840TiPA phase Ib/II study of AK104, a PD-1/CTLA-4 bispecific antibody, combined with mXELOX as first-line therapy for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma

Abstract Background AK104 is a tetravalent bispecific human IgG1 antibody, targeting two clinically validated receptors, PD-1 and CTLA-4. This bispecific antibody is designed based on Akeso Tetrabody platform (AACR, 2018). AK104 introduces novel T cell targeting MOAs that may provide an improved therapeutic index and a favorable toxicity profile when compared to the PD-1 and CTLA-4 combinations. In addition, we have shown increased avidity of AK104 binding to PD-1 and CTLA-4 compared to the combinations. The combination therapy with anti-PD-1 and anti-CTLA-4 agents is approved by FDA for metastatic melanoma, renal cell carcinoma and MSI-H/dMMR colorectal cancer. The efficacy of these drug combinations is dose dependent, and the toxicity associated with anti-CTLA-4 agents in particular is dose limiting, thereby potentially limiting full potential for combination therapy. Despite recent advances, the prognosis of patients with advanced gastric cancer remains poor. AK104 may show improved efficacy and safety in comparison to the combination of conventional anti-PD-1/L1 and anti-CTLA-4 antibodies. Trial design This multicenter, open-label, phase Ib/II study will evaluate the safety and efficacy of AK104 in combination with oxaliplatin and capecitabine (mXELOX) as first-line therapy in patients with advanced gastric or GEJ adenocarcinoma. The dose-escalation phase will evaluate three dose levels (4mg/kg, 6mg/kg, and 10mg/kg Q2W) to identify a maximum tolerated dose (MTD). Selected cohorts will be expanded up to a total of 18 patients per cohort to further establish the recommended Phase 2 dose (RP2D). Dose escalation and expansion phase will be followed by dose confirmation phase (Phase II) which will further characterize the treatment of AK104 in combination at RP2D. The primary endpoints are safety and efficacy (ORR in Phase II). Secondary endpoints include additional efficacy (PFS, DoR), pharmacokinetics, PD and immunogenicity. Exploratory endpoints include efficacy according to immune-related RECIST and correlations between potential biomarkers (PD-L1 expression, TMB) and clinical activity. Clinical trial identification NCT03852251. Legal entity responsible for the study Peking University Cancer Hospital & Institute, Beijing, China. Funding Akeso Biopharma, Inc., Zhongshan, China. Disclosure All authors have declared no conflicts of interest.