Tafasitamab Plus Lenalidomide and Rituximab for Relapsed or Refractory Follicular Lymphoma: Results from a Phase 3 Study (inMIND)

Abstract Background: Follicular lymphoma (FL) is characterized by episodes of remission and relapse, with patients (pts) requiring multiple lines of treatment (tx). While chemoimmunotherapy is often used frontline, it yields shorter response duration with successive lines of tx. In the relapsed/refractory (R/R) setting, immunotherapy approaches are preferred but there remains a need to improve durability. Lenalidomide (len) + rituximab (R) is approved after ≥1 prior line of tx and frequently used. Tafasitamab (tafa), a humanized CD19-targeting monoclonal antibody (mAb), induces direct cytotoxicity and enhances NK cell and macrophage immune-mediated mechanisms. Tafa has been previously approved in combination with len for R/R DLBCL based on the L-MIND study. inMIND (NCT04680052) is an international phase 3, double-blind, randomized, placebo (pbo)-controlled, multicenter trial evaluating efficacy and safety of adding tafa to len+R in pts with R/R FL or marginal zone lymphoma. The trial was powered to assess PFS in pts with FL only and the planned primary analysis is presented here. Methods: Pts ≥18 y with R/R CD19+ and CD20+ FL (grade 1-3A) and ECOG PS ≤2, requiring tx after ≥1 prior systemic therapy including an anti-CD20 mAb, were randomized 1:1 to receive tafa 12 mg/kg iv or pbo on days (D) 1, 8, 15, and 22 of cycles (C) 1-3 and D1 and D15 of C4-12 with standard dosing of len+R for up to twelve 28-day cycles. Primary endpoint was investigator-assessed PFS, planned for analysis after 174 events were observed. Additional endpoints included PET-CR rate (FDG-avid population), OS, PFS (by independent review committee [IRC]), ORR, DOR, safety, and TTNT. Results: 548 pts with FL were randomized: tafa, n=273; pbo, n=275. Baseline demographics were similar between arms: median age 64 y (range, 31-88); 55% male; 79% intermediate- or high-risk FLIPI; 83% high tumor burden per GELF criteria. Median number of prior lines of tx was 1 (range, 1-10), 45% had ≥2 prior lines, 32% had disease progression within 24 m (POD24), and 43% were refractory to prior anti-CD20 mAb. At data cutoff, pts in tafa and pbo arms had received a median of 12 and 11 cycles of tx, 19% and 15% were still on tx, 81% and 84% had discontinued tx, primarily due to tx completion (54% and 43%) or disease progression (11% and 31%), respectively. With median follow-up of 14.1 m, addition of tafa to len+R resulted in significantly lower risk of progression, relapse, or death vs pbo (median investigator-assessed PFS, 22.4 m vs 13.9 m; hazard ratio [HR] [95% CI], 0.43 [0.32, 0.58]; P<0.0001). Benefit was confirmed by IRC assessment (median PFS not reached [NR] with tafa vs 16.0 m with pbo; HR [95% CI], 0.41 [0.29, 0.56]; P<0.0001). PFS benefit with tafa was consistent in all prespecified subgroups analyzed including: pts with POD24, pts refractory to prior anti-CD20 mAb, pts receiving multiple prior lines of tx. PET-CR rate (49.4% vs 39.8%; P=0.029) and ORR (83.5% vs 72.4%; P=0.0014) were higher with tafa vs pbo. DOR was improved with tafa vs pbo (median 21.2 m vs 13.6 m; HR [95% CI], 0.47 [0.33, 0.68]; P<0.0001), as was TTNT (median NR vs 28.8 m; HR [95% CI], 0.45 [0.31, 0.64]; P<0.0001). Despite OS data being immature, there was a trend favoring tafa (HR [95% CI], 0.59 [0.31, 1.13]). A similar rate of tx-emergent adverse events (TEAEs) (99% vs 99%), grade (gr) 3 or 4 AEs (71% vs 69.5%), and serious AEs (36% vs 32%) were observed with tafa and pbo, respectively. Most common gr 3 or 4 AEs with tafa vs pbo were neutropenia (40% vs 38%), pneumonia (8% vs 5%), thrombocytopenia (6% vs 7%), decreased neutrophils (6% vs 7%), COVID-19 (6% vs 2%), and COVID-19 pneumonia (5% vs 1%). TEAEs leading to discontinuation were reported by 11% and 7% of pts in tafa and pbo arms. In total, 15 pts (5.5%) in the tafa arm and 23 (8.5%) in the pbo arm died during the study, including 5 (2%) vs 17 (6%) due to disease progression and 6 (2%) in each arm due to fatal AEs. Conclusions: Addition of tafa to len+R resulted in significant and clinically meaningful improvement in PFS, representing a 57% reduction in risk of progression, relapse, or death in pts with R/R FL. Although OS data are immature, a trend in favor of tafa was observed. The safety profile was manageable and consistent with expected toxicities. This study is the first to validate combining two mAbs (anti-CD19 with anti-CD20) in the tx of lymphoma. Tafa+len+R can be administered in community as well as academic settings and represents a potential new standard of care option for pts with R/R FL.