Combination of Antibody Drug Conjugate With Bispecific T-Cell Engager for Relapsed Large B-Cell Lymphoma: A Lethal One-Two Punch? Free

STUDY TITLE: A Study to Evaluate the Safety and Anti-Cancer Activity of Loncastuximab Tesirine in Combination With Other Anti-Cancer Agents in Participants With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma (LOTIS-7)

CLINICALTRIALS.GOV IDENTIFIER: NCT04970901

PARTICIPATING CENTERS: 42 international locations, including 25 U.S. sites

SPONSOR: ADC Therapeutics

ACCRUAL GOAL: Estimated enrollment of 200 patients

STUDY DESIGN: Lotis-7 is a multicenter, open-label study with a large cohort testing the CD19-directed antibody drug conjugate (ADC) loncastuximab teserine (lonca) in combination with glofitamab for patients with at least one prior line of therapy for large B-cell lymphoma (LBCL). The study includes patients with a history of autologous stem cell transplant or chimeric antigen receptor T-cell (CAR-T) therapy if provided within 100 days prior to enrollment. Patients are eligible if they have Eastern Cooperative Oncology Group performance status of grade 0 to 2 and adequate organ function. On day 1, obinutuzumab is administered to deplete circulating B cells, followed by lonca on day 2. Glofitamab is then administered with step-up dosing (2.5 mg to 10 mg to 30 mg) over the subsequent three weeks to mitigate the risk of cytokine release syndrome (CRS). Lonca is given every 21 days in combination with glofitamab for a total of eight cycles, at which point glofitamab is administered as monotherapy for an additional four cycles. Primary endpoints of the study include safety and tolerability. Secondary endpoints include overall response rate, duration of response, complete response rate, and progression-free, relapse-free, and overall survival.

RATIONALE: Over the past five years, there has been an explosion of novel therapeutic agents approved, or in late-stage clinical development, for the treatment of LBCL. Although CAR-T therapy is likely curative for a significant proportion of patients, a large majority of those who are eligible for cellular therapy do not receive it due to a combination of medical, socioeconomic, and/or geographic reasons.¹  As such, there is significant interest in the possibility that CD20-directed bispecific T-cell engagers such as epcoritamab or glofitamab could result in durable remissions and be more easily administered to a broader patient population in the community setting without the need for frequent or prolonged hospitalizations.^2,3  Unfortunately, the ramp-up time required to achieve maximum therapeutic doses is typically three to four weeks, during which many patients experience rapid disease progression leading to suboptimal outcomes of bispecific antibody treatment outside of the context of clinical trials.⁴  ADCs such as lonca offer the advantage of rapid disease control, although they generally lack durable responses in most patients.

Enter Lotis-7, the preliminary results of which were presented in June of this year at both the European Hematology Association 2025 Congress and the 18th International Conference on Malignant Lymphoma. By immediately initiating treatment with lonca followed by ramp-up of glofitamab, combination treatment in Lotis-7 delivers a “one-two punch” to provide both immediate disease control and engagement of immune effector T cells. Possibly due to the ability of lonca to deplete B cells when given in combination with obinutuzumab, the rate of CRS among the 41 patients with LBCL treated was manageable at 39%, with 2.5% experiencing grade 3 events but no patients with grade 4 or 5 events. Additionally, no patients experienced grade 3 or higher immune effector cell-associated neurotoxicity syndrome. Rates of adverse events attributed to lonca such as edema and skin rash were similar to those seen with monotherapy. Among evaluable patients, the overall response rate was 93%, with 86% achieving complete remission.

COMMENT: Although longer follow-up will be needed to determine whether patients can achieve durable response, LOTIS-7 demonstrated very encouraging overall and complete response rates in this difficult-to-treat population. This study points to a future in which novel targeted agents are used “off the shelf” in well-tolerated and highly effective combination regimens that can be administered in the community setting, greatly benefitting patients with relapsed or refractory LBCL.