The US Food and Drug Administration granted an accelerated approval April 24 for a new drug for use in patients with relapsed/refractory diffuse large B-cell lymphomas (DLBCL) who have tried at least two prior systemic therapies.
The new product, loncastuximab tesirine-lpyl (Zynlonta, ABC Therapeutics), is the first and only CD19-targeted antibody drug conjugate approved for this disease.
DLBCL is the most common type of non-Hodgkin lymphoma in the United States, but the indication also includes DLBCL not otherwise specified (NOS), DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma.
“There is a significant unmet need for treatment options for patients with [relapsed or refractory] DLBCL, including those who have been heavily pretreated and have difficult-to-treat disease,” Paolo F. Caimi, MD, University Hospitals Cleveland Medical Center and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, said in a company press release.
The company also cites data from previous clinical trials showing that more than 40% of first-line DLBCL treatments fail, and that these patients have a poor prognosis, worsening with each line of therapy that is tried.
Accelerated Approval Based on ORR
The accelerated approval was based on overall response rate (ORR) data from the single-arm LOTIS-2 trial. All patients received the new drug, administered as a 30-minute infusion once every 3 weeks for 1 year.
The trial was conducted in 145 patients with r/r DLBCL who had already tried at least two lines of systemic therapy. Caimi noted that this included patients who had been heavily pretreated, as the population included patients who previously received stem cell transplant or CAR-T cell therapy.
The ORR was 48.3% (70/145 patients), which included a complete response rate of 24.1% (35/145 patients) and a partial response rate of 24.1% (35/145 patients).
Patients had a median time to response of 1.3 months and the median duration of response (mDoR) for the 70 responders was 10.3 months.
“Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial,” the company noted.
A phase 3 confirmatory is underway: the LOTIS 5 trial (NCT04384484) compares the combination of loncastuximab tesirine and rituximab vs chemoimmunotherapy in patients with relapsed/refractory DLBCL.
The company also noted that in a pooled safety population the most common adverse reactions (≥20%) were thrombocytopenia, an increase in levels of the liver enzyme gamma-glutamyltransferase (GGT), neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.
In the LOTIS-2 trial, the most common (≥10%) grade ≥3 treatment-emergent adverse events were neutropenia (26.2%), thrombocytopenia (17.9%), GGT increase (17.2%) and anemia (10.3%).
Permanent treatment discontinuation as the result of an adverse reaction occurred in 19% of patients, and these included a GGT increase, edema, and effusion.
Dose reductions because of an adverse reaction occurred in 8% of patients, and most were the result of a GGT increase.
Dosage interruptions because of an adverse reaction occurred in 49% of patients, and these included a GGT increase, neutropenia, thrombocytopenia, and edema.
Warnings On Effusions, Infections and Skin Reactions
The product carries a warning that serious effusion and edema has been reported. Grade 3 edema occurred in 3% (primarily peripheral edema or ascites), grade 3 pleural effusion occurred in 3%, and grade 3 or 4 pericardial effusion occurred in 1%.
Prescribers are recommended to monitor patients for new or worsening edema or effusions, and to consider diagnostic imaging in patients who develop symptoms of pleural effusion or pericardial effusion, such as new or worsened dyspnea, chest pain, and/or ascites such as swelling in the abdomen and bloating.
The product also carries a warning about fatal and serious infections, including opportunistic infections, and serious cutaneous reactions, including photosensitivity reaction, rash (including exfoliative and maculopapular), and erythema.
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