A Phase I Study of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody–Drug Conjugate, in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma

Abstract

Purpose: ADCT-402 (loncastuximab tesirine) is an antibody-drug conjugate comprising a CD19-targeting antibody and pyrrolobenzodiazepine dimers. A first-in-human study evaluated the safety and preliminary clinical activity of loncastuximab tesirine in patients with B-cell non-Hodgkin lymphoma (NHL).Patients and Methods: A multicenter, phase I, doseescalation and dose-expansion study enrolled patients ages !18 years with relapsed/refractory (R/R) B-cell NHL. Patients received loncastuximab tesirine every 3 weeks at doses assigned by a 3þ3 dose-escalation design. Dose escalation was used to assess the safety and tolerability of loncastuximab tesirine to determine the dose for expansion. Secondary objectives evaluated clinical activity, characterized the pharmacokinetic profile, and evaluated antidrug antibodies.Results: During dose escalation, 88 patients with R/R B-cell NHL were treated with loncastuximab tesirine at doses 15 to 200 mg/kg. Treatment-emergent adverse events (TEAEs) were experienced by 87/88 (98.9%) patients. Most common TEAEs (!20% of patients) were hematologic abnormalities, fatigue, edema, liver test abnormalities, nausea, rash, and dyspnea. Grade !3 TEAEs (!5% of patients) included hematologic abnormalities, liver test abnormalities, fatigue, and dyspnea. Overall response rate at doses !120 mg/kg was 59.4% (41 of 69 patients; 40.6% complete response; 18.8% partial response). Median duration of response, progression-free survival, and overall survival (all doses) were 4.8, 5.5, and 11.6 months, respectively. Drug exposure increased with increasing dose, showing moderate accumulation with multiple doses !150 mg/kg. There was no evidence of immunogenicity.Conclusions: Loncastuximab tesirine had promising activity with acceptable safety in this dose-escalation study. A phase II study with initial dosing at 150 mg/kg has been initiated based on these results.

CD19 antibody-drug conjugate therapy in DLBCL does not preclude subsequent responses to CD19-directed CAR T-cell therapy

“…7 CD19 expression is lost during terminal plasma cell differentiation but maintained in hematologic B-cell malignancies. 7 Several clinical trials using monoclonal antibodies, 8 antibody-drug conjugates (ADCs), 9 and bispecific T-cell engagers targeting the CD19 antigen are ongoing in B-cell non-Hodgkin lymphoma. Studies investigating CD19-directed CAR T-cell therapies in aggressive lymphomas frequently excluded patients previously treated with CD19 targeting immunotherapies.…”

“…Loncastuximab tesirine is an ADC comprising a humanized anti-CD19 monoclonal antibody stochastically conjugated to a pyrrolobenzodiazepine dimer toxin, SG3199. 10 A phase 1 first-in-human study of loncastuximab tesirine demonstrated encouraging clinical activity in patients with relapsed/refractory DLBCL, 9 and a phase 2 study recently finished patient accrual (#NCT03589469).…”

Antibody–Drug Conjugates: The Last Decade

“…Rovalpituzumab tesirine (Rova-T or SC16LD6.5) is an anti-DLL3 ADC developed by AbbVie (Stemcentrx) tested in phase III in small cell lung cancer [87,88]. While ADC Therapeutics developed loncastuximab tesirine (ADCT-402) [89] and camidanlumab tesirine (ADCT-301) [90], both tested in pivotal phase II, respectively against B cell acute lymphoblastic leukemia and Hodgkin lymphoma (Figure 9). Tesirine (SG3249) was designed to combine powerful antitumor activity with desirable physicochemical properties (e.g., favorable hydrophobia and improved bioconjugation).…”

Antibody–Drug Conjugates for Cancer Therapy

“…However, the synthetic PBD dimers consisting of two PBD units joined through a linker can also form interstrand or intrastrand DNA cross-links. PBD dimers are sequence selective, and are distinguished from conventional DNA cross-linking agents (e.g., platinum drugs), in that the interstrand cross-links formed between DNA and PBD dimer do not cause distortion of DNA and hence go undetected by DNA repair mechanisms, maintaining its activity and ultimately leading to cell death [ 40 , 41 , 42 ]. Loncastuximab tesirine is an ADC containing anti-CD19 antibody conjugated to a PBD dimer SG3199, and is currently in a phase III clinical trial ( Table 3 ) [ 42 ].…”