Pharmacokinetics of spevatamig (PT886), a bispecific antibody targeting CLDN18.2 and CD47, in patients with advanced gastrointestinal cancers as monotherapy or combination therapy

Spevatamig (PT886) is an IgG1-based bispecific antibody targeting tumor cells expressing claudin 18.2 (CLDN18.2) and/or CD47 to mediate enhanced anti-tumor activity through innate immune cell and potentially T cell activation. Here we present the pharmacokinetic (PK) characteristics of spevatamig as monotherapy or combination therapy in patients with advanced gastrointestinal (GI) cancers. A total of 61 patients were included in this PK study: 31 patients with advanced GI cancers in spevatamig monotherapy dose escalation (0.1 mg/kg QW to 9 mg/kg Q2W) in a phase 1 trial, and 30 patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with spevatamig in combination with gemcitabine plus nab-paclitaxel (GnP) in a phase 2 trial, where 2 mg/kg once-weekly (QW), 3 mg/kg QW and other exploratory regimens were tested. Using data from these 61 patients, a 2-compartment population PK model with nonlinear (Michaelis-Menten) clearance was developed to describe spevatamig PK characteristics. Model-based PK simulation and non-compartmental analysis (NCA) were next performed at 2 mg/kg QW and 3 mg/kg QW in both monotherapy and GnP combinations. The results showed that GnP did not influence spevatamig exposure, evident by comparable AUCs. Simulated PK exposure revealed a notable accumulation following 5 repeated cycles at 2 mg/kg QW or 3 mg/kg QW in both spevatamig monotherapy and spevatamig + GnP combinations. Further, a statistically significant difference was observed between the estimated AUC 0-168 of 2 mg/kg QW spevatamig + GnP and that of 3 mg/kg QW spevatamig + GnP (p = 5.4e-10, two sample T-test), indicating that 2 mg/kg QW and 3 mg/kg QW spevatamig are two independent dose levels suitable for clinical evaluation. In conclusion, model-based simulations indicate that spevatamig exhibits dose-dependent, increase in exposures either in monotherapy or combinations at two statistically distinct potentially efficacious dose levels. Combinations with GnP did not alter spevatamig exposure at 2 mg/kg QW or 3 mg/kg QW; overall, spevatamig exhibited PK characteristics suitable for combinatorial clinical development.