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: Ji Jiafu , Shen Lin , Li Ziyu , Xu Nong , Liu Tianshu , Chen Ye , Li Changzheng , Gao Xiangyu , Ji Ke , Mao Chenyu , Wang Yan , Meng Yuanpu , Mei Yi , Jin Xiaoping , Wang Zhongmin Maxwell , Li Baiyong , Xia Yu 
Published: January 2021

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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/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. 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.