Abstract 5978: SPR2015, a highly potent and selective KRAS G12D (on) inhibitor, exhibits favorable pharmacokinetic behavior and significant anti-tumor efficacy against colorectal cancer as monotherapy in preclinical models

Abstract Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related deaths worldwide. To date, effective treatments for CRC remain limited. About 40% of colorectal patients harbor KRAS mutations, with KRAS G12D mutation accounting for the largest population. Although many KRAS G12D (off or on) selective inhibitors are currently in clinical development, with several reported promising clinical results in pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) patients, none have demonstrated clinically meaningful efficacy in CRC patients as monotherapy. SPR2015 is a highly potent and selective KRAS G12D (on) inhibitor with nanomolar proliferation inhibitory activities in various KRAS G12D cell lines while with good selectivity over KRAS wild type. Co-crystal structure showed that SPR2015 formed tri-complexes via binding tightly with cyclophilin A (CypA) and forming a covalent bond with G12D. SPR2015 exhibited longer CypA residence time and improved target engagement kinetics in both human and mouse CypA binding assays. Oral administration of SPR2015 in mice—alone or together with another G12D (on) inhibitor (cassette PK) — clearly confirmed target-mediated drug disposition (TMDD) PK behaviors of this type inhibitors. SPR2015 outperformed the other G12D (on) inhibitor achieving rapid and sustain target engagement via enhanced CypA competitive binding. In mouse PDAC/NSCLC xenograft models, SPR2015 effectively inhibited tumor growth at 10 mg/kg (oral, q.d.) and achieved tumor regression at 30 mg/kg (oral, q.d.). Accompanying PK/PD studies in these models established the correlation between tumor growth inhibition efficacy, downstream PD inhibition on DUSP6 mRNA, and drug exposures in blood, tumor, and other tissues. Furthermore, a mouse head-to-head clinical trial was evaluated between SPR2015 and another G12D (on) inhibitor in over 15 CRC cell-derived xenograft (CDX) or patient-derived xenograft (PDX) models, using a single dose at 100 mg/kg (oral, q.d.). SPR2015 showed significantly superior efficacy in these in vivo CRC xenograft models, achieving a 64.7% objective response rate (ORR) and 94.1% disease control rate (DCR) as monotherapy. On the safety part, SPR2015 demonstrated favorable in vitro safety profiles and was well-tolerated in a 28-day rodent repeat dosing tox studies. SPR2015 is currently under IND-enabling and is expected to advance to human Phase 1 study by the end of 2026. Citation Format: Yi Qian, Zirong Zhang, Zhifei Fu, Kai Zhou, Meibi Dai, Shuqin Liu, Yang Zhang, Tao Hu, . SPR2015, a highly potent and selective KRAS G12D (on) inhibitor, exhibits favorable pharmacokinetic behavior and significant anti-tumor efficacy against colorectal cancer as monotherapy in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5978.