elironrasib (RMC-6291)

Recently, RAS(ON) G12C-selective inhibitors, which bind to the active GTP-bound state of RAS, were described, and elironrasib is undergoing evaluation in multiple clinical trials...Two models reactivated RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and were vulnerable to dual inhibition by RAS(ON) G12C-selective and RAS(ON) multi-selective inhibitors, RMC-4998 and RMC-7977...Finally, one model displayed epithelial-mesenchymal transition, loss of RAS dependance, and acquired reliance on cell cycle kinases and proteins associated with DNA damage response. This work highlights KRASG12C-selective inhibitor resistant states that parallel and complement clinical findings and demonstrate that a large subset could be overcome with a RAS(ON) multi-selective inhibitor as a standalone agent or in combination with other therapies.

Here we report structure-guided medicinal chemistry efforts that led to the discovery of elironrasib, a potent, orally bioavailable, RAS(ON) G12C-selective, covalent, tri-complex inhibitor. The investigational agent elironrasib is currently undergoing phase 1 clinical trials (NCT05462717, NCT06128551, NCT06162221), with preliminary data indicating clinical activity in patients who had progressed on first-generation inactive state-selective KRASG12C inhibitors.

P1/2, N=484, Recruiting, Revolution Medicines, Inc. | N=352 --> 484

Two of these molecules, sotorasib and adagrasib, are approved for the treatment of adult patients with KRASG12C-mutated previously treated advanced non-small cell lung cancer. We demonstrate here that disease progression in vivo can also occur due to adaptive mechanisms and increased KRAS-GTP loading. Using the preclinical tool tri-complex KRASG12C-selective covalent inhibitor, RMC-4998 (also known as RM-029), that targets the active GTP-bound (ON) state of the oncogene, we provide a proof-of-concept that the clinical stage KRASG12C(ON) inhibitor RMC-6291 alone or in combination with KRASG12C(OFF) drugs can be an alternative potential therapeutic strategy to circumvent resistance due to increased KRAS-GTP loading.

P1, N=222, Active, not recruiting, Revolution Medicines, Inc. | Recruiting --> Active, not recruiting

P1, N=222, Recruiting, Revolution Medicines, Inc. | N=117 --> 222

P1/2, N=352, Recruiting, Revolution Medicines, Inc. | Not yet recruiting --> Recruiting

P1, N=210, Recruiting, Revolution Medicines, Inc. | Not yet recruiting --> Recruiting

P1/2, N=352, Not yet recruiting, Revolution Medicines, Inc.

P1, N=210, Not yet recruiting, Revolution Medicines, Inc.

P1, N=117, Recruiting, Revolution Medicines, Inc. | Not yet recruiting --> Recruiting