RMC-6291

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

P1, N=117, Not yet recruiting, Revolution Medicines, Inc.

In a mouse clinical trial consisting of multiple patient- and cell line-derived xenograft models of KRASG12C NSCLC, RMC-6291 outperformed adagrasib, a KRASG12C(OFF) inhibitor, by increasing the number of responses, the depth of tumor regressions, and the durability of responses.Combination treatment with RMC-6291 and SHP2 or SOS1 inhibitors was well tolerated in preclinical models and further increased anti-tumor activity, likely by preventing reactivation of wild-type RAS proteins that cooperate with KRASG12C to fuel cancer growth. RMC-6291 also combined well with immune checkpoint inhibitors, sensitizing KRASG12C-bearing cancer models to anti-tumor immunity.RMC-6291 is a next-generation, mutant-selective inhibitor of KRASG12C(ON) that overcomes limitations of first-generation KRASG12C(OFF) inhibitors in preclinical models by directly targeting the active form of this important oncogenic driver.