IBI363, developed by Innovent Biologics, is a first-in-class drug candidate with a PD-1/IL-2 bispecific antibody fusion protein. Its IL-2 arm is engineered for maximum efficacy and reduced toxicity, while the PD-1 binding arm achieves PD-1 blockade and selective IL-2 delivery. This dual action allows precise and efficient targeting and activation of tumor-specific T cells.

IBI363 has shown promising anti-tumor activity in various tumor-bearing models, including PD-1-resistant and metastatic models, with a good safety profile in preclinical studies. Clinical trials are ongoing in China, the United States, and Australia to assess its safety, tolerability, and preliminary efficacy in advanced malignancies.

Results presented at the 2024 ASCO Annual Meeting demonstrated IBI363's broad-spectrum anti-tumor effect and high efficacy.

Sixty-eight subjects with locally advanced or metastatic colorectal cancer who failed or were intolerant to standard treatment were enrolled and received IBI363 intravenously at dose levels between 100 μg/kg QW and 3 mg/kg Q3W. There were 83.8% of subjects with microsatellite stable (MSS)/proficient mismatch repair (pMMR), and the MMR status of the others was unknown. 76.5% of the subjects had previously received ≥ 3rd line system therapy, and 61.8% of subjects had liver metastases at baseline. 

As of Dec 22, 2023, the median follow-up time was 5.3 months. The best overall response was complete response (CR) in 1 subject, and partial response (PR) in 7 subjects respectively. The ORR was 12.7%. The ORR of the 1 mg/kg dose group was 15.0%. In 13 subjects with PD-L1 CPS ≥1, ORR was 30.8%, and DCR was 76.9%.

As for safety, grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 22 (32.4%) subjects. The most common TEAEs were arthralgia (35.3%), anemia (32.4%), pyrexia (22.1%), and hypoalbuminemia (20.6%). Grade ≥3 immune-related adverse events (irAEs) occurred in 4 (5.9%) subjects. No TRAE leading to death occurred.

KOL insights

“CRC is the third most commonly diagnosed cancer and the second leading cause of cancer death. 50%~60% of patients diagnosed with CRC develop distant metastases during their disease course, and the prognosis of metastatic CRC is poor, with a 5-year survival rate of less than 20%.  For subjects with advanced CRC who have failed standard chemotherapy, the ORR for existing treatments is only 1% ~ 4.7%, and the median overall survival is only 6 ~ 9 months. The promising efficacy of IBI363 was observed in subjects with advanced CRC, particularly in subjects with PD-L1 CPS ≥1, with a manageable safety profile. We are looking forward to the study of IBI363 monotherapy or combination therapy in advanced CRC and hope to bring new treatment options to more patients” – Expert Opinion.

Conclusion

The prognosis of advanced colorectal cancer (CRC) is poor with limited treatment options available. Traditional IL-2-based immunotherapy has limited clinical use due to its narrow therapeutic window and poor PK profiles in humans. So far, IBI363 has shown acceptable tolerability and manageable safety profiles in patients with advanced CRC. Promising efficacy of IBI363 was observed, particularly in patients with PD-L1 Combined Positive Score (CPS) ≥1. Further studies investigating IBI363 in combination with standard treatments in advanced CRC have been initiated. With the US FDA IND approval, Innovent Biologics plans to initiate a Phase II study in the US in 2024.