INTERIM RESULTS FROM a PHASE 1/2 STUDY OF BRENTUXIMAB VEDOTIN IN COMBINATION WITH NIVOLUMAB IN PATIENTS WITH RELAPSED OR REFRACTORY HODGKIN LYMPHOMA

Abstract

Introduction: Brentuximab vedotin (BV) may prime an antitumor immune response through the induction of immunogenic cell death via microtubule disruption of CD30-expressing RS cells in classical Hodgkin lymphoma (HL) (Gardai 2015). Nivolumab (nivo) blocks the programmed death-1 (PD-1) immune checkpoint pathway and restores antitumor immune responses. Both drugs have high single-agent response rates in patients (pts) with relapsed or refractory (RR) HL. In combination, these agents could yield higher complete response (CR) rates prior to autologous stem cell transplant (ASCT) and improved outcomes. Methods: This phase 1/2 study is ongoing to evaluate the safety and antitumor activity of BV + nivo in pts with RR HL who have failed frontline chemotherapy (NCT02572167). Pts were treated in 21-day cycles for up to 4 cycles. Pts received BV on Cycle 1 Day 1 and nivo on Cycle 1 Day 8. For cycles 2 through 4, BV and nivo were given on Day 1 of each cycle. Following the Cycle 4 response assessment, pts could undergo ASCT. Responses were assessed using the Lugano classification (Cheson 2014). Results: Of the 62 enrolled pts (52% female, median 36 years), 45% had primary refractory HL. 61 pts received combination treatment (tx): 53 pts completed 4 cycles, 5 pts remain on tx and 4 pts discontinued due to pt decision (2), adverse event (AE,1) and investigator decision (1). Infusion-related reactions (IRRs) occurred in 41%, most frequently during the Cycle 2 BV infusion, and required dose interruptions in 25%. The rate of Gr 3 IRRs was <5%. 60 pts (98%) had tx-emergent AEs prior to ASCT (66% ≤ Gr 2, 28% Gr 3, and 5% Gr 4); Gr 1 nausea (49%) and fatigue (33%) were most frequent. Excluding IRRs, potential immune-related AEs (IrAE) occurred in 72% of pts (66% ≤ Gr 2, 5% Gr 3, 2% Gr 4) with Gr 1 diarrhea (25%) as the most common. Systemic steroids were required in 4 pts (<10%); 1 pt each experienced Gr 4 pneumonitis and colitis, Gr 2 pneumonitis, Gr 3 diarrhea and Gr 2 colitis, and Gr 3 AST elevation. The CR rate was 64%, (55 efficacy evaluable pts; 53% Deauville ≤2, 11% Deauville 3) with an objective response rate of 85%. 4 pts (7%) had stable disease and 3 pts (5%) progressed on tx. To date, 29 pts have initiated ASCT with a median 4.7x106 CD34+ cells/kg collected, and median time to neutrophil and platelet engraftment of 11.5 and 16 days. No unusual post-ASCT toxicities were observed. Observed effects on the immune system, evaluated in peripheral blood, include a decrease in CD30+ T-regulatory cells after Cycle 1 BV while cytotoxic CD8+ T lymphocytes remained stable. With BV + nivo, CD4+ T cells increased, and T-cell receptor sequencing revealed clonal expansion. Serum TARC levels decreased with BV alone, while inflammatory mediators including IFNγ and CXCL10 increased. Conclusion: Interim data suggest BV + nivo is an active and well-tolerated outpatient therapy. These results support further exploration of this chemotherapy-free regimen for pts with RR HL. Keywords: brentuximab vedotin; classical Hodgkin lymphoma (cHL); immunochemotherapy.