KRAS G12C

We discovered BBO-11818, a potent and selective noncovalent KRAS inhibitor with activity against multiple KRAS mutants in both the active (ON) and inactive (OFF) states. BBO-11818 addresses the need for KRAS inhibitors targeting clinically relevant mutants such as KRASG12D and KRASG12V, either as monotherapy or in combination.

P1, N=312, Active, not recruiting, Daiichi Sankyo | Recruiting --> Active, not recruiting

Adagrasib monotherapy yielded a median PFS of 4.4-5.6 months, an OS of 10-19.8 months, and an ORR of 19-23%, while its combination with cetuximab reported a PFS of 6.9 months, an OS of 13.4-15.9 months and an ORR of 34-46%...When combined with panitumumab, 960 mg sotorasib demonstrated better results with a PFS of 5.6-5.7 months, OS of 15.2 months and an ORR of 12.5-30%. Similarly, divarasib monotherapy led to a PFS of 5.6-6.9 months and an ORR of 20%, while its combination with cetuximab resulted in a PFS of 8.1 months and an ORR of 62.5%. Combination therapy of olomorasib and MK-1084, which are new-generation KRAS p.G12C (c.34G > T) inhibitors, with cetuximab also demonstrated highly promising efficacy with ORR of 38-44% and 50%, respectively...Initial results of KRAS-G12C inhibitors appear highly promising when they are combined with anti-EGFR therapy compared to historical therapeutic agents indicated for patients with chemotherapy-refractory CRC. Encouraging benefits warrant frontline trials with these novel therapeutics.

P1, N=750, Active, not recruiting, Eli Lilly and Company | Recruiting --> Active, not recruiting

P3, N=82, Recruiting, AstraZeneca

P2, N=43, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting | N=24 --> 43

Herein, we report the discovery and development of a brain-penetrant inhibitor of KRAS G12C using divarasib as a starting point. Optimization efforts focused on reducing molecular weight and topological polar surface area as well as shielding of hydrogen bond donors. In this manner, active transport by both P-gp and breast cancer resistance protein (BCRP) was attenuated, and high exposure in rodent brain tissue was achieved.

We demonstrate a significant noncovalent binding component of divarasib that contributes to its potency and rapid kinetics. Divarasib has greater potency and kinetics of alkylation compared with other KRAS G12C inhibitors in vitro and shows robust tumor growth inhibition in multiple KRAS G12C-positive cell lines.

P2/3, N=13, Not yet recruiting, AstraZeneca AB

P1/2, N=190, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting | Trial completion date: Jul 2036 --> May 2037

OFA balances TAT, QNS, and detection, whereas SO-NGS offers comprehensive detection with longer TAT and higher QNS. An optimized assay combining SGP's speed, OFA's reliability, and SO-NGS's comprehensiveness could improve outcomes.

Our real-world data confirm the feasibility and clinical value of routine NGS testing for NSCLC. The findings highlight specific genomic patterns in this population and demonstrate that smoking status should not preclude comprehensive molecular testing for canonical drivers.