Abstract A097: HBI-2438, HUYABIO selective KRASG12C inhibitor with BBB penetration, inhibited tumor growth in a metastatic brain model as single agent and also displayed synergy in combination with HBI-2376 (HUYABIO SHP2 inhibitor) in a CRC PDX model
Authors: Shojaei Farbod , Ricono Jill M , Fang Che , Ning John , Lee Gloria , Gillings Mireille 
Published: December 2023

Abstract
Recent advances in targeting KRASG12C mutation and approval of sotorasib and adagrasib provided new treatment avenues for cancer patients. Additionally, about 10% of NSCLC (non-small cell lung cancer) patients carrying KRASG12C mutation are diagnosed with brain metastasis. Nearly 50% of NSCLC patients with recurrent disease also have metastatic lesions in the brain. This further signifies the therapeutic value of KRASG12C inhibitors with BBB (blood brain barrier) penetration properties. Early studies showed HBI-2438, HUYABIO selective and potent KRASG12C inhibitor, was detectable and quantifiable in CSF when administered orally. Here we tested efficacy of HBI-2438 in an intra-carotid brain metastatic model and compared its efficacy vs. AMG510 and MRTX849 in similar dose and intervals. Bioluminescent imaging and quantification showed major tumor regression in tumors treated with HBI-2438 and MRTX849 and to a lesser extent in AMG510 treated tumors, all at 30 mg/kg. Consistent with preclinical data, HBI-2438 monotherapy showed early clinical efficacy signal in Cohort 1 (150 mg) and Cohort 2 (300 mg). HBI-2438 was well tolerated and did not show any SAEs or DLTs in these early cohorts. SHP2 signaling is one of the main components of the RAS/MAPK pathway and is acting upstream of KRAS. Therefore, and has been shown recently, targeting both KRAS and SHP2 in combination therapy may enhance the response to either agent as monotherapy. Here we tested combination of HBI-2438 and HBI-2376 (HUYABIO selective SHP2 inhibitor) in a KRASG12C CRC (colorectal cancer) PDX (patient derived xenograft) model that has demonstrated partial resistance to treatment with KRASG12C inhibitors. As expected, tumor bearing mice treated with HBI-2438 or MRTX849 monotherapy showed partial tumor growth inhibition in this model. However, combination treatment, HBI-2438 (10 or 30 mpk) plus HBI-2376 (5 mpk), showed significant inhibition in tumor growth. Additionally, the combination therapy at a higher dose (HBI-2438 at 100 mpk plus HBI-2376 at 5 mpk) achieved complete tumor regression vs. MRTX849+TNO155 demonstrating synergy between the two compounds in this model. These data further demonstrated greater inhibition of KRAS/MAPK pathway leading to a better tumor growth inhibition and justifies testing combination of HUYABIO KRAS G12Ci plus SHP2i in the clinic. Therefore, we believe HBI-2438 is a well differentiated KRAS G12C inhibitor vs. the competitors due to i) BBB penetration ii) superiority in combination therapy with SHP2 inhibitor and iii) efficacy signal in early cohorts in the clinic.
Citation Format: Farbod Shojaei, Jill M Ricono, Che Fang, John Ning, Gloria Lee, Mireille Gillings. HBI-2438, HUYABIO selective KRASG12C inhibitor with BBB penetration, inhibited tumor growth in a metastatic brain model as single agent and also displayed synergy in combination with HBI-2376 (HUYABIO SHP2 inhibitor) in a CRC PDX model [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A097.