Loncastuximab and Rituximab in Elderly Unfit/Frail Patients With Previously Untreated Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) therapy is typically treated with multi-agent chemotherapy with curative intent but is often challenging or poorly tolerated in patients who are elderly, frail, or have significant comorbidities. LOTIS-9 was a phase 2 trial of loncastuximab tesirine (loncastuximab tesirine-lpyl [Lonca]) plus rituximab (Lonca-R) in patients with newly diagnosed DLBCL who were unfit (cohort A) or frail with or without cardiac comorbidities (cohort B), the majority of whom typically would be ineligible for trials. Patients received Lonca (150 µg/kg during cycles 1-2, 75 µg/kg for subsequent cycles) and R (375 mg/m2) intravenously Q3W for 3-6 cycles, adapted based on response after cycle 3. The primary endpoint of cohort A was complete response (CR) rate; coprimary endpoints of cohort B were CR rate and proportion of patients who completed treatment per protocol. The median age was 84 years (range, 80-91) in cohort A (n=17) and 80 years (range, 67-92) in cohort B (n=24). The CR rates were 52.9% (A: 9/17) and 41.7% (B: 10/24), respectively. In cohort B, 8 (33.3%) patients completed treatment. Grade ≥3 adverse events occurred in 31 (75.6%) patients, including 11 fatal events. Due to toxicity concerns in this medically fragile population, LOTIS-9 was voluntarily terminated prematurely though meaningful efficacy was demonstrated in patients who typically would be ineligible for clinical trials and/or standard of care therapies. These findings provide important insights for future trials. Additional investigation of targeted therapies in vulnerable unfit and frail patients with DLBCL is warranted. (ClinicalTrials.gov Identifier: NCT05144009).