Study of the blood–brain barrier-penetrating KRAS G12C inhibitor JMKX1899 in KRAS G12C-mutated NSCLC with brain metastases

Patients with non-small cell lung cancer (NSCLC) harboring KRAS G12C mutations frequently develop brain metastases (BM). While KRAS G12C was once considered an undruggable target, the emergence of selective inhibitors has transformed it into a viable therapeutic option. However, effective treatment for BM requires KRAS G12C inhibitors with high central nervous system (CNS) permeability. JMKX1899, a selective small molecule inhibitor of KRAS G12C, is currently in phase II clinical trials. This study presents preclinical evidence demonstrating its antitumor efficacy and CNS penetration. To assess its therapeutic potential, we conducted in vitro and in vivo studies using KRAS G12C-mutant cell lines and xenograft tumor models. JMKX1899 selectively inhibited cell viability across multiple KRAS G12C-mutant cell lines, exhibiting slightly greater potency than AMG510 and MRTX849. Notably, JMKX1899 effectively penetrated the cerebrospinal fluid, leading to significant tumor regression and prolonged survival in preclinical BM models, surpassing AMG510 in efficacy. Early clinical data from KRAS G12C-mutant NSCLC patients with BM treated by JMXK1899 further confirm its blood-brain barrier penetration and antitumor activity. These findings strongly support the continued clinical development of JMKX1899 as a promising therapeutic candidate for NSCLC patients with KRAS G12C mutations and BM.