Abstract A098: HBI-2376, HUYABIO clinical stage SHP2 inhibitor, displays efficacy signal in patients with KRAS mutations in early clinical studies

Abstract

SHP2 is an attractive target in oncology drug development due to its dual roles in tumor progression: i) direct growth and proliferation of cancer cells; ii) acting as an immune checkpoint molecule to suppress tumor immunity. HBI-2376 is an orally bioavailable selective SHP2 inhibitor developed for the treatment of solid tumors harboring KRAS or EGFR mutations, such as non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and pancreatic cancer (PAC). Additionally, HBI-2376 has the potential to suppress tumor growth via induction of the activity of immune infiltrating cells in the TME (tumor microenvironment). Preclinical studies showed greater potency of HBI-2376 to inhibit cell proliferation in a variety of cancer cell lines compared to other SHP2 inhibitors such as TNO-155 (Novartis AG) and RMC-4550 (Revolution Medicines). Additionally, HBI-2376 was found to be more efficacious in tumor growth inhibition than TNO-155 and RMC-4550 in NCI-H1975L858R_T790M_C797S osimertinib-resistant cell line and other tumor models. Furthermore, Western blotting showed inhibition of p-ERK and DUSP6 in HBI-2376 treated cells indicative of a biomarker of response to the therapy. In addition to xenograft models, we tested efficacy of HBI-2376 as single agent or in combination with anti-PD-1 mAb in MC38 CRC syngeneic model. HBI-2376 showed greater efficacy in tumor growth inhibition vs. TNO-155 and RMC-4550 both as single agent and in combination therapy. IHC data showed reduction in infiltration of M2 macrophages (F4/80+Arg1+) in the HBI-2376 treated tumors suggesting a mechanism of action for its greater efficacy in MC38 model. HBI-2376 is currently being tested in Phase 1 clinical trials. Consistent with preclinical studies, we have observed efficacy signals in early cohorts in two patients with partial responses (PR). Both patients were harboring KRAS mutations beyond KRAS G12C. Additionally, HBI-2376 was well tolerated with no SAEs or DLTs in the first four cohorts indicative of a good tolerability in cancer patients. Analysis of pERK in PBMCs isolated from the treated patients showed dose dependent inhibition in pERK further supporting a mechanism driven response to HBI-2376. Therefore, the preclinical and clinical data may represent HBI-2376 as the best-in-class SHP2 inhibitor.

Citation Format: Farbod Shojaei, Jill M Ricono, Che Fang, Yan Xing, John Ning, Gloria Lee, Mireille Gillings. HBI-2376, HUYABIO clinical stage SHP2 inhibitor, displays efficacy signal in patients with KRAS mutations in early clinical studies [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 A098.