Minimal Residual Disease (mrd), Pharmacokinetic (pk), Andpharmacodynamic (pd) Assessment Of Epcoritamab 2
Abstract Type: e-Poster Presentation
Topic: Indolent and mantle-cell non-Hodgkin lymphoma — Clinical
Background:In the pivotal EPCORE™ NHL1 trial (phase 1/2; NCT03625037), epcoritamab treatment (tx) with a 2-step step-up dose (SUD) regimen led to high overall and complete response rates of 82% and 63%, respectively, inpatients with R/R FL. Safety was manageable, with CRS events being primarily low grade. However, furthermitigation of CRS may enhance the accessibility of epcoritamab for the tx of R/R FL.
Aims:To assess MRD, PK, and PD of a 2-step SUD regimen in cycle © 1 in comparison with a 3-step optimizationregimen in C1 (C1 OPT) in patients with R/R FL.
Methods:Patients with CD20+ R/R FL (grade 1–3A) with ≥2 prior tx lines received subcutaneous epcoritamab in 2-step(0.16 and 0.8 mg) or 3-step (0.16, 0.8, and 3 mg) SUD regimens in C1, followed by 48-mg full doses in 28-day(d) Cs (QW, C1–3; Q2W, C4–9; Q4W, C≥10) until disease progression. The C1 OPT cohort receivedrecommendations for adequate hydration and dexamethasone as the preferred steroid for CRS prophylaxis. Hospitalization for monitoring was based on investigator discretion. T-cell phenotypes were assessed byvalidated flow cytometry assays and cytokines were tested with the Meso Scale Discovery platform. MRDanalysis was performed on peripheral blood mononuclear cells collected at prespecified time points(clonoSEQ® assay, Adaptive Biotechnologies). Screening tumor biopsies were used to identify trackable tumorclones; samples were quantified as tumor clones detected per 1 million nucleated cells. Overall response andprogression-free survival (PFS) were assessed by Lugano criteria per investigator assessment.
Results:PK was comparable between 2-step SUD and C1 OPT cohorts except for transient, lower epcoritamab troughconcentrations, as expected, after SUD 3 (3 mg) on C1D15 in the C1 OPT cohort compared with the 2-step SUDcohort, which received the full dose (48 mg) on C1D15. The 2-step SUD cohort showed a marked increase inmedian IL-6 levels 24 h after the first full dose on C1D15, whereas the C1 OPT cohort showed low median IL6levels in C1 and beyond, supporting the reduction of CRS in the C1 OPT cohort. Rapid, sustained depletion ofcirculating CD3−CD19+ peripheral B cells was observed by C1D15 in both groups. In addition, in both groups,T-cell margination was observed in C1, followed by recovery to baseline levels by C2D1 and modest Tcellexpansion for subsequent doses. Frequency of proliferating Ki67+ and activated PD1+ CD4+ and CD8+ T cellsincreased after each dose in C1 in both groups. T-cell proliferation and activation were prolonged to C2 in theC1 OPT cohort. From C3 onward, the frequency of proliferating and activated T cells returned to near-baselinelevels and was similar in both groups. MRD negativity was observed in 61 (67%) of 91 evaluable patients in the2-step SUD cohort and 28 (64%) of 44 patients in the C1 OPT cohort (Table). In the majority of durableresponders in both groups, epcoritamab induced MRD negativity by C3D1. In both groups, patients who lostMRD-negative status also lost their response, and the majority of nonresponders never became MRD negative.Median PFS was not reached in MRD-negative patients; for both dosing regimens, median PFS was around 4mo for responders who were not MRD negative.