Frontline combination chemotherapy regimen in untreated advanced classical Hodgkin lymphoma

Takeda Pharmaceutical Company Limited and Seattle Genetics, Inc. announced that data from the Phase III ECHELON-1 clinical trial evaluating Adcetris (brentuximab vedotin) as part of a frontline combination chemotherapy regimen in untreated advanced classical Hodgkin lymphoma was presented in the Plenary Scientific Session at the 59th American Society of Hematology (ASH) annual meeting on Sunday, December 10, 2017.

The data were also simultaneously published online in the New England Journal of Medicine and will be published in the print edition on January 25, 2018. Topline data were reported in June 2017 demonstrating the ECHELON-1 trial met its primary endpoint of a statistically significant improvement in modified progression-free survival (modified PFS) per Independent Review Facility (IRF) versus the control arm. Adcetris is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical Hodgkin lymphoma. Adcetris is currently not approved as a frontline therapy for Hodgkin lymphoma.

Key findings, which were presented by Dr. Joseph M. Connors and published in the New England Journal of Medicine, include: 1. The trial achieved its primary endpoint with the combination of Adcetris + AVD (doxorubicin, vinblastine, dacarbazine) resulting in a statistically significant improvement in modified PFS versus the control arm of ABVD (current standard of care including bleomycin, which is known to be associated with unpredictable and potentially fatal pulmonary toxicity) as assessed by an Independent Review Facility (IRF) (HR 0.77; p-value=0.035). This corresponds to a 23 percent reduction in the risk of progression, death or need for additional anticancer therapy. 2.Per IRF assessment, the two-year modified PFS rate for patients in the Adcetris +AVD arm was 82.1 percent compared to 77.2 percent in the control arm. 3. Per investigator assessment, the two-year modified PFS rate for patients in the Adcetris + AVD arm was 81.0 percent compared to 74.4 percent in the control arm (HR 0.73; p-value=0.007). This corresponds to a 27 percent reduction in the risk of progression, death or need for additional anticancer therapy. All secondary endpoints trended in favor of the Adcetris + AVD arm, including interim analysis of overall survival (OS; HR 0.72; p-value=0.19).

Other secondary endpoints include: 1. Complete response (CR) rate at the end of randomized regimen in the Adcetris + AVD arm was 73 percent compared to 70 percent in the control arm (p-value=0.22). 2. Objective response rate (ORR) at the end of randomized regimen in the Adcetris + AVD arm was 86 percent compared to 83 percent in the control arm (p-value=0.12). 3. Deauville score after completion of frontline therapy was 85 percent in the Adcetris + AVD arm compared to 80 percent in the control arm (p-value=0.03). Certain pre-specified subgroups of patients appeared to benefit more with Adcetris + AVD versus ABVD including: patients treated in North America; patients with involvement of greater than 1 extranodal site; patients with International Prognostic Score (IPS) 4 – 7; males; patients with Stage IV disease; and patients aged <60 years.

The safety profile of Adcetris + AVD in the ECHELON-1 trial was generally consistent with that known for the single-agent components of the regimen. The most common clinically relevant adverse events of any grade that occurred in at least 15 percent of patients in the Adcetris + AVD and ABVD arms were: neutropenia (58 and 45 percent, respectively), constipation (42 and 37 percent, respectively), vomiting (33 and 28 percent, respectively), fatigue (both 32 percent), peripheral sensory neuropathy (29 and 17 percent, respectively), diarrhea (27 and 18 percent, respectively), pyrexia (27 and 22 percent, respectively), peripheral neuropathy (26 and 13 percent, respectively), abdominal pain (21 and 10 percent, respectively) and stomatitis (21 and 16 percent, respectively). In both the Adcetris + AVD and ABVD arms, the most common Grade 3 or 4 events were neutropenia.