Background: Despite the success of axi-cel, ≈60% of patients (pts) have no response or relapse within ̃2 y after Tx (Jacobson C, et al. ASH 2021. #1764), highlighting the need for more therapeutic strategies. In preclinical studies, Rtx augmented CD19 CAR T-cell function and increased tumor reduction and survival in murine models via synergistic targeting with CAR T-cells (Mihara K, et al. Br J Haematol. 2010). Here, we report outcomes of ZUMA-14, a Phase 2, multicenter study of axi-cel in combination with Rtx in pts with R-LBCL after ≥2 lines of systemic therapy. Methods: Eligible pts were ≥18 y with R/R LBCL. Pts received one Rtx dose (375 mg/m²) on Day -5, a conditioning regimen of cyclophosphamide and fludarabine on Days -5, -4, and -3, and a single axi-cel infusion of 2×10⁶ CAR T cells/kg on Day 0. Starting on Day 21 post–axi-cel infusion, pts received 1 Rtx dose every 28 d for up to 5 doses. The primary endpoint was investigator-assessed complete response (CR) rate. Secondary endpoints included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and biomarker assessments. The analysis reported here occurred after all treated pts had ≥12 mo of follow-up. Results: As of 12/2/21, 27 pts were enrolled, and 26 received axi-cel and ≥1 Rtx dose (15 pts received all 6 Rtx doses); 1 pt discontinued Tx due to an adverse event (AE). Median age was 63 y (range, 38-82), 54% of pts were male, 81% had stage III/IV disease, 62% had extranodal disease, 38% had elevated LDH, and 85% had an aaIPI ≥1 (35% aaIPI 2). The CR rate was 65% (95% CI, 44-83), and the ORR was 88% (95% CI, 70-98). With a median follow-up of 17 mo, 65% of the pts had ongoing response, with 57% ongoing in CR. Medians for DOR, PFS and OS were not reached. The estimated DOR and PFS rates at 12 mo were 64% and 56%, respectively. The estimated 12 mo OS rate was 76%, and 6 pts (23%) died of progressive disease. Most pts (92%) experienced Grade ≥3 AEs. Grade ≥3 cytopenias were reported in 85% of pts, with 38% ongoing on Day 30. Grade ≥3 neurologic events (NEs) occurred in 4 pts (15%), and there was no Grade ≥3 cytokine release syndrome (CRS). Median times to onset of CRS and NEs were 4 d (range, 1-7) and 6 d (range, 3-32), respectively, with median durations of 5 d (range, 2-15) and 7 d (range, 1-39). No pts experienced myelodysplastic syndrome. Median peak CAR T-cell levels were comparable to the ZUMA-1 pharmacokinetic profile. Immune-modulating cytokines, including granzyme B, IL-6, CXCL10, IFN-g and IL-2, were induced in pts following axi-cel and Rtx infusion and were more prominently elevated in responders vs non-responders. Peak Rtx levels were also elevated in responders vs non-responders. Conclusions: Results from ZUMA-14 demonstrated that axi-cel in combination with Rtx elicited a high CR rate with no new safety signals detected in pts with R-LBCL. Clinical trial information: NCT04002401.