Loncastuximab tesirine, an anti-CD19 antibody-drug conjugate, in relapsed/refractory B-cell acute lymphoblastic leukemia

Abstract

Relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remains a therapeutic challenge. Loncastuximab tesirine is an antibody-drug conjugate against CD19, an antigen expressed in many B-cell malignancies. This open-label, single-arm, dose-escalation, dose-expansion study assessed the safety, tolerability, pharmacokinetics (PKs), immunogenicity, and preliminary clinical activity of loncastuximab tesirine in adults with R/R B-ALL. A total of 35 patients were enrolled, with a median age of 55 years (range, 20-80) and a median of 3 prior therapies (range, 1-15). All patients received at least 1 IV infusion of loncastuximab tesirine at 15 to 150 μg/kg once every 3 weeks (Q3W; n = 30) or 50 μg/kg IV weekly (n = 5). Common treatment-emergent adverse events (TEAEs) were nausea (42.9%), febrile neutropenia (37.1%), and reversible liver test abnormalities. Grade ≥3 TEAEs were reported in 85.7% patients, most commonly febrile neutropenia and other hematologic abnormalities and reversible liver test abnormalities. There were no treatment-related deaths. Four patients (11.4%) had grade 2 infusion-related reactions, and 1 patient (150 μg/kg Q3W) had a dose-limiting toxicity of hyperbilirubinemia that resolved within 6 days without further action. The maximum tolerated dose was not reached. Three patients achieved complete responses, 1 each at 30, 120, and 150 μg/kg Q3W. PK studies showed marked interpatient variability, with target-mediated drug disposition seeming to contribute to time- and dose-dependent disposition. No clinically relevant anti–drug-antibody formation occurred. The trial was terminated in the dose-escalation phase because of slow accrual. This trial was registered at www.clinicaltrials.gov as NCT02669264.

Navitoclax enhances the effectiveness of EGFR-targeted antibody-drug conjugates in PDX models of EGFR-expressing triple-negative breast cancer

“…Interestingly, recent pre-clinical studies have demonstrated that fractionated dosing of PBD-containing ADCs mitigates side effects and maintains effectiveness [ 44 ]. Although the ABBV-321 recommended clinical dosing regimen remains to be established, previous clinical testing of other PBD-loaded ADCs indicates that clinical doses have been much lower than used here, and or at much longer intervals for a very limited number of cycles [ 45 – 47 ]. Clinical dosing, safety, and tolerability will be ultimately informed by results from an ongoing phase I clinical trial investigating ABBV-321 in EGFR-overexpressing solid tumors (NCT#03234712).…”

Antibody-drug conjugates (ADCs) delivering pyrrolobenzodiazepine (PBD) dimers for cancer therapy

“…Loncastuximab tesirine showed only modest efficacy in B-cell acute lymphoblastic leukaemia [52]. In a phase 1 study in adults with relapsed or refractory disease, a total of 35 patients were enrolled with a median age of 55 and a median of three prior therapies.…”

Direct control of CAR T cells through small molecule-regulated antibodies

“…While our work focused on the reduction of toxicity for CAR-based therapies, other antibody-based drug modalities have also been associated with significant toxicities that could be reduced through the use of conditional antibodies. For example, CRS has been associated with T cell-redirecting bispecific antibodies 42 , 43 , and tumor lysis syndrome has been associated with antibody–drug conjugates 44 , 45 , both of which are especially pronounced in patients with high tumor burden. Autoimmune adverse events have been associated with monoclonal antibody-based immune checkpoint inhibitors that target PD-1 and CTLA-4 46 .…”

“…We demonstrated how these antibodies can be used to generate conditional CAR T cells with target-specific cytotoxicity whose activity can be reversibly attenuated by the addition of a small molecule to potentially mitigate therapy-associated toxicities. In addition to CAR T cells, these unique scaffolds could be applied to a broad range of antibody-based therapeutics for the development of safer therapeutics including, bispecific antibodies 43 , antibody–drug conjugates 44 , 45 , and antibody-based immune-modulatory agents 46 , which are often hindered by a variety of associated adverse effects. Endowing exogenous control over antibody-based therapeutics would dramatically enhance their therapeutic index, thereby increasing their therapeutic value in tackling difficult-to-treat diseases.…”