Exposure-Response Analyses Supporting Optimal Epcoritamab Full Dose and Dosing Schedule in Relapsed or Refractory Follicular Lymphoma

Background: Epcoritamab is the first and only bispecific antibody approved in the U.S. to treat both relapsed or refractory (R/R) follicular lymphoma (FL) and R/R diffuse large B-cell lymphoma (DLBCL). The approved dosing regimen in R/R FL includes a 3-step step-up dose (SUD) regimen (0.16 mg priming dose on Day 1, 0.8 mg first intermediate dose on Day 8, 3 mg second intermediate dose on Day 15) followed by 48 mg QW full dose until end of cycle 3, Q2W from C4-C9 and Q4W from C10 and beyond. The 3-step SUD regimen has been shown to reduce the incidence and severity of CRS in pts with R/R FL while providing deep responses [1]. The objective of this analysis is to identify the optimal full dose and dosing schedule for epcoritamab in patients with R/R FL.

Methods: A wide range of epcoritamab full doses from 0.12 mg to 48 mg were explored in patients with R/R FL. To determine the optimal full dose and dosing schedule for epcoritamab in R/R FL, comprehensive analyses of clinical safety, efficacy, pharmacokinetic, and exposure-efficacy and exposure-safety analyses were conducted using data from escalation and expansion cohorts of the EPCORE NHL-1 and EPCORE NHL-3 studies with a clinical data cutoff of Apr 21, 2023. Logistic regression analyses were used to explore the relationship between exposure-efficacy (overall response rate (ORR) and complete response, (CR)) and exposure-safety (including grade ≥3 treatment-emergent AEs (TEAEs), serious TEAEs, grade ≥3 neutropenia, grade ≥3 infections, TEAEs leading to dose delay, TEAEs leading to treatment discontinuation, any-grade CRS, grade ≥2 CRS, CRS requiring tocilizumab, ICANS, and clinical tumor lysis syndrome). In addition, Kaplan-Meier analyses were used to compare the survival probability over time (duration of response (DOR), progression-free survival (PFS) and overall survival (OS)) using exposure quartiles.

Results: Epcoritamab PK is similar between R/R FL and R/R DLBCL patients. In the expansion cohort of the EPCORE NHL-1 study, treatment with the approved full dose in R/R FL patients led to a high ORR (82%) and CR rate (60%) and durable responses in these highly refractory patient population (median duration of response, NR [95% CI, 13.7-NR]). Overall, the safety profile of epcoritamab with the recommended dosing regimen is predictable and manageable. Consistent with exposure-response relationships observed in R/R DLBCL, higher exposure in R/R FL patients also was associated with higher ORR (P<0.0005 for the EPCORE NHL-1 FL population; n=138, 114 with response) and CR rate (P<0.0005 for the EPCORE NHL-1 FL population; n=138, 85 with CR) and a potential plateau of efficacy was observed at 48 mg. Additionally, higher exposure was associated with improved PFS (P<0.0005 for the EPCORE NHL-1 FL population) and OS (P=0.001 for the EPCORE NHL-1 FL population). The DOR analysis exhibited a similar numerical trend (P=0.386 for the EPCORE NHL-1 FL population). The pooled analysis of EPCORE NHL-1 and EPCORE NHL-3 FL populations showed similar trends. 96.2% of the initial responses were achieved within the first 3 cycles (QW dosing interval), with a median time to response (CR or PR) of 1.4 months and a median time to CR of 1.5 months in the expansion part of EPCORE NHL-1. Most responders maintained or improved their responses during the subsequent Q2W and Q4W dosing schedules, independent of exposure during these periods. Consistent with the observed efficacy, median B-cell count rapidly reached undetectable levels by C1D15 and remained undetectable throughout treatment. The exposure-safety analysis did not identify increase in rate and severity of adverse events (AEs) with increasing exposure.

Conclusions: Our analyses supported the optimal 48 mg full dose and dosing schedule for epcoritamab in patients with R/R FL. The approved 48 mg full dose provided deep and durable responses with predictable and manageable safety profile in patients with R/R FL. Consistent with R/R DLBCL, lower exposures owing to lower doses may compromise efficacy without improvement of the benefit-risk profile in R/R FL, whereas increasing the full dose is unlikely to result in significantly higher efficacy. The recommended dosing intervals (QW followed by Q2W and Q4W) for epcoritamab treatment not only induced rapid responses but also maintained or improved responses during treatment.