Adcetris Combination Granted Priority Review for Hodgkin Lymphoma Treatment

Adcetris (brentuximab vedotin) was granted a priority review to a supplemental biologics license application (sBLA) by the Food and Drug Administration (FDA) to be used in combination with Adriamycin, vinblastine and dacarbazine (AVD) to treat patients with classical Hodgkin lymphoma in the frontline setting, according to Seattle Genetics, the company developing the drug.

The sBLA is based on findings from the phase 3 ECHELON-1 trial, which demonstrated superior progression-free survival (PFS) with Adcetris plus AVD compared with standard ABVD (AVD plus bleomycin). In the study, the Adcetris regimen reduced the risk of progression, death or initiation of new therapy by 23 percent compared with ABVD. The two-year modified PFS rate was 82.1 percent with Adcetris compared with 77.25 percent for standard chemotherapy.

In October, Seattle Genetics announced that Adcetris had received a breakthrough therapy designation from the FDA as a frontline treatment for Hodgkin lymphoma, based on findings from the ECHELON-1 study. Under the Prescription Drug User Fee Act, the FDA is scheduled to make its final decision on the sBLA by May 1, 2018.

“The FDA’s filing of our supplemental BLA with Priority Review represents a significant milestone in our goal to redefine the frontline treatment of advanced Hodgkin lymphoma,” Clay Siegall, Ph.D., president and chief executive officer of Seattle Genetics, said in a statement.

“We recently reported the primary data from the phase 3 ECHELON-1 clinical trial in the Plenary Scientific Session of the 2017 ASH Annual Meeting with simultaneous publication in the New England Journal of Medicine. The data demonstrated superior activity of the Adcetris-containing regimen over standard of care, and we are working with the FDA to make this bleomycin-free regimen available to newly diagnosed advanced Hodgkin lymphoma patients as soon as possible.”

The phase 3 ECHELON-1 trial enrolled 1,334 patients with stage 3/4 classical Hodgkin lymphoma. All patients had not received prior treatment with systemic chemotherapy or radiotherapy and had an ECOG performance status 2 or under. Patients ranged in age from 18 to 83, the median age was 36 years, and 58 percent were men.

In both arms, treatment was given on days one and 15 of a 28-day cycle. Doxorubicin was given at 25 mg/m2, vinblastine was administered at 6 mg/m2, and patients received dacarbazine at 375 mg/m2. In the investigational arm, Adcetris was administered at 1.2 mg/kg and in the control group bleomycin was administered at 10 units/m2.

The primary endpoint of the study was modified PFS by independent review committee. Under the modified criteria, PFS was defined as time to progression, death or receipt of additional therapy for those not in complete response. The modified endpoint was meant to eliminate the potential impact of consolidation treatment with chemotherapy or radiotherapy. Secondary endpoints included overall survival and safety.

PFS was met with 117 events in the Adcetris arm and 146 events in the AVBD arm. At a median follow-up of 24.9 months, the two year modified PFS was 82.1 percent with the Adcetris regimen compared with 77.2 percent with ABVD.

In addition, researchers found that 33 percent fewer patients treated with the Adcetris regimen received subsequent chemotherapy or high-dose chemotherapy and transplant compared with the patients treated with ABVD.

Safety profiles were consistent with known toxicities of the single agents. Grade 3 or higher infections were more common in the Adcetris group (18 percent) than the ABVD arm (10 percent).

Neutropenia was reported in 58 percent of patients who received the Adcetris regimen compared with 45 percent who received ABVD. In the Adcetris arm, the rate of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with GCSF than among those who did not (11 percent vs 21 percent).

Peripheral neuropathy occurred in 67 percent of patients receiving Adcetris plus AVD and 43 percent of patients receiving ABVD.

There were 28 deaths in the Adcetris cohort and 39 in the ABVD arm. Among the deaths that occurred during treatment, seven of nine in the Adcetris group were associated with neutropenia and 11 of 13 in the ABVD group were associated with pulmonary-related toxicity.

Adcetris is currently approved for patients with classical Hodgkin lymphoma following autologous hematopoietic stem cell transplantation (HSCT) or after failure of two prior regimens, if not candidates for HSCT. The agent is also approved as consolidation therapy for patients with Hodgkin lymphoma at high risk of relapse or progression following autologous HSCT.