Abstract PS5-07-06: BREAKER-101: a phase 1a/1b open-label study evaluating the safety, tolerability, pharmacokinetics, and efficacy of BBO-10203 in patients with advanced solid tumors

Abstract Activation of phosphatidylinositol 3-kinase alpha-protein kinase B (PI3Kα/AKT) signaling induced by canonical-upstream RTK or RAS interation has been implicated in resistance to hormonal and HER2-directed targeted therapies in advanced breast cancer (aBC). Although commercially available orthosteric PI3Kα inhibitors can suppress pathway activation, their clinical utility as monotherapy and in combination regimens has been hindered by a narrow therapeutic window due to on-target PI3Kα toxicities such as hyperglycemia. Previous studies have established that rat sarcoma (RAS)-mediated activation of PI3Kα plays a critical role in promoting oncogenic signaling while preserving normal cellular functions such as glucose metabolism. BBO-10203 is a novel, first-in-class, covalent small molecule with blood-brain barrier penetration, designed to break the PI3Kα:RAS interaction and inhibit RAS-mediated activation of the PI3K-AKT pathway while preserving the normal catalytic function of PI3Ka involved in cell growth, metabolism, and glucose homeostasis. In preclinical models of HER2-positive (HER2+) aBC, BBO-10203 demonstrated potent antitumor activity as monotherapy and exhibited strong synergy when combined with HER2-directed therapies. Similarly, BBO-10203 showed synergy with hormonal and CDK4/6 directed therapies in hormone receptor-positive, HER2-negative (HR+/HER2-) aBC models. Notably, treatment with BBO-10203 did not result in hyperglycemia or other toxicities typically associated with PI3Kα kinase inhibition. These findings support the further development and clinical evaluation of BBO-10203 as a therapeutic strategy for HR+/HER2- and HER2+ aBC. BREAKER-101 (NCT06625775) is a first-in-human, multicenter, open label Phase 1a/1b study. During Phase 1a dose escalation, this study will primarily evaluate the safety and tolerability of BBO-10203 as monotherapy in patients with HER2+ aBC, HR+/HER2- aBC, KRAS-mutant advanced non-small cell lung cancer (aNSCLC) and KRAS-mutant advanced colorectal cancer (aCRC). Secondary objectives are to characterize the pharmacokinetics (PK) of BBO-10203 and to evaluate preliminary antitumor activity by RECIST v1.1 including objective response, clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). At recommended dose(s) for expansion, additional safety, PK, and antitumor activity will be evaluated for BBO-10203 monotherapy and in combination with trastuzumab in HER2+ aBC, as well as in combination with fulvestrant ± ribociclib in HR+/HER2- aBC, and with FOLFOX + bevacizumab in aCRC. As an exploratory endpoint, intracranial activity of BBO-10203 will be evaluated using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Patients must have previously received standard of care therapy to be eligible for the study and prior treatment with a PI3Kα or AKT inhibitor is permitted during dose escalation. BBO-10203 will be taken orally, once daily, in a 21-day or 28-day treatment cycle depending on the cohort. This study is currently open for enrollment. Citation Format: A. Varkaris, M. Lipsyc-Sharf, M. Barve, M. Oprychal, A. Giordano, E. Hamilton, J. Rodon, K. Jhaveri, V. Kaklamani, C. Lemech, L. Wu, R. M. Shah, J. Rhee, Y. Ben, S. J. Luen. BREAKER-101: a phase 1a/1b open-label study evaluating the safety, tolerability, pharmacokinetics, and efficacy of BBO-10203 in patients with advanced solid tumors [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-07-06.