Odronextamab Monotherapy for the Treatment of Relapsed/Refractory (R/R) Follicular Lymphoma (FL) and Diffuse Large B-Cell Lymphoma (DLBCL): Focus on Clinical Pharmacology and Pharmacometrics in the ELM-1 and ELM-2 Studies

Abstract

Background Odronextamab is a CD20×CD3 bispecific antibody that binds CD20 on B-cells and CD3 on T-cells, triggering T-cell-mediated cytotoxicity of malignant B-cells. Odronextamab demonstrated clinically meaningful efficacy and generally manageable safety in patients (pts) with R/R FL and DLBCL in the Ph 1 ELM-1 (NCT02290951; Bannerji R, et al . Lancet Haematol. 2022) and Ph 2 ELM-2 (NCT03888105) studies (Kim TM. ASH. 2022; Kim WS. ASH. 2022). Here, assessments of pharmacokinetics (PK), pharmacodynamics (PD), and exposure-response (E-R) analyses for efficacy and safety are presented, to support posology for the treatment of R/R FL and DLBCL. Methods Pts enrolled in ELM-1 and ELM-2 received IV odronextamab step-up doses of 0.7, 4, and 20 mg in Weeks (Wks) 1-3 of Cycle (C) 1 (21-day/cycle), odronextamab QW (FL: 80 mg; DLBCL: 160 mg) during C2-4, then odronextamab Q2W (FL: 160 mg; DLBCL: 320 mg) until disease progression or unacceptable toxicity. Pts who achieved a durable complete response for ≥9 months transitioned to Q4W dosing. After odronextamab infusion, serum samples were collected over time, odronextamab serum concentrations measured, and data analyzed using descriptive and population PK methods. Blood samples were collected to measure T-cells, T-cell activation and proliferation markers (e.g. HLA-DR, Ki67), peripheral CD19 + B-cells, and cytokines. E-R for efficacy was assessed with trough concentration at time of first efficacy assessment (C trough at Wk 12) and best overall response using logistic regressions. E-R for safety was assessed with odronextamab concentrations at the time of a safety event and safety events including any grade (Gr) and Gr ≥3 treatment-emergent AEs (TEAEs) via multivariate analyses. Results The PK of odronextamab were characterized in 507 pts and were similar between different ethnic populations across B-cell non-Hodgkin lymphoma types. Concentration-time profiles were similar with step-up doses in pts with FL and DLBCL. Exposure in pts with DLBCL was 2-fold higher than in FL during C2-4, in line with the 2× higher dose. PD profiles were similar in pts with FL and DLBCL. Rapid, pronounced, and prolonged B-cell depletion in blood was observed following infusion. Early T-cell activation and proliferation was observed, with T-cell expansion higher in clinical responders vs. nonresponders. Transient cytokine release was mainly observed in C1 and was infrequent in subsequent cycles. In pts with FL, the probability of clinical response increased with odronextamab exposure and the largest response (89%) was achieved at exposures consistent with the median C trough of 80 mg QW at Wk 12, supporting use of 80 mg QW for FL. Exposures associated with 80 mg QW in C2-4 were maintained or exceeded with subsequent 160 mg Q2W maintenance doses. In pts with DLBCL, the probability of clinical response increased with odronextamab exposure, but less steeply than for FL. The largest response (57%) was achieved at exposures consistent with the median C trough of 160 mg QW at Wk 12, supporting use of 160 mg QW for DLBCL. Exposures associated with 160 mg QW were maintained or exceeded with subsequent 320 mg Q2W maintenance doses. Exposure-safety analysis showed consistent results in FL and DLBCL. Among multiple factors evaluated that had potential to be associated with TEAEs, odronextamab exposure was not associated with any Gr or Gr ≥3 TEAEs, including cytokine release syndrome and infections, over time. Conclusions PK analyses showed predictable concentration-time profiles through step-up dosing, at treatment doses, and during maintenance. PD analyses showed durable and complete depletion of B-cells; T-cell activation, proliferation, and expansion; and transient cytokine release, consistent with the mechanism of action of odronextamab. In comparison with DLBCL, clinical response increased with odronextamab exposure faster for FL and can reach a higher response at 80 mg QW. Therefore, a higher odronextamab dose of 160 mg QW is needed to achieve maximal response for DLBCL. The studied regimens showed clinically meaningful activity and acceptable tolerability, and the risk of any Gr or Gr ≥3 TEAEs is not increased from low to high odronextamab exposures. Comprehensive PK, PD, exposure-efficacy, and exposure-safety analyses demonstrated that the selected odronextamab dose regimens have favorable efficacy and generally manageable safety profiles for the treatment of R/R FL and DLBCL.