Exposure-Response Analyses to Inform the Optimal Epcoritamab Monotherapy Dosing Regimen in Relapsed or Refractory
Mahipal Sinnollareddy1,2, Kinjal Sanghavi3, Leonid Gibiansky4
1Clinical Pharmacology, AbbVie Inc., North Chicago, IL, USA. mahipal.sinnollareddy@abbvie.com.
Background:
Epcoritamab is approved for treating various relapsed/refractory (R/R) lymphomas. In a phase I/II study in R/R follicular lymphoma (FL) patients, epcoritamab demonstrated high response rates (EPCORE NHL-1: objective response rate [ORR]: 82.0%, complete response [CR] rate: 62.5% [N = 128]; EPCORE NHL-3: ORR: 95.2%, CR rate: 76.2% [N = 21]) with durable responses and a manageable safety profile with a 2-step step-up dosing (SUD) regimen (0.16/0.8/48 mg [full dose]; Cycles 1-3: once-weekly dosing [QW], Cycles 4-9: every 2-week dosing [Q2W], Cycles 10+: every 4-week dosing [Q4W]).
Methods:
A prior population pharmacokinetic model was updated and exposure-response analyses performed to support the selected dosing regimen (0.76-48 mg full doses evaluated).
Results:
Higher epcoritamab exposure was associated with higher efficacy (ORR, CR rate, progression-free survival, overall survival; p < 0.05) with potential response rate plateau at 48-mg exposures. Initial response occurred in 96.2% of responders during QW with most maintaining/improving response during Q2W and Q4W, independent of Cycle 4+ exposure. No meaningful trends between epcoritamab exposure and treatment-emergent adverse events were identified, including cytokine release syndrome (CRS). Further optimization using a 3-step SUD regimen (0.16/0.8/3/48 mg), with adequate hydration and dexamethasone prophylaxis in Cycle 1, lowered CRS frequency and severity compared with the 2-step SUD regimen. Similar pharmacokinetics and B-cell depletion occurred with 3-step and 2-step SUD regimens. Median IL-6 levels remained consistently low after each Cycle-1 dose and beyond with the 3-step but not 2-step SUD regimen.
Conclusion:
These analyses support and confirm the recommended 3-step SUD regimen with 48 mg full epcoritamab dose administered QW-Q2W-Q4W in patients with R/R FL.
Clinical Trial Registration:
ClinicalTrials.gov: NCT03625037, NCT04542824.