Background
Phase II, single-arm study. 145 patients with R/R DLBCL (including transformed FL and high-grade BCL) after ≥2 prior lines of therapy, including anti-CD20 and anthracycline. Loncastuximab tesirine (Lonca) is an anti-CD19 antibody-drug conjugate with a pyrrolobenzodiazepine (PBD) dimer payload causing DNA crosslinks.
Interventions and follow up
Regimen: Loncastuximab tesirine 0.15 mg/kg IV every 3 weeks × 2, then 0.075 mg/kg every 3 weeks thereafter (up to 1 year) in R/R DLBCL after ≥2 prior lines
Primary endpoint: Overall response rate (independent review committee)
Median follow-up: 7.3 months
Primary endpoint: Overall response rate (independent review committee)
Median follow-up: 7.3 months
Results
ORR (primary): 48.3% (95% CI 39.9–56.7%)
CR rate: 24.1%
mDOR (responders): 10.3 months
mPFS: 4.9 months
mOS: 9.9 months
CR rate: 24.1%
mDOR (responders): 10.3 months
mPFS: 4.9 months
mOS: 9.9 months
Adverse events
Overall: Grade ≥3 AEs 68.3%; treatment discontinuation due to AEs 10.3%
Hematologic: Grade ≥3 neutropenia 26.9%
PBD-related: Edema any grade 44.8% (grade ≥3 3.4%); pleural effusion 17.2%; photosensitivity 10.3%; skin reactions any grade 23.4%; elevated GGT 27.6% (grade ≥3 21.4%)
Hematologic: Grade ≥3 neutropenia 26.9%
PBD-related: Edema any grade 44.8% (grade ≥3 3.4%); pleural effusion 17.2%; photosensitivity 10.3%; skin reactions any grade 23.4%; elevated GGT 27.6% (grade ≥3 21.4%)
Conclusions
Loncastuximab tesirine achieved a 48.3% ORR in heavily pretreated R/R DLBCL, with durable responses in CR patients. The PBD-based mechanism provides a non-overlapping toxicity profile with prior ADCs, supporting its role in later-line therapy.
Key Limitations
Single-arm Phase II without a comparator. Short median follow-up (7.3 months) limits assessment of durability and OS. PBD-payload toxicities (edema, effusions, hepatic enzyme elevation, photosensitivity) require monitoring and dose modification. Shares the CD19 target with CAR-T and tafasitamab, raising unresolved sequencing/antigen-loss questions. Modest CR rate (24.1%) in heavily pretreated disease.
Clinical Context
FDA granted accelerated approval of loncastuximab tesirine (Zynlonta) in April 2021 for R/R DLBCL after ≥2 prior lines; EMA approved in 2022. ESMO and ASCO guidance include loncastuximab tesirine among later-line single-agent options for R/R DLBCL. Optimal sequencing relative to CD19 CAR-T and tafasitamab remains an open question given shared CD19 antigen.