Background: Treatment options are limited for patients (pts) with R/R DLBCL who are not candidates for autologous stem cell transplant (ASCT). ROR1 is an oncofetal protein pathologically expressed in hematologic malignancies including DLBCL. In the phase 1 first-in-human study in hematologic malignancies (waveLINE-001), the ROR1-targeting antibody-drug conjugate zilovertamab vedotin (ZV) showed promising activity and manageable safety in R/R DLBCL. The single-arm, open-label, phase 2 waveLINE-004 study (NCT05144841) is designed to evaluate activity of ZV monotherapy in pts with R/R DLBCL. Early data are reported. Methods: Eligible pts were ≥18 y old, had histologically confirmed DLBCL by WHO classification, measurable disease per Lugano 2014 criteria, PET-positive disease, and ECOG PS of 0-2. Pts must have received ≥2 prior lines of therapy (including an alkylating agent, anthracycline, and an anti-CD20 antibody) with progression after or ineligibility for ASCT and CAR T-cell therapy. All pts received ZV 2.5 mg/kg IV Q3W until disease progression, unacceptable toxicity, or withdrawal. Primary end point was ORR per Lugano 2014 criteria. Safety and tolerability was a secondary end point. Safety was evaluated in all pts who received ≥1 dose of treatment; efficacy was reported for pts with ≥3 mo follow-up. Results: At data cutoff (Nov 16, 2022), 40 pts enrolled and received ≥1 dose of treatment; 23 (58%) had discontinued and 17 (43%) were ongoing. Median age was 68.0 y, 29 (73%) pts were male, 37 (93%) had an ECOG PS of 0 or 1, 24 (60%) had ≥3 prior lines of therapy, and 10 (25%) received prior ASCT. 11 (28%) pts received prior CAR-T. Median follow-up (range) was 2.6 mo (0.3-7.9) for all pts and 6.0 mo (3.0-7.9) for pts in the efficacy analysis (n = 20). ORR by investigator review was 30% (95% CI, 11.9-54.3), with 2 pts having a CR and 4 a PR; 5 pts had SD (DCR, 55% [95% CI, 31.5-76.9]). Treatment related AEs (TRAEs) occurred in 28 (70%) pts, most commonly (≥15%) diarrhea (9 [23%]), anemia (8 [20%]), neutropenia (7 [18%]), neutrophil count decreased (7 [18%]), and alopecia (6 [15%]). Grade 3/4 TRAEs occurred in 16 (40%) pts, most commonly (≥10%) neutropenia (7 [18%]), anemia (6 [15%]), and neutrophil count decreased (4 [10%]). Discontinuation due to a TRAE of diabetic ketoacidosis occurred in 1 (3%) pt. Grade 1/2 treatment-related peripheral neuropathy occurred in 6 (15%) pts; no grade 3/4 AEs occurred. Dose reduction due to treatment-related peripheral neuropathy occurred in 3 (8%) pts. No infusion reaction or tumor lysis syndrome due to treatment occurred and no pts died because of TRAEs. Conclusions: Early results show that ZV had clinically meaningful antitumor activity in pts with R/R DLBCL who progressed after or have been ineligible for ASCT and/or CAR-T. Additionally, the safety profile was manageable and consistent with other monomethyl auristatin E–containing agents. Clinical trial information: NCT05144841.