divarasib (RG6330)

Moreover, we show that GNE-8025 increases the activity of a broad range of MAPK pathway inhibitors in vitro as well as the KRASG12C inhibitor Divarasib both in vitro and in vivo. In addition, GNE-2181 inhibits growth of an intracranial tumor model in vivo. Altogether we present a next-generation class of TEAD inhibitors representing a significant advancement towards potent, specific, and effective Hippo-targeting cancer therapies.

P3, N=338, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Sep 2027 --> May 2026

P3, N=400, Not yet recruiting, Hoffmann-La Roche

P3, N=100, Recruiting, Hoffmann-La Roche | N=23 --> 100

P2, N=920, Active, not recruiting, Hoffmann-La Roche | 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.

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=282, Recruiting, F. Hoffmann-La Roche AG

P1, N=498, Active, not recruiting, Genentech, Inc. | Trial completion date: Sep 2026 --> Dec 2027 | Trial primary completion date: Sep 2026 --> Dec 2027

P1, N=542, Recruiting, Hoffmann-La Roche | Trial completion date: Nov 2028 --> Aug 2030 | Trial primary completion date: Aug 2027 --> Aug 2030

P3, N=100, Recruiting, Hoffmann-La Roche | N=60 --> 100