Simultaneous blockade of the immune checkpoints LAG-3 and PD-1 is thought to potentiate the effects of cancer immunotherapy by producing synergistic benefits. This study investigates the safety profile and therapeutic activity of IBI110, a novel anti-LAG-3 monoclonal antibody, when combined with sintilimab, an anti-PD-1 antibody, among Chinese individuals with advanced solid tumors. An open-label phase I clinical trial was performed, incorporating a phase Ia dose-escalation assessment of IBI110 monotherapy and a phase Ib dose-escalation evaluation of IBI110 combined with sintilimab in patients with advanced solid tumors. A phase Ib dose-expansion component was also included, in which IBI110 was administered together with sintilimab and chemotherapy to treatment-naïve patients with advanced squamous non-small cell lung cancer (sqNSCLC) or HER-2-negative gastric cancer (GC). In the phase Ia escalation, IBI110 was given as monotherapy at escalating doses of 0.01/0.1/0.3/1/3/10/, 10 and 20 mg/kg every 3 weeks (Q3W). During phase Ib escalation, IBI110 doses of 0.3/0.7/1.5/3/5/8/10 mg/kg Q3W were paired with a fixed dose of sintilimab 200 mg Q3W. In the dose-expansion stage, patients received IBI110 at the recommended phase 2 dose (RP2D) in combination with sintilimab 200 mg Q3W and standard chemotherapy. The primary endpoints focused on safety and tolerability as well as efficacy parameters such as objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) per RECIST v1.1 criteria, and overall survival (OS). Secondary objectives encompassed pharmacokinetic, pharmacodynamic, and immunogenicity analyses. Treatment-related adverse events (TRAEs) were recorded in 67.9% of participants in the phase Ia dose-escalation group (n = 28), with grade ≥ 3 events occurring in 21.4% of patients. In the phase Ib combination dose-escalation group (n = 45), TRAEs affected 75.6% of patients and grade ≥ 3 TRAEs occurred in 22.2%. No dose-limiting toxicities (DLTs) were identified across the escalation phases. The predominant TRAE was anemia (17.9%, with 3.6% grade ≥ 3) during IBI110 monotherapy in phase Ia (n = 28). In the phase Ib escalation of the combination (n = 45), increased aspartate aminotransferase was most frequent (28.9%, all grades 1-2). In the sqNSCLC dose-expansion cohort (n = 20), anemia occurred in 70.0% of patients (all grades 1-2), while decreased neutrophil count was the leading event in the GC cohort (n = 17; 64.7%, including 17.6% grade ≥ 3). The RP2D for IBI110 was established as 200 mg (equivalent to 3 mg/kg) Q3W. The ORR was 3.6% with IBI110 monotherapy and 14% with IBI110 plus sintilimab in the dose-escalation stage. In the chemotherapy-containing dose-expansion cohorts, unconfirmed and confirmed ORR values were 80.0% (95% CI: 56.3–94.3) and 75.0% (95% CI: 50.9–91.3), respectively, in sqNSCLC (n = 20), and 88.2% (95% CI: 63.6–98.5) and 70.6% (95% CI: 44.0–89.7), respectively, in GC (n = 17). Both IBI110 monotherapy and its combination with sintilimab exhibited acceptable tolerability in Chinese patients diagnosed with advanced solid tumors. The addition of IBI110 to sintilimab and chemotherapy yielded promising antitumor activity in patients with sqNSCLC and GC.
