 3% of those receiving ABVD.

Among the deaths during treatment, 7 of 9 in the A+AVD group were associated with neutropenia, and 11 of 13 in the ABVD group were associated with pulmonary-related toxicity, reported the investigators.

In a press statement, investigator Connors said that the new combination of A+AVD is notable in part because it removes bleomycin from the first-line treatment of these patients.

"The ECHELON-1 study results demonstrated superior efficacy of the brentuximab plus chemotherapy regimen when compared to the standard of care while removing bleomycin, an agent that can cause unpredictable and sometimes fatal lung toxicity, completely from the regimen. This represents a meaningful advance for this often younger patient population," he commented.

Preventive treatment with granulocyte colony-stimulating factor is recommended with brentuximab plus chemotherapy for the first-line treatment of stage III or IV classic Hodgkin's lymphoma

Brentuximab vedotin has a boxed warning that highlights the risk for John Cunningham virus infection resulting in progressive multifocal leukoencephalopathy, a rare brain infection that can cause death.

This is the fifth FDA-approved indication for brentuximab. The drug was previously approved to treat classic Hodgkin's lymphoma after relapse and classic Hodgkin's lymphoma after stem cell transplant for patients at high risk for relapse or progression.

Some clinicians are uncertain of the role that brentuximab should play in the treatment of classic Hodgkin's lymphoma.

In introductory remarks at the plenary session of the 2017 ASH annual meeting, George Canellos, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, summarized the impressive results previously seen with brentuximab in relapsed/refractory classic Hodgkin's lymphoma. He also noted that of the many regimens that have been tried in an attempt to improve the results seen with the current standard of care, ABVD, none has led to an improvement in overall survival.

Canellos indicated that in comparing a new brentuximab-containing regimen with ABVD, additional issues need to be addressed, including overall survival and costs. Those costs include not only the high cost of the brentuximab relative to chemotherapy but also the cost of all the supportive care that is needed.

Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick

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