A Phase 2, Open-Label Study of Loncastuximab Tesirine in Combination with Rituximab (Lonca-R) in Previously Untreated Unfit/Frail Patients with Diffuse Large B-Cell Lymphoma (DLBCL) (LOTIS-9)

Background: Rituximab in combination with chemotherapy (R [rituximab]-CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone]) is the standard first-line therapy for patients with DLBCL. With an aging population, unfit or frail patients who may not tolerate R-CHOP represent an increasing unmet need. There is also significant heterogeneity in how fitness for therapy is assessed. The simplified geriatric assessment (sGA) identifies three distinct categories (fit, unfit, and frail) based on age, activities of daily living (ADL), instrumental activities of daily living (IADL), and the Cumulative Illness Rating Scale for Geriatrics (CIRS-G, J Clin Oncol 2021;39(11):1214-1222). Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca), an antibody-drug conjugate comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin, is approved in relapsed or refractory (R/R) DLBCL based on data from the phase 2 LOTIS-2 pivotal trial (Lancet Oncol 2021;22(6):790-800). The safety and efficacy of Lonca-R in combination is also being studied in patients with R/R DLBCL versus immunochemotherapy in an ongoing, separate study (LOTIS-5; NCT04384484).

Objectives: To determine the safety and efficacy of Lonca-R in previously untreated unfit/frail patients with DLBCL, as characterized by the sGA, in the LOTIS-9 clinical trial (NCT05144009).

Methods: This is a phase 2, open-label, response-adapted study of Lonca-R in previously untreated unfit (Cohort A) or frail (Cohort B) patients with DLBCL. Key inclusion criteria include diagnosis of DLBCL (including DLBCL transformed from indolent lymphoma), high-grade B-cell lymphoma, or grade 3b follicular lymphoma; Eastern Cooperative Oncology Group performance status of 0-2; and measurable disease (2014 Lugano Classification). Each cohort will enroll 40 patients, with fitness (Cohort A) and frailty (Cohort B) assessed using the sGA. The primary objectives are to assess efficacy (Cohorts A and B) and tolerability (Cohort B) of Lonca-R. The primary endpoint will be the complete response (CR) rate (Cohorts A and B) and tolerability defined by the percentage of patients completing a total of 4 cycles of therapy (Cohort B). Lonca-R treatment consists of R intravenously (IV) 375 mg/m² on day 1 of cycles 1-4 (subcutaneously allowed starting at C2), Lonca 150 µg/kg IV on day 2 of cycle 1 and day 1 of cycle 2, and Lonca 75 µg/kg IV on day 1 of cycles 3 and 4. After completion of 3 Lonca-R cycles, patients who achieve CR or partial response (PR) will continue to receive 1 or 3 additional cycles of Lonca-R, respectively. Patients in Cohort A who do not achieve a CR or PR will discontinue study treatment. Patients in Cohort B who achieve stable disease and derive clinical benefit, per the treating physician, may continue to receive an additional 3 cycles of Lonca-R. All patients will be followed every 12 weeks for 1 year, every 24 weeks for up to 3 years, and then annually for up to 5 years.

Results: The study is currently enrolling patients in the United States and will be available to centers in additional countries in the coming months, including Spain, Italy, and Israel.

Funding: ADC Therapeutics SA; medical writing: CiTRUS Health Group.

Westin:Merck: Consultancy; Iksuda: Consultancy; Calithera: Consultancy, Research Funding; MonteRosa: Consultancy; AstraZeneca: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; MorphoSys/Incyte Corporation: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Abbvie/GenMab: Consultancy; SeaGen: Consultancy. Burke:Kura: Consultancy; Epizyme: Consultancy; Roche/Genentech: Consultancy; Nurix: Consultancy; Morphosys: Consultancy; Kymera: Consultancy; Bristol Myers Squibbs: Consultancy; BeiGene: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; Adaptive Biotechnologies: Consultancy; Abbvie: Consultancy; SeaGen: Consultancy, Speakers Bureau; TG Therapeutics: Consultancy; Verastem: Consultancy; X4 Pharmaceuticals: Consultancy. Chapman:ADC Therapeutics: Consultancy; Roche: Consultancy. Kilavuz:ADC Therapeutics: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Xu:ADC Therapeutics: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Schmuely:ADC Therapeutics: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Stanford:ADC Therapeutics: Ended employment in the past 24 months. Beedle:ADC Therapeutics: Ended employment in the past 24 months. Radford:BMS: Consultancy, Honoraria; Takeda: Consultancy, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy, Current equity holder in private company, Current holder of stock options in a privately-held company, Honoraria, Speakers Bureau; The University of Manchester and Christie Hospital NHS Foundation Trust: Current Employment; Kite Pharma: Consultancy; Astrazenca: Current equity holder in private company, Current holder of stock options in a privately-held company.

The safety and efficacy of loncastuximab tesirine (Lonca) in combination with rituximab in previously untreated unfit/frail patients with DLBCL is being investigated in the LOTIS-9 clinical trial. Lonca is FDA-approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, DLBCL not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma.