Author: [AUTHOR] Published on 5/7/2021 9:10:00 AM

FDA Approves ZYNLONTA (Loncastuximab Tesirine-lpyl) for the Treatment of Adult Patients with Elapsed or Refractory Large B-Cell Lymphoma after Two or More Lines of Systemic Therapy

On April 23, 2021, the US Food and Drug Administration (FDA) approved ZYNLONTA (loncastuximab tesirine-lpyl) for the 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. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

ZYNLONTA is administered as an intravenous (IV) infusion over 30 minutes on Day 1 of each cycle (every 3 weeks). The approved recommended dosage of ZYNLONTA is 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles. Patients should be premedicated with dexamethasone 4 mg orally or IV twice daily for 3 days beginning the day before administering ZYNLONTA. If dexamethasone administration does not start the day before ZYNLONTA, begin at least 2 hours prior to administration of ZYNLONTA. 

Additional information regarding dosage and administration as well as warnings and precautions about effusion and edema, myelosuppression, infections, cutaneous reactions, and embryo-fetal toxicity can be found in the full prescribing information linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK) 

• MOA: Loncastuximab tesirine-lpyl is a CD19-directed antibody and alkylating agent conjugate. The small molecule component is SG3199, a pyrrolobenzodiazepine dimer and alkylating agent. 
• General PK: The mean (CV%) exposure of loncastuximab tesirine-lpyl at the approved recommended dosage in Cycle 2 and at steady state is shown in Table 1. Loncastuximab tesirine-lpyl steady state C_max was 28.2% lower than the C_max after the first dose. The time to reach steady state was 210 days.
• Distribution: The mean (CV%) loncastuximab tesirine-lpyl volume of distribution was 7.11 (26.6%) L. 
• Elimination: The mean (CV%) loncastuximab tesirine-lpyl clearance decreased with time from 0.499 L/day (89.3%) after a single dose to 0.275 L/day (38.2%) at steady state. The mean (standard deviation) half-life of loncastuximab tesirine-lpyl was 20.8 (7.06) days at steady state. 
• Metabolism: The monoclonal antibody portion of loncastuximab tesirine-lpyl is expected to be metabolized into small peptides by catabolic pathways. The small molecule cytotoxin, SG3199, is metabolized by CYP3A4/5 in vitro. 
• Excretion: The major excretion pathways of SG3199 have not been studied in humans. SG3199 is expected to be minimally renally excreted. 
• Cardiac Electrophysiology: At the maximum recommended therapeutic dose of 0.15 mg/kg during Cycle 1 and Cycle 2, loncastuximab tesirine-lpyl does not cause large mean increases (i.e., > 20 msec) in the QTc interval. 
• Immunogenicity: In LOTIS-2 trial, 0 of 134 patients tested positive for antibodies against loncastuximab tesirine-lpyl after treatment. The potential effect of anti-drug antibodies to ZYNLONTA on pharmacokinetics, efficacy, or safety is unknown. 

Use in Specific Populations
No clinically significant differences in the PK of loncastuximab tesirine-lpyl were observed based on age (20 to 94 years), sex, race (White vs. Black), body weight (42.1 to 160.5 kg), ECOG status (0 to 2), mild to moderate renal impairment (CLcr 30 to 90 mL/min using the Cockcroft-Gault equation), or mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin > 1 to 1.5 × ULN and any AST). 

The effect of severe renal impairment (CLcr 15 to 29 mL/min), end-stage renal disease with/without hemodialysis, or moderate or severe hepatic impairment (total bilirubin > 1.5 ULN and any AST) on loncastuximab tesirine-lpyl PK is unknown.

Efficacy and Safety
Efficacy of ZYNLONTA was evaluated in LOTIS-2, an open-label, single-arm trial in 145 adult patients with relapsed or refractory DLBCL after at least 2 prior systemic regimens. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

Most common (≥ 20%) adverse reactions, including laboratory abnormalities, are thrombocytopenia, increased gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.

Full prescribing information is available at https://go.usa.gov/xHnK9.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

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Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.