Abstract 3788: BBO-8520, a first-in-class direct dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRASG12C, exhibits robust efficacy in non-small cell lung cancer preclinical models
Authors: James P. Stice, Anna E. Maciag, Alok K. Sharma, Albert H. Chan, Ken Lin, Devansh Singh, Marcin Dyba, Yue Yang, Saman Setoodeh, Cathy Zhang, Brian P. Smith, Dana Rabara, Zuhui Zhang, Erik K. Larsen, John-Paul Denson, Michela Ranieri, Mary Meynardie, Rui Xu, Felice Lightstone, Kwok-Kin Wong, Andrew G. Stephen, Keshi Wang, Dhirendra K. Simanshu, Kerstin W. Sinkevicius, Dwight V. Nissley, Bin Wang, Eli Wallace, Frank McCormick, Pedro J. Beltran
Journal: Cancer Research (2025)

Abstract Sotorasib and adagrasib, allele-specific KRASG12C covalent inhibitors that only target KRASG12C in the inactive GDP-bound (OFF) state, have been approved for patients with KRASG12C locally advanced or metastatic non-small cell lung cancer (NSCLC). While these inhibitors have improved the treatment paradigm for patients with tumors harboring KRASG12C mutations, they are limited in their depth and duration of response. The suboptimal efficacy of KRASG12C (OFF)-only inhibitors is likely driven by adaptation through increasing the population of drug-insensitive KRASG12C bound to GTP (ON). Patient responses may be improved with a compound that exhibits dual activity, capturing both GTP-bound (ON) and GDP-bound (OFF) forms of KRASG12C in the cell. To address this unmet clinical need, we have developed BBO-8520, a potent, selective, orally bioavailable, direct covalent inhibitor of KRASG12C, with dual activity against both the GTP-bound (ON) and GDP-bound (OFF) states of KRASG12C. BBO-8520 binds KRASG12C with high affinity in its active and inactive conformations, locking it in the inactive state 1 confirmation, in which it is unable to bind its key effector RAF1. Cell-based assays show that BBO-8520 potently and selectively inhibits KRASG12C in the single digit nanomolar range or below across a panel of NSCLC cell lines on pERK and 3D viability. Unlike KRASG12C (OFF) inhibitors, BBO-8520 rapidly disrupts the binding of KRASG12C to RAF1 and maintains potency in growth factor activated states. In vivo, BBO-8520 demonstrates favorable pharmacokinetic (PK) and pharmacodynamic (PD) properties in mouse models of NSCLC. Single dose, oral administration results in dose- and time-dependent inhibition of pERK in KRASG12C-driven cell-derived xenograft (CDX) models. As a monotherapy, BBO-8520 demonstrates robust tumor growth inhibition in KRASG12C-driven NSCLC CDX models both sensitive and resistant to KRASG12C (OFF) inhibitors as well as in patient-derived xenograft (PDX) and genetically engineered mouse (GEM) models. BBO-8520 also exhibits strong combination benefit in vivo in the KRASG12 CDX model NCI-H2122 when combined with either BBO-10203, a selective RAS:PI3Kα breaker that blocks RAS-mediated activation of AKT in clinical development (NCT06625775), or the anti-EGFR antibody cetuximab. In summary, BBO-8520 is a first in class, potent and selective KRASG12C dual GTP-bound (ON) and GDP-bound (OFF) inhibitor that exhibits robust efficacy and may improve upon approved, KRASG12C GDP-bound (OFF)-only inhibitors in NSCLC. BBO-8520 has entered phase 1 clinical trials in patients with KRASG12C NSCLC that are either naïve or have experienced first-generation KRASG12C (OFF) inhibitors (NCT06343402). Citation Format: James P. Stice, Anna E. Maciag, Alok K. Sharma, Albert H. Chan, Ken Lin, Devansh Singh, Marcin Dyba, Yue Yang, Saman Setoodeh, Cathy Zhang, Brian P. Smith, Dana Rabara, Zuhui Zhang, Erik K. Larsen, John-Paul Denson, Michela Ranieri, Mary Meynardie, Rui Xu, Felice Lightstone, Kwok-Kin Wong, Andrew G. Stephen, Keshi Wang, Dhirendra K. Simanshu, Kerstin W. Sinkevicius, Dwight V. Nissley, Bin Wang, Eli Wallace, Frank McCormick, Pedro J. Beltran. BBO-8520, a first-in-class direct dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRASG12C, exhibits robust efficacy in non-small cell lung cancer preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3788.