A Phase 2 Study of Loncastuximab Tesirine Plus Mosunetuzumab in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

• Published in: Blood 2024-11, Vol.144, p.1742.1-1742.1
• Main Authors: Kambhampati, Swetha, Kallam, Avyakta, Borogovac, Azra, Chen, Lu, Puverel, Sandrine, Johnson, Jennifer, Melgar, Ivana, Baird, John H., Danilov, Alexey, Godfrey, James, Khan, Niloufer, Mei, Matthew, Phillips, Tycel J. J., Siddiqi, Tanya, Shouse, Geoffrey, Zain, Jasmine, Kwak, Larry W., Rosen, Steven T., Forman, Stephen J., Song, Joo Y., Herrera, Alex F., Budde, Elizabeth
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-198727

Background While the majority of diffuse large B-cell lymphoma (DLBCL) patients are cured with frontline chemoimmunotherapy, up to 30-40% of patients will have refractory or relapsed (R/R) disease. Though treatment for R/R DLBCL has evolved with chimeric antigen-receptor (CAR) T, most of these patients will ultimately relapse with poor survival outcomes, and improved therapy for R/R DLBCL remains an unmet need. Two novel therapies in DLBCL include loncastuximab tesirine (Lonca), an approved antibody-drug conjugate targeting CD19, and mosunetuzumab (Mosun), a CD3/CD20 bispecific antibody, which have both demonstrated promising response rates and safety in R/R DLBCL including in the post- CAR T setting. Here, we propose to combine Lonca and Mosun for the treatment of patients with R/R DLBCL. The rationale for combining these agents is multifold and includes 1) high responses seen with each agent (when used as single agent); 2) minimal overlapping toxicity profile; 3) distinct but potentially complementary mechanisms of action; 4) targeting of both CD19 and CD20, which may overcome antigen downregulation/escape mechanisms of resistance; and 5) outpatient administration. We hypothesize that Lonca/Mosun will be safe and efficacious in R/R DLBCL. Methods This is a single-center, open-label, phase 2 investigator-initiated trial of Lonca/Mosun for patients with R/R DLBCL (NCT05672251). Eligibility includes R/RL DLBCL after ≥2 prior lines of therapy with CD20-positive, measurable disease . Patients who have received prior Lonca or CD3/CD20 bispecific antibodies, stem cell transplant or CAR T therapy within 30 days, active infection, systemic immunosuppression, or active central nervous system involvement are excluded. The trial consists of a safety lead-in to evaluate the safety/tolerability of Lonca/Mosun and a Phase 2 stage to evaluate the anti-tumor activity of the regimen in the study population. During the safety lead-in, Lonca/Mosun will be administered at standard doses of both drugs in dose level 1. There will be a de-escalation dose level (dose level -1) where Mosun start is delayed to Cycle 2 Day 1, only if necessary. The safety lead-in segment (6 patients) will utilize a standard rolling six design based on observed toxicity during Cycles 1 & 2, and enrollment will be staggered for the first three patients in the safety lead-in. In the Phase 2 portion, study therapy will be administered at the final dose level deemed tolerable established during the safe