S2207: Randomized Phase II Study of the Addition of Targeted Agents to Tafasitamab-Lenalidomide in Transplant Ineligible Patients with Relapsed/Refractory LBCL

Large B-cell lymphoma (LBCL) is the most common lymphoma worldwide. About 40% of patients relapse, and many are not eligible for stem cell transplantation, CAR-T cell therapy, or bispecific agents due to chemoresistant and/or aggressive disease, advanced age, comorbidities, or lack of access to tertiary care. R/R LBCL remains an area of great unmet need, with median survival measuring less than one year. Recently, several less intensive agents and regimens designed for outpatient administration have been approved in the United States. Tafasitamab-lenalidomide, an outpatient and well-tolerated regimen, demonstrates durable remissions especially for patients treated in the second-line setting. We hypothesize that if tafa-len is a well-tolerated and effective backbone, then the addition of biologically targeted agents could improve outcomes without excess toxicity. SWOG 2207 is a national randomized study testing the addition of tazemetostat or zanubrutinib to the tafa-len backbone (NCT05890352).

Following a safety run-in of 12 patients per each experimental arm, the randomized Phase II study will enroll 180 patients to Arm 1: tafa-len + tazemetostat; Arm 2: tafa-len (control); or Arm 3: tafa-len + zanubrutinib. The primary objective of the phase II portion is to compare the PFS of patients treated on the experimental Arms against the control. Secondary objectives will include estimating hazard ratios for PFS based on immunohistochemistry (IHC)-determined GCB and non-GCB subtypes for control verses each experimental treatment arm to evaluate the impact of cell-of-origin (COO) on efficacy. Exploratory objectives will include exploring PFS by molecular profile and genetic subtypes. Frailty and its correlation to outcome will be assessed. In addition, patient-reported lymphoma specific symptoms will be measured by PRO-CTCAE and quality of life by FACT-Lym, and these will be compared between arms.

Patients will be treated on a 28-day cycle for no more than 13 cycles. Tafa-len will be administered per package insert. Tazemetostat or zanubrutinib will be dosed at the RP2D twice daily for a 28-day cycle. Eligibility will allow for patients to have histologically confirmed R/R LBCL as defined by WHO guidelines, FL grade 3B, transformed lymphoma, and HGBCL with/without MYC, BCL2 and/or BCL6 rearrangements. Patients must have COO determination by Hans IHC algorithm. Patients must have had 1-5 prior therapies and not be a candidate for or have declined transplant. Those who have disease progression following transplant or CAR-T are eligible. Disease assessment with PET-CT or contrast enhanced CT, and patient reported outcomes will occur at baseline and by cycle 3, 6 and EOT. The goal of the SWOG 2207 study is to improve outcomes of patients with R/R LBCL who are not candidates for transplant with potentially biologically targeted, well tolerated therapy.

Funding: NIH/NCI/NCTN grants U10CA180888 and U10CA180819