AK104 (PD-1/CTLA-4 bispecific) combined with chemotherapy as first-line therapy for advanced gastric (G) or gastroesophageal junction (GEJ) cancer: Updated results from a phase Ib study.
Authors: Jiafu Ji, Lin Shen, Ziyu Li, Nong Xu, Tianshu Liu, Ye Chen, Changzheng Li, Xiangyu Gao, Ke Ji, Chenyu Mao, Yan Wang, Yuanpu Meng, Yi Mei, Xiaoping Jin, Zhongmin Maxwell Wang, Baiyong Li, Yu Xia
Journal: Journal of Clinical Oncology (2021)

232 Background: OS and PFS benfits have been observed in combination of anti-PD-1 agent plus chemotherapy compared to chemotherapy alone as first-line advanced G/GEJ cancer (Checkmate-649). It uncovers the significant treatment prospects of immune checkpoint inhibitors combination therapies. The PD-1/CTLA-4 dual blockade has consistently demonstrated higher response rate compared to PD-1 monotherapy but higher toxicity. AK104, a PD-1/CTLA-4 bispecific antibody, is designed as a novel tetrameric form. It could preferentially binds to tumor-infiltrating lymphocytes (TILs) co-expressing PD-1 and CTLA-4 with higher avidity in the tumor micro-environment than peripheral sites. Therefore, AK104 is designed to retain the efficacy benefit derived from the combination of anti-PD-1 and anti-CTLA-4 while conferring superior safety compared to the co-administration of these individual agents. This Phase Ib study evaluates the safety and efficacy of AK104 and mXELOX in the first-setting of G/GEJ cancer cohorts (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/m 2 and capecitabine 1000 mg/m 2 ] 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. Antitumor activity was assessed by RECIST v1.1. Results: As of Sep 9, 2020, 34 pts (73.5% male, median age 63.1 yrs [29-75], 76.5% G and 23.5% GEJ ) have received AK104 at doses of 4 mg/kg (n = 18), 6 mg/kg (n = 14) and 10 mg/kg (n = 2) + mXELOX. AK104-related adverse events (TRAEs) occurred in 79.4% of pts. G3 TRAEs occurred in 29.4% (10/34) and no G4 or G5 TRAE was reported. Most frequent TRAEs (incidence ≥ 15%) were neutrophil count decreased (26.5%), platelet count decreased (20.6%), white blood cell count decreased (17.6%), anaemia (17.6%) and infusion related reaction(17.6%). Grade ≥3 TRAEs reported in ≥2 pts were neutrophil count decreased (8.8%). Grade ≥3 immune-related AEs were reported in 8.8% of pts (hepatitis, pneumonitis, hyponatraemia). Of 24 pts evaluable for antitumor activity, ORR was 66.7% (95% CI 44.7, 84.4 ) including 2 CRs and 14 PRs . The disease control rate (DCR) was 95.8% (95% CI 78.9, 99.9). Response was seen regardless of PD-L1 status. At a median follow-up of 8.6 mons for the 4mg/kg cohort, 6-mons PFS rate was 69.5% (95%CI 41.3, 86.1). 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 6 mg/kg and 10 mg/kg cohort. Clinical trial information: NCT03852251.