Abstract
Introduction: Surovatamig (formerly AZD0486) is a novel, IgG4 fully human CD19xCD3 bispecific TCE that is being evaluated in an ongoing first-in-human phase 1 study (NCT04594642). Here, we present efficacy, safety, and pharmacokinetics/pharmacodynamics (PK/PD) data from dose escalation of surovatamig in patients (pts) with R/R DLBCL.
Methods: Eligible pts had R/R CD19+ B-cell non-Hodgkin lymphoma and ≥2 prior lines of therapy (pLOT), which could include prior CD19 CAR T-cell therapy (CAR T) and/or CD20 TCEs. Escalating target doses of surovatamig were administered intravenously using no, single, or double step-up dosing (SUD) schedules in cycle 1, followed by target dose every 2 weeks in 28-day cycles for up to 24 months of treatment. Pts with 2 consecutive complete responses (CRs) could receive dosing every 4 weeks after cycle 6. The primary objective was to assess safety, tolerability, and PK and to determine the recommended phase 2 dose. Response was assessed by central imaging review per RECIL 2017 criteria. MRD was assessed by PhasED-Seq using Foresight CLARITY for Lymphoma test in plasma circulating tumor DNA. Cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) were graded per 2019 ASTCT criteria. Adverse events (AEs) were graded by CTCAE v5.0.
Results: As of May 19, 2025, 106 pts with R/R DLBCL received surovatamig at target doses of ≤0.8 mg (n=2), 2.4 mg (n=18), 7.2 mg (n=39), 15 mg (n=28), and 25 mg (n=19). The median number of pLOT was 3 (range, 2–13), with 28 (26%), 17 (16%), and 29 (27%) pts having received 3, 4, and ≥5 pLOT, respectively. Forty-four (42%) pts had previously received CD19 CAR T, 25 (24%) polatuzumab vedotin, 16 (15%) CD20 TCE, and 9 (8%) other non–CAR T CD19-directed therapies. A dose-dependent improvement in both overall response rate (ORR) and CR rate was observed: 47%/38% at a target dose of 7.2 mg, 59%/44% at a target dose of 15 mg, and 77%/54% at a target dose of 25 mg, respectively. Exposure–response analysis also indicated improved ORR and CR rate with higher exposure to surovatamig. In pts who had progressed after a CD20 TCE or a CD19 CAR T, CR was achieved in 45% (5/11) and 35% (11/31) of pts, respectively, including 2 pts who had received both a CD20 TCE and a CD19 CAR T. Of the 29 pts with CR who were evaluable for MRD at dose levels ≥7.2 mg, 90% (26/29) achieved MRD negativity with 6/7 at 25 mg. With a median follow-up of 7 months (range, 1–39) for pts who received a target dose ≥7.2 mg, estimated 12-month rates were as follows: duration of response was 76%, duration of CR was 91%, and progression-free survival was 44%. The most common (≥5%) grade ≥3 treatment-emergent AEs were neutropenia (29%), anemia (15%), thrombocytopenia (8%), pneumonia (9%), and ICANS (8%). Of 90 pts receiving a double SUD schedule, CRS was observed in 49% (all low grade) and ICANS was observed in 27% of pts. Grade 3 ICANS occurred in 7 pts with a median age of 79 years. These events were fully reversible with corticosteroids and were transient (median duration, 35 hours). Higher target doses were not associated with increased rates of treatment-related grade ≥3 AEs, serious AEs, frequency/severity of CRS or ICANS, or infections.
Conclusion: Surovatamig is active in pts with heavily pretreated DLBCL, including those who received prior CD20 TCEs and CD19 CAR T. Responses appear to be target dose–dependent up to 25 mg, which is supported by exposure–response analysis. Higher target doses were not associated with greater clinically relevant toxicity.
