Consolidation with loncastuximab tesirine for large B-cell lymphoma patients in partial response after CART: Planned interim futility analysis of a phase II trial

Abstract Introduction. Approximately 30% of patients with large B-cell lymphoma (LBCL) achieve a partial response (PR) after CAR T-cell therapy (CART). While about 70% of PR patients will progress, there is no standard consolidation strategy for these patients, who are typically only observed. Loncastuximab tesirine (Lonca) is an antibody-drug conjugate targeting (ADC) CD19, currently approved by the FDA for the treatment of LBCL patients who relapse or progress after at least 2 lines of systemic therapy. As CD19 expression is maintained in most patients who relapse or progress after CART and no negative effect on T cells has been shown for this ADC, we hypothesized that Lonca would be a safe and effective consolidation strategy for those who achieve a PR after CART. Methods. This single arm phase II study (NCT05464719) was conducted between October 2022 and January 2025 (data cut-off 06/2025). Adult patients with relapsed or refractory LBCL achieving PR after commercial autologous anti-CD19 CART were included in the study. Lonca was administered intravenously, on day 1 of a 21-day cycle, at a dose of 150 mcg/kg for the first 2 cycles, and 75 mcg/kg subsequently, for a total of 6 cycles. Toxicity was evaluated according to CTCAE v5 and response by Lugano 2014 criteria. A first interim futility analysis was planned after the first 10 patients completed treatment, and the study considered futile if less than 4 patients converted to a complete response (CR) or more than 3 experienced an unacceptable toxicity. Results. Ten patients were included in this first interim futility analysis. Median age was 74 (range, 45-84), 8 (80%) were male, 6 (60%) had received axicabtagene ciloleucel and 4 (40%) had received lisocabtagene maraleucel. At time of study entry, median lesion diameter was 3.2 cm (range, 1.1-7.6 cm), 4 (40%) patients had a maximum standardized uptake volume > 10, and 3 (30%) a Deauville score of 5. The most common (>1) grade (G) 3-4 adverse events were thrombocytopenia (60%), neutropenia (60%) and anemia (20%); the most common (>2) G1-2 toxicities were infections (70%), fatigue (50%), AST elevation (50%), ALT elevation (40%), skin rash (40%), thrombocytopenia (30%), ascites (30%) and peripheral edema (30%); 2 (20%) experience photosensitivity (both G1-2), and 3 (30%) GGT elevation (G3 in 1). Median number of Lonca cycles was 6 (range, 3-6), 6 (60%) experienced a cycle delay (3 due to thrombocytopenia, 2 due to COVID19 infection, and 1 due to paresthesia), and 1 patient required dose reduction (due to thrombocytopenia). Five (50%) patients discontinued treatment before completion, 3 due to progression, 1 due to persistent thrombocytopenia, 1 due to persistent GGT elevation (the latter 2 were considered unacceptable toxicities). Of ten patients, 4 (40%) converted to CR (3 after 3 cycles, and 1 after 6 cycles). After a median follow-up of 19 months (95% CI 4-34 months), all the 4 patients who experienced a conversion to CR on lonca have maintained their response without relapse. To date, 5 (50%) patients have died: 4 due to progression and 1 due to infection while in CR (16 months later). Conclusions. Our results indicate that Lonca is a feasible consolidation strategy for LBCL patients who achieve PR after CART. This study will continue to enroll another 10 patients to achieve the second interim futility analysis. Correlative analyses will include serial assessment of minimum residual disease and descriptive analysis of tumor molecular biology, including DNA and RNA sequencing.