Introduction Both CD20 and CD19 are selectively and strongly expressed on the surface of diffuse large B-cell lymphoma (DLBCL) cells. For newly diagnosed and untreated DLBCL, the anti-CD20-targeted R-CHOP regimen is the standard of care. Tafasitamab, a humanized, Fc-modified, anti-CD19 monoclonal antibody, in combination with lenalidomide (LEN), has received regulatory approvals for the treatment of adult patients with R/R DLBCL not otherwise specified, including DLBCL arising from low-grade lymphoma, and who are ineligible for ASCT. A treatment strategy targeting both of these B cell surface molecules, and supplemented by LEN to enhance the cytotoxicity activity of tafasitamab and rituximab, may limit target evasion and reduce resistance to R-CHOP. First-MIND (NCT04134936) is a Phase Ib randomized study to assess the safety and tolerability of R-CHOP + tafasitamab ± LEN in patients with previously untreated and newly diagnosed DLBCL, and an International Prognostic Index (IPI) score of 2-5. The primary analysis demonstrated the feasibility of adding tafasitamab + LEN to R-CHOP without impairing its dosing and scheduling, with toxicities similar to those expected with R-CHOP alone (ASH 2021; #3556). The combination of R-CHOP and tafasitamab + LEN as first-line therapy is being investigated further in the global, randomized, Phase III frontMIND study (NCT04824092) in untreated patients with DLBCL and an IPI score of 3-5. Here, we report the 18-month follow-up analysis from the First-MIND study in all patients and in patients with an IPI score of 3-5. Methods Eligible patients were randomized 1:1 to six 21-day (D) cycles of either R-CHOP (R-CHOP, D1-5) + tafasitamab (12 mg/kg IV, D1, 8, 15) (Arm T) or R-CHOP + tafasitamab + LEN (25 mg orally, D1-10) (Arm T/L). The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary endpoints included overall response rate (ORR) and PET-negative complete response (CR) rate at end of treatment (EoT). Safety was assessed using the NCI CTCAE V5.0, and tumor measurements by PET/CT or PET/MRI at EoT were performed according to Lugano 2014 criteria. Minimal residual disease (MRD) was assessed using immunoglobulin gene next-generation sequencing in cell-free DNA. Results At the data cut-off (May 5, 2022), of the 66 patients randomized (Arm T, n=33; Arm T/L, n=33), a total of 27 patients (40.9%) were still on study (Arm T, n=13; Arm T/L, n=14) with a median follow-up of 17.6 months for progression-free survival (PFS). Baseline characteristics were well balanced: 60.6% of patients in Arm T and 66.7% in Arm T/L had an IPI score of 3-5; 94.0% and 87.9% had an ECOG PS of 0-1, respectively; and 93.9% of patients in both Arms were Ann Arbor stage III/IV. ORR at EoT visit and best response across all visits were higher in Arm T/L, as were 18-month DoR, PFS, and OS rates (Table 1). In patients treated in Arm T/L and with an IPI score of 3-5 (n=22), ORR and 18-month DoR, PFS, and OS rates were comparable with the overall Arm T/L cohort (Table 1). The 12-month PFS rate by MRD status at EoT in Arm T/L was 100% in MRD-negative patients (n=12) (Figure 1) and 67% in MRD-positive patients (n=3). MRD-negativity at Cycle 2 Day 1 appeared to be predictive for durable PFS responses. The frequency of Grade ≥3 TEAEs was 72.7% in Arm T and 90.9% in Arm T/L; the most common TEAEs were neutropenia, anemia, leukopenia, and thrombocytopenia in both arms. Serious TEAEs occurred in 42.4% in Arm T and 51.5% in Arm T/L, with no difference between treatment arms in the incidence of febrile neutropenia (15.2%), and an incidence of infections and infestations of 9.1% in Arm T and 6.1% in Arm T/L. Conclusion Adding tafasitamab in combination with LEN to R-CHOP shows numerically higher clinical efficacy than adding tafasitamab alone, and is consistent with the synergy between tafasitamab and LEN, leading to durable responses in treatment-naïve patients with DLBCL. The long-term safety profile of tafasitamab ± LEN when added to R-CHOP showed no new safety signals to those reported previously. Although the sample size is limited, patients with an IPI score of 3-5 treated with tafasitamab + LEN + R-CHOP showed efficacy comparable to that of the overall treatment arm cohort, including MRD-negative patients who remained disease-free for ≥18 months. frontMIND will further evaluate tafasitamab + LEN + R-CHOP in previously untreated patients with high-intermediate and high-risk (IPI score 3-5) DLBCL. Funding MorphoSys AG Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal