Background: E4412 is a Phase 1/2 ECOG-ACRIN sponsored study of the combinations of brentuximab (BV), nivolumab (N), and ipilimumab (I) in patients with R/R HL. Here we present the long-term safety and response data on the full cohort of patients treated in Phase 1 (Arms A-I).
Methods: Patients with confirmed R/R HL were treated in sequential dose escalation cohorts using 3+3 design. Additional patients were enrolled in expansion cohorts. Dose limiting toxicity (DLT) was evaluated within the first cycle of therapy.
Results: Between March 7, 2014, and Dec 28, 2017, 64 patients were enrolled; 3 patients were excluded due to ineligibility after enrolment. Thirty-five patients (57%) were refractory to their prior therapy; twenty-one (34%) had autologous stem cell transplant (SCT), 4 (6%) had prior alloSCT. Eight patients (13%) had prior BV. Safety: All 64 enrolled patients are included in the safety analysis. The most common (>30%) treatment-related grade 1–2 AEs were: nausea, peripheral sensory neuropathy, diarrhea, fatigue, elevated liver transaminases, anemia, and rash. Grade 3+ rash was more common in BV-I, in 22% of 23 patients compared with 7% of 41 patients in the other groups. Grade 3-4 events occurred in ten (43%) patients on BV-I, three (16%) patients on BV-N, and 12 (55%) patients in the triplet group. Two (3%) patients had treatment related death, one on BV-N (pneumonitis) and one in the BV-N-I group (dyspnea).
Response: The overall response rate (ORR) was 76% for BV-I, with a complete remission (CR) rate of 57%, for BV-N the ORR was 89% with a CR rate of 61% and for BV-N-I the ORR was 82% with a CR rate of 73%. The median follow-up (Q1, Q3) for PFS and OS is 2.24 (1.67, 2.72) years and 2.98 (2.83, 3.04) years. Duration of response (DOR) is 1.32 years for BV-I responders, not reached for BV-N and BV-N-I responders (Figure 1A). The median PFS is 1.1 years, NR, and 2.49 years for BV-I, BV-N and BV-N-I respectively (Figure 1B). The median OS has not been reached for any of the arms (Figure 1C).
Conclusion: Long term data from the Phase 1 component of E4412 shows no late safety concerns, and significant durability of response in both N containing arms with median follow-up of nearly 3 years. Analysis of the impact of transplant and depth of response will be updated by the time of the meeting. Optimization of this strategy is ongoing in E4412, now a randomized phase 2 study comparing the doublet of BV-N to the triplet of BV-N-I.
Catherine Diefenbach, Opeyemi Jegede, Richard Ambinder, Jonathon Cohen, Michael Robertson, Kevin David, Ranjana Advani, Timothy Fenske, Stefan Barta, Neil Palmisiano, Jakub Svoboda, David Morgan, Reem Karmali, Brad Kahl, Stephen M. Ansell