FDA Approves Adcetris Combination for Hodgkin Lymphoma

Adcetris (brentuximab vedotin), in combination with chemotherapy, was granted approval by the Food and Drug Administration (FDA) as a frontline treatment option for patients with stage 3 or 4 classical Hodgkin lymphoma, according to the manufacturer of the drug, Seattle Genetics.

The approval is based on findings from the phase 3 ECHELON-1 trial, which demonstrated superior progression-free survival (PFS) with Adcetris plus Adriamycin, vinblastine and dacarbazine (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.

The approval, which follows a breakthrough therapy designation the FDA granted frontline Adcetris in October 2017 for use in this setting, also converts the accelerated approval the FDA previously granted the drug for adults with systemic anaplastic large cell lymphoma after failure of at least one multiagent chemotherapy regimen to regular approval.

“The standard of care for treating newly diagnosed advanced Hodgkin lymphoma has not changed in more than four decades. For years, the physician community has been conducting clinical trials to identify improved regimens that are both less toxic and more effective to no avail,” said Joseph M. Connors, M.D., FRCPC, clinical director, Center for Lymphoid Cancer at BC Cancer in Vancouver, Canada, said in a statement.

“The ECHELON-1 study results demonstrated superior efficacy of the Adcetris 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,” added Connors.

The phase 3 ECHELON-1 trial enrolled 1334 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 of up to 2. 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 1 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.