Claudin18.2 (CLDN18.2) is a cancer target expressed on several gastrointestinal (GI) carcinomas; it's also expressed on gastric mucosa, which is believed to cause nausea and vomiting (N/V) when bound by CLDN18.2-targeting agents. Spevatamig (PT886) is a novel IgG1-based bispecific antibody with a native IgG structure. Unlike many CLDN18.2-targeting agents that usually have two anti-CLDN18.2 arms, spevatamig has only one anti-CLDN18.2 arm that allows it to have weaker binding to gastric mucosa, potentially causing less N/V. In addition, it has one arm against CD47, which is highly expressed on gastric, pancreatic, and biliary tract tumor cells, but not on gastric mucosa. Spevatamig with high binding to tumor cells through both arms provides the potential to maintain efficacy while limiting on-target, off-tumor GI toxicity. In the monotherapy dose escalation study (N=31), at up to 9 mg/kg Q2W of spevatamig, no Grade ≥ 3 nausea was observed; one incidence of Grade 3 vomiting was observed at the 6 mg/kg Q2W dose level, which is above the expected efficacious dose (2 or 3 mg/kg QW) considered for combination treatment. Starting from the 3 mg/kg QW dose level, anti-emetic premedications were gradually introduced. The final N/V management strategy was similar to those used for other anti-CLDN18.2 agents and the introduction of an optimized premedication regimen and adjustments to the infusion time significantly improved N/V in patients. In 35 patients, spevatamig was combined with gemcitabine + nab-paclitaxel (GnP) at dose levels (or weekly equivalent doses) from 2 mg/kg QW to 4 mg/kg QW, to assess safety, tolerability and efficacy in first-line (1L) pancreatic ductal adenocarcinoma (PDAC). At 2 mg/kg QW spevatamig + GnP (N=16), a potentially efficacious dose, the rates of nausea and vomiting were 75% and 25%, respectively. No Grade ≥ 3 nausea or vomiting was observed.. Combination with 3 mg/kg QW + GnP is ongoing, with no Grade ≥ 3 nausea or vomiting observed to date. Overall, the vomiting rate (all grade) is comparable to rates observed in pivotal studies of GnP, suggesting that spevatamig does not add vomiting risk. Although the nausea rate is higher, all the events were effectively managed with no N/V related dose reductions or treatment discontinuation. The bispecific design of spevatamig, which contains an anti-Claudin 18.2 arm and an anti-CD47 arm, reduced the overall risk of N/V associated with CLDN18.2 targeting at potentially efficacious doses, enabling combinability with GnP for 1L PDAC and treatment adherence that may lead to better efficacy outcomes compared to chemotherapy.