Abstract 6585: Combination RASG12C(ON) and RASMULTI(ON) inhibition overcomes resistance and prolongs durability in preclinical models of mutant KRASG12C-driven cancers

Abstract Inhibitors of the GDP-bound state of mutant KRASG12C protein (KRASG12C (OFF) ), e. g. , adagrasib and sotorasib, have shown clinical activity in patients with KRASG12C-driven NSCLC, CRC and PDAC. However, most patients exhibit progression on monotherapy treatment in months, underlining the need for combination therapeutic approaches that improve the durability of the anti-tumor activity seen with KRASG12C inhibitors. RMC-6291 is a mutant-selective covalent inhibitor of the GTP-bound RAS (ON) form of RASG12C, while RMC-6236 is a non-covalent RASMULTI (ON) inhibitor of both mutant and wild-type variants of canonical RAS isoforms. In models harboring diverse alterations driving resistance mechanisms to KRASG12C (OFF) inhibitors – including reactivation of KRASG12C and wild-type RAS by increased RTK signaling, acquired secondary oncogenic RAS mutations, and KRAS amplification – both RMC-6291 and RMC-6236 exhibited superior anti-cancer activity as single agents when compared to KRASG12C (OFF) inhibitors. Thus, we hypothesized that a combination of RMC-6291 and RMC-6236 could address a broad spectrum of observed clinically relevant resistance mechanisms to KRASG12C (OFF) inhibitors that reactivate RAS signaling via mutant and wild-type RAS isoforms and compromise the depth and durability of anti-tumor response. In a mouse clinical trial with KRASG12C xenograft models, daily oral administration of RMC-6291 induced objective responses in 18 out of 25 NSCLC PDX and CDX models as assessed by mRECIST. In a subpanel of 7 NSCLC models that are relatively refractory to KRASG12C (OFF) inhibitor monotherapy, RMC-6236 alone somewhat prolonged the durability of response, while the combination of RMC-6291 with RMC-6236 improved the depth of response and significantly extended the durability thereof. In contrast to NSCLC, in models of KRASG12C CRC tumors a more heterogeneous response to RMC-6291 monotherapy was observed with objective responses in 4 out of 15 CRC models. The addition of RMC-6236 to RMC-6291 substantially improved the depth and duration of anti-tumor response in the resistant models to KRASG12C inhibitor alone. The combination of RMC-6291 with RMC-6236 at preclinical target doses did not affect the systemic or tumor exposures of each compound and was well tolerated in tumor-bearing immune-deficient animals. Both investigational agents RMC-6236 and RMC-6291 have shown promising anti-tumor activity as monotherapies in preclinical models and, more recently, showed preliminary clinical activity in patients with RAS-driven tumors at exposures that were well tolerated. The addition of RMC-6236 to RMC-6291 shows combinatorial activity in preclinical models that are relatively less responsive to either inhibitor alone. A clinical trial combining RMC-6291 with RMC-6236 in patients with mutant KRASG12C tumors is currently enrolling. Citation Format: Xing Wei, Matthew Holderfield, Yu Chi Yang, Kyle Seamon, Jay Dinglasan, Nilufar Montazar, Bianca Lee, Shurui Cai, Lick Lai, Ida Aronchik, Stephanie Chang, Zhican Wang, Pete Wildes, Jacqueline A. Smith, Jingjing Jiang, Mallika Singh. Combination RASG12C (ON) and RASMULTI (ON) inhibition overcomes resistance and prolongs durability in preclinical models of mutant KRASG12C-driven cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6585.