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Background Ubamatamab, a mucin 16 × cluster of differentiation 3 (MUC16×CD3) bispecific antibody, bridges MUC16-positive tumor cells and MHC-independent T cells, promoting cytotoxicity. In a Phase 1/2 study, ubamatamab activity was observed in patients with recurrent advanced OC. CRS is a common adverse event during initial ubamatamab doses. Sarilumab, an anti-interleukin-6 (IL-6) receptor α-subunit monoclonal antibody, has pharmacodynamic effects including neutrophil margination. Here, we assessed sarilumab prophylaxis as a mitigation strategy for ubamatamab-induced CRS ( NCT03564340).Methods Patients received a single dose of sarilumab 350 mg intravenously before ubamatamab (sarilumab/ubamatamab), or ubamatamab alone without sarilumab. Ubamatamab step-up dosing: 1 mg Day (D)1, and 10 mg D8 and D9, followed by full dose in Week 3 (administered every three weeks), 800 mg (patients with OC) or 250 mg (patient with EC). CRS was graded using Lee Criteria. Serum sarilumab pharmacokinetics were analyzed over 6 weeks. Pharmacodynamic effects on cytokines, chemokines, and C-reactive protein (CRP) were evaluated.Results Overall, 32 patients received sarilumab/ubamatamab (OC: n=31; EC: n=1); 207 received ubamatamab alone. CRS was observed in 15.6% (sarilumab/ubamatamab: Grade [G]1, 12.5%; G2, 3.1%) and 84.5% (ubamatamab alone: G2, 38.2%; G3, 1.0%) of patients ( figure 1). Fewer incidences of infusion-related reactions (6.3% vs 18.4%) and Grade 3 anemia (6.3% vs 21.7%) occurred in patients treated with sarilumab/ubamatamab versus ubamatamab alone, respectively. No sarilumab/ubamatamab-treated patients experienced immune effector cell-associated neurotoxicity syndrome, while 3.4% of those receiving ubamatamab alone did. Neutropenia was observed in 31.3% and 5.8% of patients treated with sarilumab/ubamatamab and ubamatamab alone, respectively. No neutropenic fever cases were observed, and infection rates were similar between cohorts (sarilumab/ubamatamab: 43.8%; ubamatamab alone: 44.0%).Serum sarilumab concentration maintained active levels through Week 3. After sarilumab infusion, median peripheral IL-6 increased compared with baseline (20.7 vs 3.2 pg/mL, respectively) and continued to increase during ubamatamab step-up dosing compared with patients who received ubamatamab alone (median peak IL-6: >1166.0 vs 187.9 pg/mL, respectively) (figure 2A). Median peak CRP levels were lower in patients treated with sarilumab/ubamatamab versus ubamatamab alone (88.7 vs >186.0 mg/L, respectively) (figure 2B). In sarilumab/ubamatamab-treated patients, interferon-gamma, IL-8, tumor necrosis factor alpha, eotaxin, and monocyte chemoattractant protein-4 increased at Week 1; macrophage-derived, and thymus and activation-regulated chemokines increased at Week 4.Conclusions A single sarilumab dose before ubamatamab reduced CRS incidence and severity. Pharmacokinetic and pharmacodynamic findings demonstrated sarilumab activity throughout ubamatamab step-up dosing. Evaluation of sarilumab prophylaxis for ubamatamab-induced CRS is ongoing.Acknowledgements This study was supported by Regeneron Pharmaceuticals, Inc. Medical writing assistance was provided by Joe Bolton, of Oberon, a division of OPEN Health Communications, funded by Regeneron Pharmaceuticals, Inc., according to Good Publication Practice (GPP) guidelines (www.ismpp.org/gpp-2022).Trial Registration NCT03564340Ethics Approval The study was conducted in accordance with the principles of the Declaration of Helsinki, International Council for Harmonisation Good Clinical Practice guidelines, and all applicable regulatory requirements. The research protocol was approved by the relevant institutional review boards or ethics committees at each site. All patients provided written informed consent.Abstract 546 Figure 1Sunburst plot of the incidence of CRS by grade over the first 4 weeks of ubamatamab administration in patients treated A) with sarilumab prophylaxis and B) without sarilumab prophylaxisAbstract 546 Figure 2Median IL-6 (A) and CRP (B) levels in patients treated with and without sarilumab prophylaxis