Mosunetuzumab and polatuzumab combined with axicabtagene ciloleucel induce high complete response rates at day+90 in Relapsed/Refractory large B-cell lymphoma

Abstract Introduction CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy has become a standard of care for patients (pts) with relapsed or refractory (r/r) aggressive large B cell lymphomas (LBCL). Despite high overall response rates (ORR), only 30-40% of patients achieve long-term durable remissions, leaving a significant unmet clinical need. Multiple mechanisms of relapse have been identified, including loss of CD19 (~30% of patients post CAR-T), high burden of disease and a hostile tumor microenvironment. Mosunetuzumab (mosun), an anti CD20-CD3 targeting bispecific antibody, and polatuzumab vedotin (pola), a CD79b-targeting antibody drug conjugate, have shown promising activity when combined in r/r LBCL, with complete response (CR) rates of 46% (Budde, Nat Med 2023). We hypothesized that combining mosun-pola with axicabtagene ciloleucel (axi-cel) could address multiple mechanisms of CAR-T resistance and improve durable response rates. Here we report an interim analysis of a Phase II study evaluating the safety and efficacy of mosun-pola in combination with axi-cel in pts with r/r LBCL. Methods: This single-institution, investigator-initiated Phase II study (NCT05260957)evaluated the combination of mosun-pola with axi-cel in adults with r/r LBCL who had received ≥1 prior line of systemic therapy. The primary endpoint was CR at Day +90 after axi-cel infusion (Lugano 2014 criteria), with a null hypothesis of a CR rate of 40%. Futility (assessed dynamically) was rejected after 11 pts achieved a CR at Day +90. Treatment consisted of 3 phases: following leukapheresis on Day -36, pts received bridging therapy with step-up dosing of mosun IV (1 mg on Day -35, 2 mg on Day -28 and 60 mg on Day -21) combined with pola IV (1.8 mg/kg on Day -21); pts then received standard lymphodepletion with fludarabine and cyclophosphamide from Day -5 to Day -3, followed by axi-cel infusion on Day 0. Pts with ≤Grade 1 CAR-T related toxicities could receive mosun 30 mg on Day +14; pts without progressive disease (PD) on Day +28 restaging received up to 3 doses of consolidation mosun (30 mg) and pola (1.8 mg/kg) on Days +35, +56 and +77. Results: As of July 1, 2025, 25 patients have been enrolled, with 22 evaluable for the primary outcome at Day +90 post axi-cel infusion. The median age was 63 years (range 26 – 83), and 12 (48%) were male. Seventeen pts (68%) met criteria for 2nd line axi-cel due to primary refractory disease or early relapse; however, 15 (60%) received ≥2 prior lines of therapy (median 2, range 1-6). Twelve (48%) pts had elevated LDH, and 5 (21%) pts had bulky disease ≥10cm. The median time from leukapheresis to axi-cel infusion was 38 days (IQR 36 – 39.25). At Day -7 restaging, the overall response rate (ORR) to bridging was 60%, including 32% CR and 28% partial response (PR); 32% had stable disease (SD), and 8% PD. One patient died of PD during bridging. Twenty-four (96%) pts received axi-cel. Among 22 pts evaluable at Day +28, the ORR was 100%. At Day +90, 19/21 (90%) of pts achieved a CR, with 2 pts experiencing PD. One pt with Day +90 CR relapsed at 6 months, and one pt died in remission (not attributed to mosun-pola). After median follow-up of 15 months post-infusion, 12-month overall survival (OS) was 80% (95% CI, 55.1 – 92), and 12-month progression-free survival (PFS) was 80% (95% CI, 67 – 97.5). By intention to treat, D+90 CR was 86% and 12-month OS and PFS from leukapheresis was 77%. All 25 pts were evaluable for safety outcomes. Five pts experienced grade 1 Cytokine Release Syndrome (CRS) during mosun-pola bridging. Of 24 pts infused with axi-cel, 23 (96%) experienced CRS, all grade 1-2. Immune effector cell-associated neurotoxicity syndrome (ICANS) was seen in 14 pts (58%): grade 1-2 in 7 pts (29%) and grade 3 in 7 pts (29%). Nineteen (79%) pts received Day +14 mosun. Among 22 patients currently past Day +28, the number of doses of consolidation mosun-pola received were: 0 (2 pts, 9%), 1 (6 pts, 27%), 2 (5 pts, 23%), and 3 (9 pts, 41%). Grade ≥3 neutropenia, thrombocytopenia and anemia occurred 88%, 28% and 36%, respectively; Grade 3 infections were observed in 6 pts (25%). No treatment-related deaths occurred during the study. Conclusion: Mosun-pola in combination with axi-cel was effective, inducing high complete response rates at Day +90. No increase in acute CAR-T related toxicities were seen. Follow-up to assess durability of CR is ongoing.