A Phase 3 Study of Tafasitamab Plus Lenalidomide in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (firmMIND)

Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive form of lymphoma and the most common subtype of non-Hodgkin's lymphoma representing ~31% of all cases (Thandra KC, et al. Med Sci. 2021;9:5). Treatment with the anti-CD20 monoclonal antibody (mAb) rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone is the standard first-line therapy; however, 30-40% of patients experience relapsed or refractory (R/R) disease (Harris LJ, et al. Int J Mol Sci. 2020;21:8553). High-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) improve outcomes for patients with R/R disease; however, many patients are ineligible for HDC/ASCT owing to age, comorbidities, or frailty. Therapies targeting CD19, which is expressed on normal and malignant B cells and regulates proliferation, have also shown promising results in the treatment of R/R DLBCL.

Tafasitamab is a humanized mAb targeting CD19, and Fc-engineered for increased affinity to Fcγ receptors on immune effector cells. Preclinical data showed that tafasitamab acts synergistically with the immune modulator lenalidomide. The phase 2 L-MIND study (NCT02399085) evaluated tafasitamab plus lenalidomide in patients with R/R DLBCL who were ineligible for HDC/ASCT. The objective response rate (ORR) was 57.5% (n=46/80), including a complete response in 40.0% (n=32/80) of patients. Responses were durable, with a median duration of response of 43.9 months at ≥35 months of median follow-up. Based on the results of L-MIND, tafasitamab plus lenalidomide was approved in the United States (accelerated approval), Canada and European Union (conditional approval), and other countries for adult patients with R/R DLBCL who are not eligible for ASCT.

The firmMIND study (NCT05429268) is a post-authorization commitment study to confirm the efficacy, safety, and overall benefit/risk of the combination of tafasitamab plus lenalidomide in R/R DLBCL.

Study Design and Methods: In this single-arm, multicenter, open-label, phase 3 study, patients will receive tafasitamab (12 mg/kg IV on days 1, 8, 15, and 22 of a 28-day cycle [cycles 1-3] with an additional loading dose on cycle 1 day 4, then days 1 and 15 [cycles 4-12]) plus lenalidomide (25 mg orally once daily, days 1-21/cycle) for 12 cycles, followed by tafasitamab monotherapy (in patients with stable disease or better) until progressive disease, withdrawal of consent, or unacceptable toxicity. Radiologic assessments will be performed at baseline, cycles 3, 5, 7, 10, 13, 16, 19, 22, 25, and then every 12 months until end of treatment (EOT). Positron emission tomography will be performed at baseline and then throughout treatment to EOT.

Eligible patients are ≥18 years of age with a histologically confirmed diagnosis of DLBCL, T-cell/histiocyte-rich large BCL, Epstein-Barr virus-positive DLBCL of the elderly, grade 3b follicular lymphoma, composite lymphoma with a DLBCL component and subsequent DLBCL relapse, or histological transformation of a low-grade lymphoma into DLBCL. Patients must have measurable R/R disease; received at least 1 but no more than 3 previous systemic regimens for DLBCL, one of which must have been an anti-CD20-targeted therapy; be ineligible for intensive salvage therapy including ASCT; ECOG performance status of 0-2; and adequate organ function. Patients with any other lymphoid neoplasm including primary mediastinal large B-cell lymphoma, Burkitt lymphoma, DLBCL with simultaneous MYC2, BCL2, and/or BCL6 translocations, or prior central nervous system lymphoma, prior treatment with CD19-targeted therapy or an immunomodulator, ASCT ≤3 months before study start, primary refractory DLBCL (disease progressing <6 months of first-line treatment), or prior allogenic stem cell transplantation are excluded.

The primary endpoint is ORR assessed by an independent review committee (IRC) based on the Lugano criteria (Cheson BD, et al. J Clin Oncol. 2014;32:3059-3068). Secondary endpoints include safety, IRC-assessed progression-free survival, and overall survival. It is planned to enroll 81 patients into the study.

Larsen:Genentech: Research Funding; Roche: Consultancy; Novartis: Consultancy; Gilead Sciences: Consultancy; Bristol Myers Squibb: Consultancy. Manzke:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Leibovitz:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Arbushites:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company.