IBI351 Monotherapy Shows Promise in Metastatic CRC with KRASG12C Mutation

IBI351 Monotherapy

IBI351 is an innovative KRASG12C inhibitor that can be taken orally and has significant potency. It is specifically designed to target the exchange of GTP/GDP, a crucial process in pathway activation, by modifying the cysteine residue of the KRASG12C protein in a covalent and irreversible manner. Before advancing to clinical trials, extensive studies were conducted to assess the selectivity of IBI351 towards G12C, with results indicating a high level of specificity. As a result, IBI351 effectively hampers the downstream signaling pathway, leading to the induction of apoptosis in tumor cells and arresting their cell cycle progression.

During the ASCO 2023 conference, a combined analysis of two Phase I studies (NCT05005234, NCT05497336) was presented, evaluating the effectiveness and safety of IBI351 as a single treatment for metastatic colorectal cancer (CRC) patients with the KRASG12C mutation. The patients received IBI351 orally at various dose levels, primarily 700 mg once daily. The primary endpoints included measuring the objective response rate (ORR).

As of the data cutoff in February 2023, a total of 54 patients with metastatic CRC were enrolled in the studies and received at least one dose of IBI351. This included 3 patients at 700 mg once daily, 4 patients at 450 mg twice daily, 46 patients at 600 mg twice daily, and 1 patient at 750 mg twice daily. Among the evaluable group of 42 patients who received 600 mg twice daily, the ORR was 42.9% (18 out of 42), and the confirmed ORR was 31.0% (13 out of 42). The disease control rate (DCR) was 88.1% (37 out of 42).

Out of the 23 patients who had received at least two lines of prior systemic anticancer therapy, the ORR was 65.2% (15 out of 23), confirmed ORR was 43.5% (10 out of 23), and DCR was 87.0% (20 out of 23). The median duration of response (DoR) had not been reached yet, with a median follow-up of 5.5 months. The 3-month DoR rate was 85.7%. As of the data cutoff, 92.3% of the confirmed responders were still continuing treatment.

Regarding safety, IBI351 was generally well-tolerated. Treatment-related adverse events (TRAEs) occurred in 87.0% (47 out of 54) of the patients, with the majority being Grade 1-2 in severity. The most common TRAEs included anemia, decreased white blood cell count, pruritus, increased alanine aminotransferase, decreased neutrophil count, increased aspartate aminotransferase, increased blood bilirubin, and asthenia. Approximately 18.5% of the patients reported Grade 3 TRAEs. There were no Grade 4-5 TRAEs or TRAEs that led to the discontinuation of treatment.

KOL insights

“KRASG12C mutation occurs in about 2.5% of colorectal cancer in China. The prognosis of advanced colorectal carcinoma patients with KRASG12C mutation is worse than KRAS wild-type patients with limited therapeutic options. Currently, there are no approved drugs targeting KRASG12C available on the market in China. IBI351 is a novel, irreversible covalent inhibitor of KRASG12C mutation. The preliminary data shows favorable safety and promising activity of IBI351 monotherapy in KRASG12C mutated advanced colorectal cancer. We look forward to more positive clinical data from this study.” –Expert Opinion.


The use of IBI351 as a single treatment has shown encouraging antitumor activity and a favorable safety profile in patients with advanced colorectal cancer carrying the KRASG12C mutation. Both of these studies are currently ongoing, suggesting that further data will be collected to enhance our understanding of IBI351's efficacy and safety. Notably, IBI351 has received Breakthrough Designation from the NMPA (National Medical Products Administration) as monotherapy for previously treated advanced non-small cell lung cancer (NSCLC) and colorectal carcinoma in January 2023 and May 2023, respectively