Abstract
Introduction: A paucity of data exists about loncastuximab tesirine (loncastuximab) activity in follicular lymphoma (FL). Fourteen patients with relapsed/refractory (r/r) FL were enrolled in the original phase I study, demonstrating an overall response rate (ORR) of 78.6% with a complete response rate of 64.3% and not reached median progression-free survival (PFS) or overall survival (OS). We conducted a clinical trial evaluating loncastuximab with rituximab in r/r FL based on these encouraging results and preclinical data demonstrating synergistic activity between both agents. We have now completed study enrollment and present the results of this novel combination.
Methods: This is asingle-institution phase II investigator-initiated study evaluating loncastuximab with rituximab in r/r FL (NCT04998669). Adult patients previously treated with ≥1 line of systemic therapy and presented with POD24 or GELF criteria were eligible for enrollment.The primary study endpoint was the complete metabolic response (CMR) by week 12 PET/CT based on Lugano 2014 criteria. Bone marrow biopsy was required at screening and repeated at week 12 if originally involved. The initial 21 weeks of therapy consisted of 4 weekly doses of rituximab i.v. 375mg/m2 followed by 1 dose every 8 weeks for a total of 5 doses in combination with loncastuximab i.v. 0.15mg/kg every 3 weeks for 2 doses followed by 0.075mg/kg every 3 weeks for a total of 7 doses. Premedication with dexamethasone 4 mg twice daily for 3 days was required. Patients achieving CMR at week 21 discontinued loncastuximab and received two more doses of rituximab every 8 weeks. No prophylaxis was required per study protocol. Enrollment occurred according to a Simon's minimax two-stage design with a total sample size of 39 patients based upon a projected CR rate ≥50% vs ≤30% (H0), type I error alpha 5%, power 80%.
Results: Thirty-nine patients were enrolled from January 2022 to June 2024; all patients were evaluated for toxicity and 35 for response. Median age was 68 years (range 47 to 89). Most were men (53.8%), with advanced-stage (82%), high-disease burden by GELF criteria (87.2%), and/or POD24 after frontline immunochemotherapy (51.3%). The median FLIPI score was 3, with most patients allocated to the high-risk group (61.5%). Median lines of prior therapy were 1 (range 1 to 6). R-CHOP was the most common first-line therapy (56.5%), followed by bendamustine with rituximab (25.6%), single-agent rituximab (15.3%), and fludarabine, mitoxantrone and dexamethasone (2.6%).
The most common treatment-emergent adverse events included neutropenia (53.8%), alkaline phosphatase elevation (53.8%), anemia (46.1%), maculopapular rash (46.1%), fatigue (43.5%), and ALT and AST elevation (38.4%, each). Grade ≥3 neutropenia occurred in 5 cases (23.8%) with a single episode of neutropenic fever in a patient with cellulitis after upper extremity trauma. UTI was the most common infection affecting 4 (10.2%) patients (all grade 2). Fluid accumulation was predominantly grade ≤2 and treatable with diuretics. No treatment-related deaths occurred during the study period.
Among 35 patients evaluable for response, the ORR at week 12 was 97.1% [CMR rate of 68.6% (n=24), partial metabolic response (PMR) rate of 28.6% (n=10)]. All CMRs were maintained, and 4 of the 10 PMRs (one patient not assessed yet) improved to CMR at week 21 for a best CMR rate of 80% (n= 28). Baseline FL bone marrow involvement resolved in all patients (n=10) at week 12 reassessment. Patients with POD24 demonstrated an ORR of 100% with a CMR rate of 80%.
With a median follow-up of 15.6 (0.1 to 28.5) months, the time-to-event endpoints were as follows: 12-month PFS 94.2% (95%CI 78.7-98.5%) and OS 93.3% (95%CI 75.6-98.3%), 18-month PFS 90.1% (95%CI 71.9-96.8%) and OS 93.3% (75.6-98.3%), and not reached median PFS and OS. Three events occurred at the current follow-up. Two patients with disease progression on imaging had biopsy-proven transformation to diffuse large B-cell lymphoma and died from aggressive lymphoma, and one patient had relapsed FL and is currently on observation due to asymptomatic and localized disease. Updated results will be presented at the meeting.
Conclusion: Loncastuximab with rituximab demonstrates dramatic activity with robust CMR and 12-month PFS of 94.2% in high-risk r/r FL. Our study supports this combination as a new treatment option in FL, and a multicenter expansion cohort is ongoing.
Alderuccio:Regeneron: Consultancy; AbbVie: Consultancy; Genmab: Research Funding; ADC Therapeutics: Consultancy, Research Funding; BeiGene: Research Funding; Genentech: Consultancy. Alencar:Epizyme: Consultancy; Abbvie: Consultancy; TG therapeutics: Consultancy; Amgen: Consultancy; Kite: Consultancy; SeaGen: Consultancy; Janssen: Consultancy; Beigene: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Loxo/Lilly: Consultancy, Research Funding. Kuker:ADCT: Research Funding. Pongas:CRISPR Therapeutics: Current holder of stock options in a privately-held company; MEVOX LTD: Current equity holder in publicly-traded company; Amgen: Current holder of stock options in a privately-held company; Eli Lilly: Current holder of stock options in a privately-held company. Lossos:University of Miami: Current Employment; ADCT: Research Funding; Not specified: Patents & Royalties. Moskowitz:Merk: Research Funding; ADCT: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; SGEN: Research Funding.