The U.S. Food and Drug Administration (FDA) has accepted its Biologics License Application (BLA) from ADC Therapeutics for loncastuximab tesirine, previously know as ADCT-402, for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and granted priority review status. The FDA has set a Prescription Drug User Fee Act (“PDUFA”) target date of May 21, 2021.
Loncastuximab tesirine is an antibody-drug conjugate composed of a humanized monoclonal antibody directed against human CD19 and conjugated through a linker to a pyrrolobenzodiazepine (PBD) dimer cytotoxin. Once bound to a CD19-expressing cell, the investigational drug is designed to be internalized by the cell, following which the warhead is released.
The PBD-payload is designed to bind irreversibly to DNA to create highly potent interstrand cross-links that block DNA strand separation, thus disrupting essential DNA metabolic processes such as replication and ultimately resulting in cell death. CD19 is a clinically validated target for the treatment of B-cell malignancies.
Loncastuximab tesirine is ADC Therapeutics lead product candidate. The drug has been evaluated in a 145-patient pivotal Phase II clinical trial for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) that showed a 48.3% overall response rate (ORR), which exceeded the target primary endpoint. Loncastuximab tesirine is also being evaluated in LOTIS 3, a Phase I/II clinical trial in combination with ibrutinib in patients with relapsed or refractory DLBCL or mantle cell lymphoma, and LOTIS 5, a Phase III confirmatory clinical trial in combination with rituximab in patients with relapsed or refractory DLBCL.
“The FDA’s acceptance of our BLA and granting of priority review for loncastuximab tesirine is a tremendous accomplishment that brings ADC Therapeutics one step closer to being able to offer patients with relapsed or refractory DLBCL a greatly needed new treatment option in 2021,” noted Chris Martin, Chief Executive Officer of ADC Therapeutics.
“We look forward to working with the FDA during its review of our BLA submission for loncastuximab tesirine. Our organization remains focused on robust planning for a successful launch next year,” Martin added.
The BLA submission is based on data from LOTIS 2, the pivotal Phase II multi-center, open-label, single-arm clinical trial evaluating the efficacy and safety of Lonca in patients with relapsed or refractory DLBCL following two or more lines of prior therapy. In June 2020, researchers presented maturing data from LOTIS 2 at the virtual 25th Congress of the European Hematology Association.
Patients participating in the Lotus 2 study received 30-minute intravenous infusions of loncastuximab tesirine once every three weeks (Q3W) at a dose of 150 μg/kg for the first two cycles, followed by 75 μg/kg for subsequent cycles for up to one year or until disease progression, unacceptable toxicity, or other discontinuation criteria, whichever occurred first. As of the data cut-off date of April 6, 2020, 145 patients were enrolled and received a mean of 4.3 cycles of loncastuximab tesirine (range: 1-15).
Loncastuximab tesirine achieved an overall response rate (ORR) of 48.3% (70/145 patients) and a complete response rate (CRR) of 24.1% (35/145 patients), compared to an ORR of 45.5% (66/145 patients) and CRR of 20.0% (29/145 patients) in the previous data cut (October 14, 2019). Patients refractory to first-line or last-line prior therapy had ORRs of 37.9% and 36.9%, respectively.
The tolerability profile was manageable with the most common grade ≥3 treatment-emergent adverse events in ≥10% of patients being: neutropenia (25.5%) with low incidence of febrile neutropenia (3.4%), thrombocytopenia (17.9%), GGT increase (16.6%), and anemia (10.3%).
Data from subgroup analyses of LOTIS 2 will be presented in a poster (abstract #1183) at the upcoming 62nd American Society for Hematology (ASH) Annual Meeting on Saturday, December 5, 2020.
Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma – NCT03589469
Safety and Antitumor Activity Study of Loncastuximab Tesirine and Durvalumab in Diffuse Large B-Cell, Mantle Cell, or Follicular Lymphoma – NCT03685344
Safety and Efficacy Study of Loncastuximab Tesirine + Ibrutinib in Diffuse Large B-Cell or Mantle Cell Lymphoma – NCT03684694
Study to Evaluate Loncastuximab Tesirine With Rituximab Versus Immunochemotherapy in Participants With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (LOTIS 5) – NCT04384484
Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Acute Lymphoblastic Leukemia (B-ALL) – NCT02669264
Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL) – NCT02669017
 Depaus J, Ervin-Haynes A, Bryan L, Magagnoli M, Gritti G, Chao G, Boni J, Dautaj I, Wagner-Johnston N. Interim results of a Phase I/II study of loncastuximab tesirine (Lonca) combined with ibrutinib in advanced diffuse large B-cell lymphoma (DLBCL) o mantle cell lymphoma (MCL). EHA Library. Depaus J. 06/12/20; 293773; EP1284 [Abstract]
 Carlo-Stella C, Luigi Zinzani P, Kahl B, Caimi P, Solh M, Ardeshna K, Stathis A, Hamadani M, Ai W, et al. Initial results of a phase 2 study of loncastuximab tesirine, a novel pyrrolobenzodiazepine-based antibody-drug conjugate, in patients with relapsed or refractory diffuse large B-cell lymphoma. EHA Library. Carlo-Stella C. 06/12/20; 295053; S233 [Abstract]
 Caimi PF, Ai WZ, Alderuccio JP, Ardeshna KM, Hamadani M, Hess BT, Kahl BS, Radford JA, et al. Efficacy and Safety of Loncastuximab Tesirine (ADCT-402) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma. ASH Virtual program Program: Oral and Poster Abstracts | Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Saturday, December 5, 2020, 7:00 AM-3:30 PM [Abstract]