On April 23, 2021, loncastuximab tesirine-lpyl, a CD19-directed antibody and alkylating agent conjugate, was granted accelerated approval for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two 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.1
Supporting Efficacy Data
Approval was based on findings in the phase II LOTIS-2 trial (ClinicalTrials identifier.gov NCT03589469).2 In the trial, 145 adult patients with relapsed or refractory DLBCL or high-grade B-cell lymphoma after at least two prior systemic regimens were treated with loncastuximab tesirine at 0.15 mg/kg every 3 weeks for two cycles and at 0.075 mg/kg every 3 weeks for subsequent cycles via intravenous (IV) infusion. Patients received treatment until progressive disease or unacceptable toxicity. Patients with bulky disease or active central nervous system lymphoma were excluded from the trial.
Among all patients, median age was 66 years (range = 23–94 years), 59% were male, and 90% were White, 3% Black, and 2% Asian. Overall, 94% had an Eastern Cooperative Oncology Group performance status of 0 or 1. Diagnosis was DLBCL-not otherwise specified or arising from low-grade lymphoma (20%) in 88% and high-grade B-cell lymphoma in 8%. The median number of prior therapies was three (range = 2–7), 63% had refractory disease, 17% had prior stem cell transplantation, and 9% had prior chimeric antigen receptor T-cell therapy.
The main efficacy outcome measure was overall response rate, as assessed by independent review committee using Lugano 2014 criteria. Median follow-up was 7.3 months (range = 0.3–20.2 months). An objective response was observed in 70 patients (48.3%, 95% confidence interval [CI] = 39.9%-–6.7%), with a complete response in 35 (24.1%, 95% CI = 17.4%–31.9%). Median response duration was 10.3 months (95% CI = 6.9 months to not estimable). Of the 70 patients with an objective response, 25 (36%) were censored for response duration prior to 3 months; 18 (26%) had a response for ≥ 6 months.
How It Works
Loncastuximab tesirine is an antibody-drug conjugate targeting CD19. The monoclonal IgG1 kappa antibody component binds to human CD19, a transmembrane protein expressed on the surface of cells of B-lineage origin. The small-molecule component is SG3199, a pyrrolobenzodiazepine dimer and alkylating agent. Upon binding to CD19, loncastuximab tesirine is internalized, followed by release of SG3199 via proteolytic cleavage.
The released SG3199 binds to the DNA minor groove and forms highly cytotoxic DNA interstrand crosslinks, subsequently inducing cell death. Loncastuximab tesirine exhibited anticancer activity in animal models of lymphoma.
How It Is Used
The recommended loncastuximab tesirine dosage is 0.15 mg/kg every 3 weeks for two cycles, followed by 0.075 mg/kg every 3 weeks for subsequent cycles via 30-minute IV infusion.
Unless contraindicated, patients should be premedicated with dexamethasone at 4 mg orally or IV twice daily for 3 days beginning the day before administration of loncastuximab tesirine. If dexamethasone administration does not begin the day before, it should begin at least 2 hours prior to administration of the antibody-drug conjugate. Product labeling provides information on dosage modification for adverse reactions, including neutropenia, thrombocytopenia, edema or effusion, and other (grade ≥ 3) nonhematologic adverse reactions.
If loncastuximab tesirine dosing is delayed by more than 3 weeks due to toxicity, subsequent doses should be reduced by 50%; discontinuation should be considered if toxicity recurs following dose reduction. If toxicity requires dose reduction following the second dose of 0.15 mg/kg (cycle 2), the patient should receive the dose of 0.075 mg/kg for cycle 3.
Among the 145 patients receiving loncastuximab tesirine in the LOTIS-2 trial, the median number of cycles received was three, with 34% of patients receiving at least five cycles.
In the trial, the most common adverse events of any grade (≥ 20%), including laboratory abnormalities, were thrombocytopenia (58%), increased gamma-glutamyltransferase (57%), neutropenia (52%), anemia (51%), hyperglycemia (48%), increased aspartate transaminase (41%), fatigue (38%), hypoalbuminemia (37%), increased alanine transaminase (34%), rash (30%), edema (28%), nausea (23%), and musculoskeletal pain (23%). The most common grade ≥ 3 nonlaboratory abnormality adverse events included edema (3%) and abdominal pain (3%). The most common grade 3 or 4 laboratory abnormalities were neutropenia (30%), increased gamma-glutamyltransferase (21%), thrombocytopenia (17%), and hyperglycemia (8%).
Serious adverse events occurred in 28% of patients, with those occurring in ≥ 2% being febrile neutropenia, pneumonia, edema, pleural effusion, and sepsis. Adverse events led to dose reductions in 8%, most commonly due to increased gamma-glutamyltransferase (≥ 4%), and to dosage interruption in 49%. Treatment was permanently discontinued in 19%. Death from adverse events occurred in 1% of patients, due to infection.
Loncastuximab tesirine has warnings/precautions for effusion and edema, myelosuppression, infections, cutaneous reactions, and embryofetal toxicity. Patients should be monitored for the development of pleural effusion, pericardial effusion, ascites, peripheral edema, and general edema and diagnostic imaging should be considered when symptoms develop or worsen. Patients should have blood counts monitored and should be monitored for infection and new or worsening cutaneous reactions, including photosensitivity reactions. Patients should be advised not to breastfeed while receiving loncastuximab tesirine.
1. U.S. Food and Drug Administration: FDA grants accelerated approval to loncastuximab tesirine-lpyl for large B-cell lymphoma. Available at https://www.fda.gov/drugs/fda-grants-accelerated-approval-loncastuximab-tesirine-lpyl-large-b-cell-lymphoma. Accessed May 11, 2021.
2. Zynlonta (loncastuximab tesirine-lpyl) for injection, for intravenous use, prescribing information, ADC Therapeutics SA, April 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761196s000lbl.pdf. Accessed May 11, 2021.