BI 1823911: A Promising KRASG12C Inhibitor's Efficacy in Preclinical Models

The KRASG12C mutation is prevalent in non-small cell lung cancer (NSCLC) at 13%, colorectal cancer (CRC) at 3%, and less so in pancreatic ductal adenocarcinoma (PDAC) at 1%. The mutation alters the 12th amino acid from glycine to cysteine, affecting RAS's ability to undergo hydrolysis. Despite this, KRASG12C still requires GEF stimulation for full activation, leading to the activation of downstream signaling and cell proliferation. Recent studies have indicated that KRASG12C inhibitors can induce anti-proliferative effects and apoptosis in mutant cancer cell lines. Early clinical trials for AMG 510 and MRTX849 showed response rates of 35-45% in NSCLC and 7-17% in CRC.

The compound BI 1823911 has demonstrated significant anti-proliferative effects in KRASG12C mutant cancer cell lines, with potency comparable to the most advanced clinical compounds. In NSCLC cell lines, BI 1823911 treatment resulted in the downregulation of MAPK pathway genes, such as DUSP6 and CCND1, and a correlation was observed between pathway modulation and sensitivity. The compound also inactivated the MAPK pathway at the protein level, as indicated by p-ERK as a pharmacodynamic biomarker.

In vivo, BI 1823911 at a dosage of 60 mg/kg showed similar anti-tumor activity to its competitors at clinically relevant exposures. Further in-depth analysis of pharmacokinetics, pharmacodynamics, and efficacy is underway. Additionally, BI 1823911 was tested in NSCLC and CRC mouse models at a daily oral dose of 60 mg/kg, showing comparable efficacy to AMG 510 and MRTX849.

Given that monotherapy with a KRASG12C inhibitor may not be sufficient for a durable response, combination therapy could potentially enhance anti-tumor efficacy and overcome adaptive resistance. BI 1823911 was combined with a variety of compounds in KRASG12C mutant cancer cell lines to identify synergistic anti-proliferative effects. Among them, a SOS1::KRAS inhibitor, BI 1701963, was identified as a promising partner. In vitro and in vivo combination studies in NSCLC and CRC tumor models demonstrated deep and durable responses, providing a strong basis for the clinical investigation of this combination.