Safety and efficacy of surovatamig (AZD0486) in adolescent and adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL): Updated Results from the Phase 1/2 SYRUS study

Abstract Introduction: Management of R/R ALL remains challenging. While CD19-targeted therapies haveshown compelling clinical activity, existing agents are limited by notable toxicity, inconvenient administration schedules, and limited access. Surovatamig (formerlyAZD0486) is a novel, fully human IgG4 CD19xCD3 bispecific T-cell engager that can address these limitations, with extended half-life enabling dosing every 2 wks (Q2W). Herein, we present updated results from a phase 1 dose-escalation study of surovatamig in R/R B-ALL (SYRUS Part A; NCT06137118), highlighting its promising role in this challenging landscape. Methods Eligible patients (pts) for Part A were aged 16–80 y with R/R CD19+ B-ALL. Surovatamig was administered intravenously in 28-day cycles, starting with triple step-up dosing (SUD, cycle 1 day 1 [C1D1], C1D4, and C1D8). Target dose (TD: 2.4, 7.2, or 15 mg) was administered on C1D15 and then Q2W. The primary objective for Part A was safety and tolerability. Disease assessments were performed by the investigator based on NCCN criteria. Minimal residual disease (MRD) was assessed by local multiparametric flow cytometry (MFC) and central next-generation sequencing (NGS) clonotype assay (eg, ClonoSEQ) if MRD was negative by MFC. Results As of July 4, 2025, 42 pts were enrolled (TD 2.4 mg [n=13], 7.2 mg [n=12], and 15 mg [n=17]). Median age was 50 y (range 17–77); median prior lines of therapy was 3 (range 2–9). Across doses, 26 pts (62%) had been treated with CD19-targeted treatment (tx) including blinatumomab (43%) and/or CAR-T (40%), and 25 (60%) pts had >50% bone marrow blasts. Overall response rate (ORR; defined as complete remission [CR]/CR with partial or incomplete hematologic recovery) within 3 cycles was 67% (46%, 2.4 mg; 58%, 7.2 mg; 82%, 15 mg). CR rate within 3 cycles was 50% (38%, 2.4 mg; 42%, 7.2 mg; 65%, 15 mg). ORR was 88% (7/8) in pts with extramedullary disease (EMD). Among pts receiving TD of 15 mg, ORR was 88% in pts with prior blinatumomab tx, 73% in pts with prior CAR-T, 86% in double-exposed pts (prior blinatumomab and CAR-T), and 86% in triple-exposed pts (double-exposed + prior inotuzumab ozogamacin). Six of 7 pts with Philadelphia chromosome–positive disease achieved CR within 3 cycles. Among responders, MRD negativity was achieved by MFC in 83% (2.4 mg) and 100% (7.2 mg and 15 mg). By NGS-based assay, MRD negativity with the threshold of 10-4 and 10-6 was achieved in 92% and 60% of evaluable CR pts, respectively. At data cutoff, 14 pts remained on tx; 11 discontinued tx while in CR, of whom 8 proceeded to allogeneic stem cell transplantation and 1 to donor lymphocyte infusion. Among responders (n=28), with a median follow-up of 6.2 mo, median duration of response had not been reached. Only 3 pts experienced relapse, all at 2.4 mg (2 within 3 mo and 1 after 6 mo; 2 were CD19-negative). In these 3 pts who experienced relapse, best MRD status while in CR was as follows: positive by MFC at 10-4, negative by ClonoSeq at 10-4, and negative by ClonoSeq at 10-5. Notably, no relapses have been observed to date in 12 pts who achieved MRD negativity at 10-6. Dose-limiting toxicities were observed in 1 pt (TD 2.4 mg; SUD 0.09/0.27/1.0 mg) with grade (G) 4 thrombocytopenia and G3 ALT/AST elevation and 1 pt (TD 15 mg; SUD 0.27/1.0/2.4 mg) with G4 thrombocytopenia; both resolved and the pts continued planned TD. G3+ related tx-emergent adverse events (AEs) were reported in 9 (21%) pts; 4 fatal infections were reported during C1, none considered related to surovatamig. With optimized SUD (0.09/0.27/1.0 mg, n=23), G2+ CRS events occurred in 9% and no G2+ ICANS events were observed. Following TD administration (n=36), no G3+ CRS events were reported and a G3+ ICANS event was observed in 1 pt (G3, TD 7.2 mg). Plasma cytokine peak levels were highest after D1 dose, which was dose-dependent. Cytokine production was substantially lower after subsequent doses (D4, D8, and D15) across different SUD and TD. Exposure–response analysis (n=34) showed a positive correlation between increased drug exposure (Cavg) and higher ORR. Conclusion Surovatamig up to a TD of 15 mg is well tolerated in pts with R/R B-ALL. SUD 0.09/0.27/1.0 mg mitigates the incidence and severity of CRS and ICANS. The 15-mg TD showed the highest efficacy, including in pts with prior CD19-targeted therapy and with EMD. These results will guide dose selection for SYRUS Part B (dose optimization) and Part C (efficacy expansion).