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Dual inhibition of LAG-3 and PD-1 with IBI110 and sintilimab in advanced solid tumors: the first-in-human phase Ia/Ib
Chenyu Mao1, Anwen Xiong2, Jiong Qian1
1The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Background:
Co-inhibition of immune checkpoints lymphocyte-activation gene 3 (LAG-3) and PD-1 is believed to enhance cancer immunotherapy through synergistic effects. Herein, we evaluate the safety and efficacy of IBI110 (anti-LAG-3 antibody) with sintilimab (an anti-PD-1 antibody) in Chinese patients with advanced solid tumors.
Methods:
In this open-label phase I study, phase Ia dose escalation of IBI110 monotherapy and phase Ib combination dose escalation of IBI110 plus sintilimab were conducted in patients with advanced solid tumors. Additionally, phase Ib combination dose expansion of IBI110 plus sintilimab and chemotherapy was conducted in previously untreated, advanced squamous non-small cell lung cancer (sqNSCLC) and HER-2 negative gastric cancer (GC). In phase Ia dose escalation, patients received IBI110 monotherapy at 0.01/0.1/0.3/1/3/10/20 mg/kg Q3W. In phase Ib dose escalation, patients received IBI110 at 0.3/0.7/1.5/3/5/8/10 mg/kg Q3W plus sintilimab 200 mg Q3W. In phase Ib combination dose expansion, patients received IBI110 at recommended phase 2 dose (RP2D) plus sintilimab 200 mg Q3W and chemotherapy. The primary endpoints were safety, tolerability and efficacy including objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) assessed by RECIST v1.1 and overall survival (OS). The secondary endpoints included pharmacokinetics, pharmacodynamics and immunogenicity.
Results:
In phase Ia dose escalation (n = 28), treatment-related adverse events (TRAEs) occurred in 67.9% patients and grade ≥ 3 TRAEs occurred in 21.4% patients. In phase Ib combination dose escalation (n = 45), TRAEs occurred in 75.6% patients and grade ≥ 3 TRAEs occurred in 22.2% patients. No dose-limiting toxicity (DLT) was observed. The most common TRAE was anemia (17.9%, including 3.6% ≥ G3) in phase Ia dose escalation of IBI110 monotherapy (n = 28), aspartate aminotransferase increased (28.9%, all G1-G2) in phase Ib dose escalation of IBI110 plus sintilimab (n = 45), anemia (70.0%, all G1-G2) in phase Ib dose expansion in sqNSCLC (n = 20), and neutrophil count decreased (64.7%, including 17.6%≥ G3) in phase Ib dose expansion in GC (n = 17). The RP2D of IBI110 was determined at 200 mg (3 mg/kg) Q3W. ORR in phase Ia/Ib dose escalation was 3.6% with IBI110 monotherapy and 14% with IBI110 plus sintilimab. In phase Ib combination dose expansion of IBI110 plus sintilimab and chemotherapy, unconfirmed and confirmed ORR in sqNSCLC (n = 20) was 80.0% (95% CI, 56.3-94.3) and 75.0% (95% CI, 50.9-91.3), respectively and in GC (n = 17) was 88.2% (95% CI, 63.6-98.5) and 70.6% (95% CI, 44.0-89.7), respectively.
Conclusions:
IBI110 monotherapy and in combination with sintilimab were well-tolerated in Chinese patients with advanced solid tumors. Encouraging efficacy of IBI110 in combination with sintilimab and chemotherapies was observed in sqNSCLC and GC.
Trial Registration:
ClinicalTrials.gov Identifier: NCT04085185.
Insights
This study found that IBI110 (anti-lymphocyte-activation gene 3 antibody) combined with sintilimab (anti-PD-1 antibody) was safe and effective in Chinese patients with advanced solid tumors, particularly in squamous non-small cell lung cancer and gastric cancer.
Area of Science:
- Oncology
- Immunotherapy
- Clinical Trials
Background:
- Co-inhibition of immune checkpoints lymphocyte-activation gene 3 (LAG-3) and PD-1 aims to enhance cancer immunotherapy via synergistic effects.
- This study evaluated the safety and efficacy of IBI110 (anti-LAG-3) with sintilimab (anti-PD-1) in Chinese patients with advanced solid tumors.
Purpose of the Study:
- To assess the safety and efficacy of IBI110 monotherapy and its combination with sintilimab in advanced solid tumors.
- To determine the recommended phase 2 dose (RP2D) of IBI110 for combination therapy.
- To evaluate the efficacy of IBI110 plus sintilimab and chemotherapy in specific cancer types.
Main Methods:
- An open-label, phase I study involving dose escalation of IBI110 monotherapy (phase Ia) and IBI110 plus sintilimab (phase Ib).
- Phase Ib also included dose expansion with IBI110, sintilimab, and chemotherapy in advanced squamous non-small cell lung cancer (sqNSCLC) and HER-2 negative gastric cancer (GC).
- Primary endpoints included safety, tolerability, objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS).
Main Results:
- Treatment-related adverse events (TRAEs) were observed, with the most common being anemia and increased aspartate aminotransferase in monotherapy and combination arms, respectively. Grade ≥3 TRAEs were manageable.
- The recommended phase 2 dose (RP2D) of IBI110 was established at 200 mg (3 mg/kg) Q3W.
- ORR in phase Ia/Ib dose escalation was 3.6% for IBI110 monotherapy and 14% for IBI110 plus sintilimab. In the dose expansion phase, confirmed ORR was 75.0% in sqNSCLC and 70.6% in GC.
Conclusions:
- IBI110, both as monotherapy and in combination with sintilimab, demonstrated a favorable safety profile and tolerability in Chinese patients with advanced solid tumors.
- The combination of IBI110 with sintilimab and chemotherapy showed encouraging efficacy in sqNSCLC and GC, warranting further investigation.
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