FDA approves ADC’s Zynlonta
The Food and Drug Administration (FDA) granted accelerated approval to Zynlonta (loncastuximab tesirine-lpyl) for the treatment of adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy. Now that the FDA has approved Zynlonta, ADC Therapeutics can offer patients who have diffuse large B-cell lymphoma an option if CAR-T therapy does not work. Additional clinical trials that are underway might expand use of the antibody drug conjugate to more cancer patients.
While the most serious cases of lymphoma can be treated with a drug made by engineering a patient’s immune cells to target tumors, CAR-T therapy does not work in all situations. In securing its first FDA drug approval, ADC Therapeutics is now able to offer such patients another kind of treatment option.
Zynlonta is a type of drug called an antibody drug conjugate. This kind of drug has received FDA approval for several cancers, but ADC’s drug is the first of this type of therapy approved for DLBCL, a type of non-Hodgkin 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.
In the phase 2 ZUMA-2 study, KTE-X19 CAR-T therapy demonstrated a lasting clinical benefit and manageable side effects in relapsed/refractory mantle cell lymphoma. Continued approval for this indication may be subject to verification and description of clinical benefit in a confirmatory trial.
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). It was assessed by an independent review committee using Lugano 2014 criteria.
Findings showed an ORR of 48.3 percent (n=70; 95 percent CI, 39.9–56.7), with 24.1 percent (n=35; 95 percent CI, 17.4–31.9) of patients achieving complete response and 24.1 percent (n=35; 95 percent 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 percent CI, 6.9-not estimable) among responders. Patients also had a median time to response of 1.3 months (range, 1.1–8.1).
The most common adverse reactions (20 percent 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.
