Abstract CT120: AK104, a PD-1/CTLA-4 bispecific antibody in combination with chemotherapy as first-line therapy in a phase Ib trial in patients (pts) with advanced gastric (G) or gastroesophageal junction (GEJ) cancer

Background: The platinum/fluoropyrimidine-based combination therapy as first-line regimen in pts with advanced G/GEJ cancer has limited clinical benefit (ORR of 35%; OS of ≈ 1 y). The combined PD-1/CTLA-4 (nivolumab/ipilimumab) led to higher response rate and long-term OS in pts with advanced G/GEJ cancer but with higher toxicity (Janjigian Y, ASCO 2016). Early data suggested that AK104 had encouraging anti-tumor activities and may have improved tolerance compared with the combination of PD-1/CTLA-4 (Markman B, SITC 2019). This is the first clinical trial of a PD-1/CTLA-4 bispecific in combination with chemotherapy in first-line setting. Here we report safety and efficacy in the G/GEJ cancer cohorts of a phase Ib/II, multicenter, open-label study of AK104 (NCT03852251). Methods: Pts with untreated, inoperable advanced G/GEJ adenocarcinoma regardless of PD-L1 status were enrolled to cohorts of 3-6 pts at AK104 doses of 4, 6 and 10 mg/kg q2w + mXELOX [oxaliplatin 85 mg/m2 and capecitabine 1000 mg/m2] during dose escalation. Selected cohorts were expanded up to 18 pts to further establish the recommended Phase II dose. Tumor tissue for determination of PD-L1 status with combined positive score (CPS) must be provided from ≤ 6 months before study treatment. Baseline and on-therapy blood samples were collected for the proliferation marker Ki-67 and cytokine analysis. Immunohistochemical and RNA-Seq analysis was performed on available pre- and post-treatment tumor biopsies. Antitumor activity was assessed by RECIST v1.1. Results: As of Jan 17, 2020, 20 pts (80% male, median age 63 yrs [28-74]), 40% with liver or lung metastasis) have received AK104 at doses of 4 mg/kg (n = 17) and 6 mg/kg (n = 3) + mXELOX. AK104-related adverse events (TRAEs) occurred in 45% of pts. G3 TRAEs occurred in 20% (4/20), and there were no G4 TRAEs. No TRAEs led to treatment discontinuation. No dosing limiting toxicity (DLT) was identified. Most frequent TRAEs were platelet count decreased (25%), ALT increased (15%), AST increased (15%), blood glucose increased (15%), neutrophil count decreased (15%), white blood cell count decreased (15%) and rash (15%). Of 15 pts evaluable for antitumor activity, ORR was 60% (9/15) and disease control rate (DCR) was 93.3% (14/15). Seven responders remained in response with duration of response ranging 1+ to 168+ days. One pt progressed due to new lesion and had target lesion reduction of 40%. Response was seen regardless of PD-L1 status. Conclusions: AK104 in combination with mXELOX had a manageable safety profile and encouraging antitumor activities in pts with advanced G/GEJ adenocarcinoma regardless of PD-L1 status. Enrollment is currently ongoing for expansion cohort at 6 mg/kg and enrollment for 10 mg/kg cohort in the escalation phase will be started in early Feb, 2020. Citation Format: Jiafu Ji. AK104, a PD-1/CTLA-4 bispecific antibody in combination with chemotherapy as first-line therapy in a phase Ib trial in patients (pts) with advanced gastric (G) or gastroesophageal junction (GEJ) cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT120.