Results from a pivotal 145-patient Phase II clinical trial of loncastuximab tesirine (ADCT-402; ADC Therapeutics) for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) have shown positive results.
To date, loncastuximab tesirine has achieved an overall response rate (ORR) of 45.5% (66/145 patients), including 20% complete responses and 25.5% partial responses, across a broad population of relapsed or refractory DLBCL patients, even those who are difficult to treat.
Loncastuximab tesirine is an antibody-drug conjugate (ADC) composed of a humanized monoclonal antibody directed against human CD19. The antibody is stochastically conjugated via a valine-alanine cleavable, maleimide linker to a pyrrolobenzodiazepine (PBD) dimer cytotoxin.
PBD dimers are generated out of PBD monomers, a class of natural products produced by various actinomycetes. They work by crosslinking specific sites of the DNA, blocking the cancer cells’ division that cause the cells to die. As a class of DNA-crosslinking agents they are significantly more potent than systemic chemotherapeutic drugs.
Mechanism of action
Once bound to a CD19-expressing cell, loncastuximab tesirine is designed to be internalized by the cell, after which the cytotoxic payload is released. The 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, a protein which is highly expressed on the surface of B-cell hematological tumors, is a clinically validated target for the treatment of B-cell malignancies.
Comparably, the ORR in the 183-patient Phase I clinical trial of loncastuximab tesirine at the initial dose used in Phase II was 41.4% (29/70 patients), including 21.4% complete responses and 20% partial responses. Loncastuximab tesirine has demonstrated manageable toxicity in patients with relapsed or refractory DLBCL. The most common grade ≥3 treatment-emergent adverse events in the Phase 2 clinical trial were neutropenia, thrombocytopenia and increased gamma-glutamyltransferase.
“These data exceeded our primary endpoint target and reinforce the significant single-agent anti-tumor activity and manageable toxicity profile of loncastuximab tesirine in patients with relapsed or refractory DLBCL who have failed established therapies,” noted Jay Feingold, MD, Ph.D, Senior Vice President and Chief Medical Officer at ADC Therapeutics.
“Loncastuximab tesirine has demonstrated its potential to fill a critical unmet need for a new therapy and become a key part of the treatment paradigm for all heavily pretreated patients with DLBCL. We plan to present final data from the pivotal Phase II clinical trial at a future scientific meeting,” Feingold added.
Based on the results, the company is on track for Biologics License Application (BLA) submission of loncastuximab tesirine in 3Q 2020
“We look forward to submitting a BLA to the U.S. Food and Drug Administration for accelerated approval of loncastuximab tesirine for the treatment of relapsed or refractory DLBCL patients who have failed two or more treatment regimens later this year and we are building our commercial organization in anticipation of a launch in the second quarter of 2021,” said Chris Martin, Chief Executive Officer of ADC Therapeutics, said,
The single-arm, multi-center, open-label Phase II clinical trial evaluated the safety, efficacy and pharmacokinetics of loncastuximab tesirine as a monotherapy in patients with relapsed or refractory DLBCL. Patients received 30-minute intravenous infusions of loncastuximab tesirine once every three weeks 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.
In addition to the pivotal Phase II clinical trial in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), researchers at ADC Therapeutics are investigating loncastuximab tesirine in a Phase Ib trial in combination with ibrutinib (Imbruvica®; Pharmacyclics/Janssen Biotech), in patients with R/R DLBCL or mantle cell lymphoma (MCL) and a Phase Ib trial in combination with durvalumab (Imfinzi® ; AstraZeneca) in patients with R/R DLBCL, MCL or follicular lymphoma.
Earlier in the development of loncastuximab tesirine the U.S. Food and Drug Administration (FDA) granted orphan drug designation to loncastuximab tesirine for the treatment of R/R DLBCL and MCL.
Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma – NCT03589469
Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL) – NCT02669017
Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Acute Lymphoblastic Leukemia (B-ALL) – NCT02669264
Safety and Antitumor Activity Study of Loncastuximab Tesirine + Ibrutinib in Diffuse Large B-Cell or Mantle Cell Lymphoma – NCT03684694
Safety and Antitumor Activity Study of Loncastuximab Tesirine and Durvalumab in Diffuse Large B-Cell, Mantle Cell, or Follicular Lymphoma – NCT03685344