Frontline Therapy with Brentuximab Vedotin Combined with ABVD or AVD in Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma

Hodgkin lymphoma (HL) is a lymphoid neoplasm defined by the presence of CD30-positive Hodgkin Reed-Sternberg (HRS) cells in a background of inflammatory cells. Frontline treatment is generally ABVD alone or in combination with other chemotherapy regimens or radiation. Although a standard ABVD regimen is curative for the majority of patients with advanced stage HL, up to 30% of patients will require a second-line therapy. Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). In a phase 2 study, an objective response rate of 75% and multiple durable complete remissions (CRs) (34%) were obtained with single-agent brentuximab vedotin in highly treatment-refractory patients with HL.

A phase 1, open-label, multicenter study is being conducted to evaluate the safety of brentuximab vedotin when administered in combination with standard therapy (ABVD) or a modified standard (AVD) (ClinicalTrials.gov #NCT01060904). Patients received doses of 0.6, 0.9, or 1.2 mg/kg brentuximab vedotin with standard doses of ABVD or 1.2 mg/kg brentuximab vedotin with AVD, depending upon cohort assignment. The combination regimens were administered on Days 1 and 15 of each 28-day cycle for up to 6 cycles of therapy. Each regimen evaluated a dose limiting toxicity (DLT) period, defined as any Cycle 1 toxicity requiring a delay of ≥7 days in standard ABVD or AVD therapy. Determination of antitumor activity is based on investigator assessment of objective response according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007).

Interim data are presented for the first 31 patients treated. Six patients received 0.6 mg/kg, 13 received 0.9 mg/kg, and 6 received 1.2 mg/kg with ABVD; 6 patients received 1.2 mg/kg with AVD. Baseline characteristics included: Stage IV, 55%; IPI score ≥4, 29%; male, 77%; median age, 35 years (range, 19–59). Combination treatment was generally well tolerated, with no DLT observed up to 1.2 mg/kg in either regimen. Overall, AEs reported in ≥45% of patients, regardless of severity, were nausea and neutropenia (77% each); peripheral sensory neuropathy (48%); and fatigue (45%). Infusion-related reactions occurred in 23% of patients. Grade 3/4 AEs observed in >10% of patients were neutropenia (74%), febrile neutropenia (16%), and anemia (13%). No Grade 5 events were observed. Overall, 6 patients discontinued combination treatment due to an AE. In the ABVD cohorts (n=25), AEs of pulmonary toxicity, dyspnea, and interstitial lung disease that could not be distinguished from bleomycin toxicity led to discontinuation of bleomycin in 7 patients. Five of these 7 patients continued treatment with AVD and brentuximab vedotin. All 10 patients who had a response assessment available after completion of frontline therapy achieved CR. Currently, an expansion cohort of approximately 20 patients is enrolling to explore 1.2 mg/kg brentuximab vedotin combined with AVD therapy.

In this interim analysis of 31 patients with newly diagnosed HL, the maximum tolerated dose in combination with ABVD or AVD was not reached; no DLT was observed up to 1.2 mg/kg, the maximum planned dose. Brentuximab vedotin treatment was associated with manageable AEs; the most frequent AEs in the study were nausea and neutropenia. The safety profile observed thus far in this study suggests that brentuximab vedotin has potential for combination therapy with ABVD or AVD. Updated safety and response data will be presented at the meeting.

Younes:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau, Travel Expenses; Novartis: Honoraria, Research Funding, Speakers Bureau; Sanofi-Aventis: Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding; SBIO: Research Funding; Syndax: Research Funding; Celgene: Speakers Bureau; Gilead: Honoraria; Pharmacyclic: Honoraria. Off Label Use: Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). It is an investigational agent that is being studied in CD30+ malignancies. Connors:Seattle Genetics, Inc.: Research Funding. Park:Seattle Genetics, Inc.: Research Funding. Hunder:Seattle Genetics, Inc.: Employment, Equity Ownership. Ansell:Seattle Genetics, Inc.: Research Funding.