The Food and Drug Administration (FDA) has granted accelerated approval to ZynlontaTM (loncastuximab tesirine-lpyl) for the treatment of adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma.
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. Upon binding to CD19, loncastuximab tesirine is internalized where enzymes release the cytotoxic PBD-based dimer, which binds to DNA to create interstrand cross-links. These cross-links are designed to disrupt DNA metabolic processes such as replication, which ultimately leads to cell death.
The accelerated approval was based on data from the open-label, single-arm phase 2 LOTIS-2 study (ClinicalTrials.gov: NCT03589469), which evaluated the efficacy and safety of loncastuximab tesirine in 145 adults with relapsed or refractory DLBCL after at least 2 prior systemic regimens. Patients received loncastuximab tesirine 0.15mg/kg every 3 weeks for 2 cycles, then 0.075mg/kg every 3 weeks for subsequent cycles until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR), as assessed by an independent review committee using Lugano 2014 criteria.
Findings showed an ORR of 48.3% (n=70; 95% CI, 39.9-56.7), with 24.1% (n=35; 95% CI, 17.4-31.9) of patients achieving complete response and 24.1% (n=35; 95% CI, 17.4-31.9) having partial response. After a median follow-up time of 7.3 months (range, 0.3-20.2), the median duration of response was 10.3 months (95% CI, 6.9-not estimable) among responders. Patients also had a median time to response of 1.3 months (range, 1.1-8.1).
As for safety, the most common adverse reactions (20% or more) were thrombocytopenia, increased gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain. Treatment with loncastuximab tesirine has also been associated with effusion and edema, as well as cutaneous reactions.
Zynlonta is supplied in a single-dose vial containing 10mg of loncastuximab tesirine-lpyl as a lyophilized powder for intravenous infusion after reconstitution and further dilution. The Advancing Patient Support Program has also been launched by ADC Therapeutics to assist eligible patients receiving Zynlonta.
- ADC Therapeutics announces FDA approval of Zynlonta™ (loncastuximab tesirine-lpyl) in relapsed or refractory diffuse large B-Cell lymphoma. [press release]. Lausanne, Switzerland: ADC Therapeutics SA; April 23, 2021.
- FDA grants accelerated approval to loncastuximab tesirine-lpyl for large B-cell lymphoma. [press release]. Silver Spring, MD: US Food and Drug Administration; April 23, 2021.
- Zynlonta [package insert]. Murray Hill, NJ: ADC Therapeutics America; 2021.