Abstract To evaluate the efficacy and safety of KN026, a novel bispecific HER2 (ECD2 and ECD4) antibody, plus KN046, a PD-L1, and CTLA4 bispecific antibody, in patients with advanced HER2-positive solid tumors. We conducted two sequentially designed phase Ib and II studies with similar target populations and evaluation schedules. The primary endpoints included safety, maximum tolerated dose (MTD), the recommended phase II dose (RP2D) for the phase Ib study, and the objective response rate (ORR) and duration of response (DoR) for the phase II study. Hereby, we solely report the results from 113 nonbreast cancer patients. In phase Ib, MTD was not reached. Dose 3 was confirmed to be acceptable for the phase II study. An objective response has been exclusively observed in HER2-positive patients. Any grade treatment-related adverse events (TRAEs) were reported in 108 (95.6%) patients. The most common TRAEs were infusion reactions (38.9%), anemia (37.2%), elevated AST (31.0%), and diarrhea (30.1%). Among the 108 patients evaluated for efficacy, the overall ORR was 55.6% (95%CI, 45.7%, 65.1%). In the HER2-positive GC subgroup, 38 patients received this regimen as the 1st-line treatment and 30 patients achieved an objective response, with an ORR of 78.9% (95%CI, 62.7%, 90.4%). Among 27 pretreated patients, the ORR was 44.4% (95%CI, 25.5%, 64.7%). In the other HER2-positive solid tumor subgroup (n = 34), the ORR was 52.9% (95%CI 35.1%,70.2%). Thus, KN026 plus KN04 exhibits promising efficacy and acceptable safety profiles in HER2-positive nonbreast cancer, as does the 1st-line treatment for GC.