Effect of E7777 Immunogenicity on Pharmacokinetics, Efficacy, and Safety in Adult Patients With Relapsed or Refractory Cutaneous T-Cell Lymphoma.

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E7777 is a therapeutic recombinant fusion protein comprised of diphtheria toxin fragments and human interleukin-2 (IL-2). Treatment with E7777 generates anti-drug antibodies (ADA). E7777-G000-302 assessed the efficacy and safety of E7777 in patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL). Here, we describe the association between E7777 (at 9 μg/kg) and ADAs, and its effect on pharmacokinetics (PK), efficacy, and safety. Of 91 patients with immunogenicity results at baseline, 78.0% and 5.5% had preexisting anti-E7777 (E-ADAs) and anti-IL-2 antibodies (I-ADAs), respectively. The prevalence of E-ADAs and I-ADAs peaked at C3D1 (median titer 650,175) and C8D1 (median titer 32,805), respectively. However, I-ADA fold increases (1312-fold) were higher than E-ADA increases (181-fold). ADAs' effect on PK was assessed after treatment. E7777 reached Cmax at 60 min after infusion, with clearance of 44.6 mL/min at C1D1 and 133 mL/min at C5D1. Cmax and AUC(0-t) decreased by 60% and 84%, respectively, at C5D1 compared with C1D1. Of patients in the safety analysis set (n = 84) evaluated for treatment-emergent (TE) ADAs, 92.9% were considered TE E-ADA positive and 82.1% were TE I-ADA positive. The objective response rate was 39.0% in TE E-ADA-positive patients and 42.6% in TE I-ADA-positive patients. Serious TE adverse events were reported by 32.1% of TE E-ADA-positive patients, 29.0% of TE I-ADA-positive patients, 100% of E-ADA-negative patients, and 73.3% of I-ADA-negative patients. These results indicate that the presence of ADAs decreased E7777 exposure over time but did not adversely impact efficacy and safety in patients with CTCL.