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
Year: 2025
Type: conference-abstract
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).
Source: Blood
Authors: Ibrahim Aldoss, Pere Barba, Pau Montesinos, Anna Castleton, Gautam Borthakur, Jae-Ho Yoon, Chieh-Lin Teng, Franco Locatelli, Yosr Hicheri, David Taussig, Bela Patel Wrench, Adam DuVall, Veit Buecklein, Cristina Papayannidis, Nicola Gökbuget, Bijal Shah, Raghuveer Mali, Yuyin Liu, Damilola Olabode, Margaret Wey, Marcio Andrade-Campos, Prof. Dr. Max S Topp, Hagop Kantarjian
Institutions: City Of Hope National Medical Center, City of Hope, Vall d'Hebron Hospital Universitari, Hospital Universitari i Politècnic La Fe, The Christie NHS Foundation Trust, The University of Texas MD Anderson Cancer Center, Catholic University of Korea, Taichung Veterans General Hospital, Università Cattolica del Sacro Cuore, Bambino Gesù Children's Hospital, Institut Paoli-Calmettes, Royal Marsden NHS Foundation Trust, Queen Mary University of London, Barts Cancer Institute, University of Chicago, Ludwig-Maximilians-Universität München, Istituto di Ematologia di Bologna, University Hospital Frankfurt, Moffitt Cancer Center, AstraZeneca (United States), AstraZeneca (Spain), Universitätsklinikum Würzburg
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W7108450496