Results from a pivotal phase II study of brentuximab vedotin (SGN-35) in patients with relapsed or refractory Hodgkin lymphoma (HL).

Abstract

Background: Relapsed/refractory (R/R) Hodgkin lymphoma (HL) remains a significant clinical challenge. We hypothesized that using an immune checkpoint inhibitor to activate the immune cells in the tumor microenvironment, and concurrently targeting tumor cells with the CD30 antibody-drug conjugate brentuximab vedotin (BV) could overcome resistance. E4412 is a Phase 1 ECOG-ACRIN sponsored study of the combinations of BV and ipilimumab (Ipi) and nivolumab (Nivo) in patients with R/R HL. Here we present the updated safety and response data on the full cohort of patients treated with BV + Nivo (Arms D-F). Methods: Patients with confirmed R/R HL were treated with Nivo 3 mg/kg and BV 1.2 mg/kg (Arm D) or 1.8 mg/kg (Arm E) with a 3 + 3 design, and an expansion cohort (Arm F) of 9 patients. BV and Nivo are given every 21 days for 16 cycles; Nivo may be continued for an additional year. Dose limiting toxicity (DLT) was defined within the first cycle of therapy. Results: As of 3/10/17 19 patients (1 ineligible) have been treated. Median age was 40, range (21-70); 9 patients were male. Patients were treated with a median of 3 prior therapies. Eight patients had prior SCT; 4 patients had prior BV. Safety: Nineteen of 19 patients are evaluable for safety. There were 2 significant treatment related adverse events (AEs): 1 patient in Arm E experienced a DLT (pneumonitis grade 3 with grade 3 dyspnea and hypoxia, and typhilits), and made a full recovery; 1 elderly patient in Arm F had grade 5 pneumonitis occurring in cycle 2. There were no other Grade 4 or 5 AEs; grade 3 AEs were one each: rash, puritis, and neutropenia. The most common grade 1-2 AEs were: transaminitis (9), peripheral sensory neuropathy (8), and rash (6); other grade 1-2 AEs included: diarrhea (4), blurry vision (3), and myalgias (2). One grade 1-2 infusion reaction was noted, this patient was able to receive subsequent therapy with pre-medication. Response: Response is shown below in Figure 1. Seventeen of 18 eligible patients are evaluable for response, one patient died after cycle 2 and response could not be assessed. The overall response rate (ORR) for the combination was 89%, with a CR rate of 50% (9/18) (95% CI: 26%-74%). There were 2 CRs and 1 PR in patients treated with prior BV. The 6 month PFS is 91% (95% CI: 75-100%), and median OS with a median follow-up of 6 months is not reached. Conclusion: In this study of the combination of Nivo and BV for R/R HL, therapy was generally well tolerated, however two patients experienced pneumonitis. In a heavily pretreated patient population, the ORR of 89% and CR rate of 50% suggests a deepening of response compared to either therapy alone. Optimization of this strategy is planned with ongoing accrual to cohorts receiving BV + Ipi + Nivo. Data will be updated to include longer term PFS and OS by the time of the meeting.

Phase 1 multicenter trial of brentuximab vedotin for steroid-refractory acute graft-versus-host disease

“…Brentuximab vedotin (BV) is a CD30-directed antibody-drug conjugate consisting of the human CD30 antibody cAC10 and the microtubule-disrupting agent, monomethyl auristatin E (MMAE). BV is approved for the treatment of relapsed classical Hodgkin lymphoma 7 and systemic anaplastic large-cell lymphoma 8 and has also been preliminarily shown to be safe and effective for treatment of relapsed disease after allogeneic HCT. 9 Here, we report the results of a multicenter phase 1 study investigating BV for the treatment of SR-aGVHD.…”

Phase II Study of Bendamustine in Relapsed and Refractory Hodgkin Lymphoma

“…Recently, brentuximab vedotin was approved for this specific patient population, but even with this active agent, median progression-free survival was approximately 6 months. 4 Patients who achieve adequate responses to post-ASCT salvage therapies are often referred for an allogenic stem-cell transplantation (alloSCT), which is associated with long-term remission rates ranging from 20% to 59%; however, minimal disease state at the time of transplantation is important for favorable outcome. [5][6][7] Bendamustine is a bifunctional alkylating agent with only partial cross resistance to other alkylating agents, making it an attractive agent for use in the relapsed setting.…”

Current Status of Autologous Stem Cell Transplantation in Relapsed and Refractory Hodgkin's Lymphoma

“…A phase I, open-label trial in 42 HL patients who had failed a median of three previous chemotherapies, including 73% with prior ASCT, showed durable objective responses, with mild toxicity in the majority of patients [79]. Recently a pivotal phase II study confirmed the efficacy and safety of this agent in 102 patients with relapsed or refractory HL after ASCT [80]. An ongoing, randomized, placebo-controlled, multicenter phase III trial is evaluating the efficacy and safety of brentuximab vedotin in patients who have received ASCT in the previous 30 -45 days and are at high risk for residual HL post-ASCT, defined as those with a history of refractory disease who relapse or progress within 1 year from receiving frontline chemotherapy and those who have extranodal disease at the time of relapse (ClinicalTrials.gov identifier, NCT01100502).…”