KN026, a Bispecific Anti-HER2 Antibody, Combined with KN046, an Anti-CTLA-4/PD-L1 Antibody, in Patients with HER2-positive Advanced Gastrointestinal Cancer: a multicenter, open-label, nonrandomized, phase Ib study

Abstract Background Anti-HER2 antibodies combined with immune checkpoint inhibitors exert synergistic effects on innate and adaptive immunity. This phase Ib study assessed the safety and efficacy of KN026 plus KN046 in patients with HER2-positive gastrointestinal cancer. Methods Treatment naïve or pretreated locally advanced or metastasis, gastrointestinal cancer patients with HER2 alterations were enrolled. Four dose combinations of KN026 (20 mg/kg Q2W or 30 mg/kg Q3w) and KN046 (3 mg/kg Q2w or 5 mg/kg Q2w/Q3w) were designed. The primary objective was to assess dose-limiting toxicity (DLT) and preliminary efficacy. Results Overall, 47 patients were enrolled. No DLTs were observed. Any-grade treatment-related adverse events (TRAEs) were observed in 42 patients (89.4%). Anemia (40.4%), infusion-related reactions (36.2%), and elevated alanine transaminase (ALT) (27.7%) were the most common TRAEs. Grade 3 or worse TRAEs occurred in 17% of the patients. Twenty-four of the 47 patients suffered immune-related adverse events (irAEs). Rash (14.9%), hypothyroidism (6.4%) and interstitial lung disease (6.4%) were most commonly observed. Forty of 47 patients were included in efficacy assessment. The objective response rates (ORRs) in the patients with HER2-positive gastric cancer and gastroesophageal junction (GC/GEJ) adenocarcinoma in the first-line and late-line settings were 71.4% and 37.5%, respectively. No disease remission was observed in the patients with low HER2 expression or HER2 mutation. Notably, half of the patients (2/4) pretreated with trastuzumab and a programmed cell death-1 (PD-1) blockade achieved partial response (PR). Conclusions and Relevance : KN026 combined with KN046 exhibited acceptable safety profiles and encouraging efficacy in patients with HER2-positive gastrointestinal cancer. Trial registration: ClinicalTrials.gov, NCT NCT04040699, Registered August 1,2019.