Limited Duration Loncastuximab Tesirine Induces a High Rate of Complete Responses in Patients with Relapsed/Refractory Marginal Zone Lymphoma - Report of First Planned Interim Futility Analysis of a Multicenter Phase II Study

Introduction: Marginal zone lymphoma (MZL) is a heterogeneous disease representing 7% of non-Hodgkin lymphomas (NHL). Three subtypes are recognized by the primary site of involvement: extranodal (EMZL), nodal (NMZL), and splenic (SMZL) and all are characterized by frequent relapses. Complete response (CR) rate is demonstrated as one of the most important prognostic factors in MZL and was recently validated as the best surrogate marker in EMZL patients treated with systemic therapy. In relapse setting, there is no standardized therapeutic approach and CR is infrequently achieved. We initiated a multicenter clinical trial to examine loncastuximab tesirine (Lonca) efficacy in inducing CR and improving survival in relapsed/refractory (r/r) MZL patients needing treatment. Methods: This is an open label multi-institutional investigator-initiated study evaluating safety and efficacy of Lonca in r/r MZL (NCT05296070). Adult patients, previously treated with ≥1 line of systemic therapy, were eligible if needing treatment based on symptoms, predefined criteria by MZL subtype, or if they experienced POD24. Patients are staged by routine subtype and organ directed tests, PET-CT and CT or MRI imaging. Treatment is given every 3 weeks with i.v. Lonca 0.15mg/kg for 2 cycles followed by 0.075mg/kg for 4 cycles. The primary endpoint is CR after 6 cycles based on Lugano 2014 criteria using PET-CT (if FDG avid at presentation) or CT/MRI (for non-avid disease). Premedication with dexamethasone 4 mg twice daily for 3 days and prophylaxis with spironolactone 100 mg (to prevent fluid overload) was required. The study implements a Bayesian Optimal Phase 2 design, with two sequential interim analyses of the CR rate, at 20 (3 or more CRs to continue accrual) and 40 (9 or more CRs to continue accrual) evaluable patients, and a final analysis with 50 evaluable patients. At the time of study design, the best reported CR rate in r/r MZL was 16% achieved with umbralisib, that we used as P0 assumption under the null hypothesis. We expected at least a 15% increase in the CR rate, resulting in a CR rate of 31% (P1 under the alternative hypothesis). Results: 22 patients were enrolled from July 2022 to June 2024. Median age was 64 years (range 45-80) with 14 (63.6%) females. Eleven were white non-Hispanic, 8 Hispanic, 1 Black non-Hispanic and 2 Asian. Distribution by MZL subtypes: 14 EMZL, 7 NMZL and 1 SMZL. 18 patients had advanced-stage disease. After frontline systemic treatment, 14 had relapse, including POD24 in 11, and 8 patients had primary refractory MZL. The median number of previous treatments was 2 (range 1 to 4). Across all lines of treatment, the most common treatments were R-chemotherapy (n=18), targeted/immuno-modulatory agents (n=7) and single-agent rituximab (n=7); 1 patient had CAR-T. As of July 1, 2024, 20 patients were evaluable for response. Currently, the ORR is 85% (n=17) with CR rate of 75% (n=15 out of 20). Ten patients were in CR at the end of treatment (n=9 after cycle 6, and n=1 after cycle 4 (treatment stopped due toxicity)), 1 patient in CR after cycle 2 (stopped treatment, off study), and 4 patients in CR after cycle 2 (ongoing treatment). Additionally, 2 patients in PR and 1 patient in SD at the end of 6 cycles of treatment, and 2 patients in SD after cycle 2 (ongoing treatment). Lonca led to CR in 7 of 9 patients (77%) with POD24 that were assessed for response and one patient who progressed after CAR-T. All but 1 CR are currently maintained with longest follow up of 23 months from the start of treatment (median duration of CR 10 months). One patient with dural EMZL relapsed 17 months after achieving CR. Updated results will be presented at the meeting. All 22 patients experienced expected adverse events (AE), most commonly grade 1-2. Grade 3 and 4 AEs were observed in 11 and 1 (neutropenia) patients, respectively. Most common AEs were grade 1-2 photosensitivity and maculopapular rashes in 15 (68%), elevated LFTs in 15 (68%; grade 3 in 5 (22.7%) patients) and infections in 11 (50%, grade 3 in 3 (13.6%)). Local edema was observed in 1 (4.5%) patient. 2 patients needed dose reduction and 1 patient discontinued treatment after cycle 4 because of cholestatic hepatitis. The patient clinically fully recovered with normalization in LFTs abnormalities. Conclusion: Lonca is demonstrating clinically meaningful activity with robust CR rate in r/r MZL patients in our ongoing phase 2 study.