primary analysis of the smart stop trial: Lenalidomide, tafasitamab, rituximab, and acalabrutinib alone and with combination chemotherapy in newly diagnosed diffuse large B-cell lymphoma

Abstract Background: First-line therapy for newly diagnosed large B-cell lymphoma (LBCL) has remained chemotherapy-based for nearly five decades, with only incremental advances such as the addition of rituximab and polatuzumab vedotin. The Smart Stop trial (NCT04978584) was designed to evaluate whether chemotherapy could be reduced or removed in patients with newly diagnosed aggressive lymphoma who respond to initial targeted therapy. Preliminary results from Cohort 1 (n=30), in which patients achieving a complete response (CR) after targeted therapy received only 2 cycles of chemotherapy (others received 6 cycles), were reported at ASH 2023. After 4 cycles of targeted therapy, 63% of patients achieved a CR by PET/CT and 33% had undetectable ctDNA using the phasED-Seq assay (PMID: 34294911), and at end of treatment 100% of patients had a CR. We now report the primary analysis from the Smart Stop trial. Methods: Eligibility criteria include patients with newly diagnosed LBCL who were at least 18 years old with adequate organ and bone marrow function. Patients were treated in 21 day (d) cycles with lenalidomide (L) 25mg on d1-10, tafasitamab (T) 12mg/kg IV on d1, 8, and 15, rituximab (R) 375mg/m2 IV on d1, and acalabrutinib (A) 100mg orally twice/d (LTRA). After 4 cycles of LTRA, PET/CT response (CR = 5 point score of 1–3) guided treatment adaptation. All patients continued LTRA for 6 additional cycles, which included 6 cycles of CHOP if patients did not achieve an initial CR (groups B & D). In Cohort 1, those in CR received only 2 cycles of CHOP (group A); in Cohort 2, those in CR continued without CHOP (group C). The primary objectives were to determine the 1A: overall response rate (ORR) after 4 cycles of LTRA and 1B: CR at the end of therapy with LTRA +/-CHOP. Results: 61 patients were enrolled from May 2022 – May 2024 (cohort 2 started August 2023), with a median follow up of 22 months for survival. The median age was 62 years (range: 23-91), 30% were ≥ 70 years, and 49% were female. 56% of patients have poor risk R-IPI, 76% had advanced stage, and 66% had an elevated LDH. 61% had non-GCB and 36% had GCB DLBCL. Median dose intensity was 88% for L, 93% for T, and 100% for both R and A. Rash occurred in 41% of patients (grade 3 in 7%), and 57% required a dose reduction of lenalidomide. After 4 cycles of LTRA, the ORR was 90% (endpoint 1A, n=55/61) and the CR rate was 57%. At end of therapy for all patients, the CR rate was 96.7% (endpoint 1B, n=59/61). In patients with less than an initial CR, 92.3% (n=24/26) had a CR at end of therapy. In patients with an initial CR, 100% (n=35/35) had a CR at end of therapy. A total of 35 patients (57%) achieved a CR after 4 cycles of LTRA and had less than 6 cycles of CHOP. Of the 19 patients with early CR in cohort 1 who received 2 cycles of CHOP (group A), one had progressive lymphoma at month 33 (non-LBCL), and the estimated progression free survival (PFS) rate at 30 months is 100%. Of the 16 patients with early CR in cohort 2 who received no cycles of CHOP (group C), four patients had progressive LBCL (median 21 months) and were subsequently treated off protocol with R-CHOP-like therapy, achieving a CR in all cases. The estimated PFS rate at 18 months for group C is 91.7%. The PFS and overall survival for the entire cohort at 24 months have an estimated rate of 85% and 98%, respectively. An 85 year old patient with stage 4 GCB LBCL withdrew consent after 1 cycle of LTRA for social reasons and has an ongoing and confirmed remission more than 15 months later. Conclusions: The Smart Stop trial establishes that reducing or removing chemotherapy is feasible in patients with newly diagnosed LBCL who achieve a complete response after targeted therapy, without compromising curative potential. The combination of lenalidomide, tafasitamab, rituximab, and acalabrutinib is highly effective as an initial chemotherapy-free combination in patients with newly diagnosed LBCL. Time to event data and ctDNA analysis will be updated for presentation at the meeting. Further trials are warranted to explore the Smart Stop approach in multicenter randomized trials, and additional combinations are planned.