Regulatory Decision Summary for Adcetris

Echelon-1 was a randomized, open-label, 2-arm, multicenter trial in previously untreated Hodgkin lymphoma (HL) patients with advanced Stage III or IV disease. The study compared the safety and efficacy of Adcetris in combination with doxorubicin, vinblastine and dacarbazine (Adcetris + AVD) versus the standard of care therapy of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD). Of 1,334 total HL patients, 664 patients were randomized to treatment with Adcetris + AVD and 670 HL patients were randomized to treatment with ABVD. The primary endpoint was modified progression-free survival (mPFS). It is a modified analysis because in addition to disease progression and death an event was also defined as receipt of additional anticancer therapy for patients who were not in complete remission at the end of 6 cycles of therapy.

Patients treated with Adcetris + AVD had an overall mPFS benefit compared to patients randomized to the ABVD control arm. This was reported as a 23% reduction in the risk of progression, death or for patients not in complete remission subsequent therapy. The overall mPFS benefit of Adcetris was driven primarily by a reduction in events in Stage IV patients treated with Adcetris + AVD. No mPFS benefit of Adcetris + AVD was reported for patients with Stage III disease over ABVD standard of care. At the time of the primary mPFS analysis, the interim overall survival results were immature and no statistically meaningful differences in overall survival were reported between the two arms.

In Echelon-1, there were more serious adverse events reported in the Adcetris + AVD arm compared to the ABVD arm study (240 [36%] vs. 125 [19%], respectively). The most significant adverse events were neuropathy and neutropenia. Patients with any form of neuropathy, including asymptomatic Grade 1 neuropathy, were excluded from the Echelon-1 clinical study and the benefit-risk of Adcetris + AVD has not been established in these patients. The study protocol was also amended during study to initiate prophylactic treatment with granulocyte-colony stimulating factor (G-CSF) in Cycle 1 for patients being treated with Adcetris + AVD in an attempt to reduce the incidence, duration and severity of neutropenia of this combination therapy. The recommendation for G-CSF prophylaxis in Cycle 1 has been included in the Product Monograph along with a statement that consideration should be given to weigh the benefits and risks, including alternative therapies, before administering Adcetris + AVD to patients who have baseline neuropathy.

The benefit-risk profile for Adcetris + AVD over ABVD was considered positive for previously untreated Hodgkin lymphoma patients with Stage IV disease.

A Notice of Compliance was recommended.