RAS(ON) Inhibitors May Overcome Resistance to Traditional KRAS Inhibitors in Solid Tumors

Alexander I. Spira, MD, PhD, FACP, FASCO

With the development of novel RAS(ON) inhibitors such as zoldonrasib (RMC-9805) and daraxonrasib (RMC-6236), investigators are aiming to surmount acquired resistance in patients with pretreated solid tumors following treatment with currently available RAS inhibitors.

KRAS is the most common altered oncogenic protein in solid tumors and was thought to be resistant to drug therapy until recent improvements in drug design, leading to the development of the FDA-approved KRAS G12C inhibitors sotorasib (Lumakras) and adagrasib (Krazati).¹ These agents are RAS(OFF) inhibitors, meaning they bind to a switch II region pocket accessible when KRAS is in the GDP-bound inactive state; the agents covalently engage with the mutant cysteine and lock the oncogene in its inactive state.2 Although sotorasib and adagrasib have displayed impressive efficacy in non–small cell lung cancer and colorectal cancer, patients often develop resistance to these agents.

Comparatively, RAS(ON) inhibitors target the active, GTP-bound state of RAS.1 Targeting RAS in this manner has shown the potential to overcome resistance to RAS(OFF) inhibitors in preclinical studies.²

Multiple RAS(ON) inhibitors in the development pipeline are showing promise. During the American Society of Clinical Oncology 2025 Gastrointestinal Cancers Symposium (ASCO GI), investigators presented early data from clinical trials evaluating the RAS(ON) inhibitors zoldonrasib and daraxonrasib in advanced solid tumors, including pancreatic ductal adenocarcinoma (PDAC).

Zoldonrasib and Daraxonrasib Display Early Signs of Efficacy in PDAC

Zoldonrasib is a potent RAS(ON) G12D-selective covalent tricomplex inhibitor designed to directly inhibit uncontrolled RAS(ON) signaling.³ In a phase 1 study (NCT06040541), investigators evaluated the agent in adult patients with KRAS G12D–mutated advanced solid tumors who had received prior standard therapy appropriate for their disease.

Data from the dose-escalation portion of the study presented during ASCO GI demonstrated that patients with PDAC who received zoldonrasib at a dose of 1200 mg either once or twice daily (n = 40) achieved an overall response rate (ORR) of 30%. The disease control rate (DCR) was 80%. Additionally, among the patients evaluable for changes in KRAS G12D variant allele frequency (VAF; n= 28), 86% had at least a 50% decrease and 39% had a 100% decrease in KRAS G12D VAF after treatment with zoldonrasib.

“[The VAF data] tell us that patients who are responding but have not demonstrated [a response] on imaging are also doing very well,” Alexander I. Spira, MD, PhD, FACP, FASCO, said in an interview with OncologyLive. “That [contributes] to clinical benefit rate and, hopefully, the overall survival [OS] rate. We’re getting a benefit from the drug in multiple ways, which can lead us to bigger, phase 3 studies and likely improvements in OS and progression-free survival [PFS].”

Spira is codirector of the Virginia Cancer Specialists Research Institute in Fairfax and director of the Thoracic and Phase I Program and a clinical assistant professor at Johns Hopkins School of Medicine in Baltimore, Maryland. He also presented the findings from the phase 1 study during ASCO GI.

Regarding safety, no patients across disease groups who received zoldonrasib (n = 179) experienced a treatment-related adverse effect (TRAE) that led to treatment discontinuation, and only 3% of patients had an event leading to a dose reduction. Common any-grade TRAEs included nausea (30%), diarrhea (16%), and vomiting (15%). There were no grade 4 or 5 TRAEs or serious AEs.

“[Zoldonrasib] was a very well-tolerated drug, [with] very [few] grade 3 and 4 AEs,” Spira noted. “Because this is an allele-specific [drug], we did not see [AEs] we’ve seen with other RAS inhibitors. [There was] a very low incidence of rash and very few dose reductions.”

In a phase 1 study (NCT05379985), daraxonrasib, another RAS(ON) tricomplex inhibitor, is being examined in adult patients with advanced solid tumors harboring RAS mutations who had received prior standard therapy appropriate for tumor type and stage.⁴ Daraxonrasib is a multiselective inhibitor that also directly inhibits uncontrolled RAS(ON) signaling.

Patients with RAS-mutated PDAC who received daraxonrasib at the recommended phase 2 dose (RP2D) of 300 mg daily (n= 37) achieved a median PFS of 8.5 months (95% CI, 5.9-not evaluable [NE]). The median OS was NE (95% CI, 8.5-NE), and the 6-month OS rate was 97% (95% CI, 79%-100%). The ORR and DCR were 27% and 95%, respectively.

Among patients with KRAS G12X–mutated PDAC treated at the RP2D (n = 22), the median PFS and OS were 8.8 months (95% CI, 8.5-NE) and NE (95% CI, NE-NE), respectively; notably, the 6-month OS rate was 100% (95% CI, 100%-100%). The ORR and DCR were 36% and 91%, respectively.

Ignacio Garrido-Laguna, MD, PhD, MBA

“We feel that the PFS data are remarkable,” Ignacio Garrido-Laguna, MD, PhD, MBA, said in an interview with OncologyLive. “The PFS in the second-line setting compares very positively with historical controls; in this setting, we typically see a [median] PFS in the range of 3 months.”

Garrido-Laguna is the director of the Phase 1 Program, coleader of the GI Oncology Multidisciplinary Disease Group, and a professor of oncology at the University of Utah Huntsman Cancer Institute in Salt Lake City. Garrido-Laguna presented the findings from the phase 1 study of daraxonrasib during ASCO GI.

Evaluable patients with KRAS G12X–mutated disease who received daraxonrasib at 160 mg to 300 mg daily (n = 60) experienced a reduction in KRAS G12X VAF of at least 50% at a rate of 93%; 48% of patients achieved a 100% decrease. Among evaluable patients with RAS-mutated disease (n = 73), these rates were 90% and 45%, respectively.

Among patients with PDAC in the safety population who received daraxonrasib at the RP2D (n = 76), 96% experienced any-grade TRAEs. Common any-grade TRAEs included rash (91%), diarrhea (53%), and nausea (38%). TRAEs leading to dose modification, interruption, or reduction, occurred at rates of 42%, 40%, and 25%, respectively. No patients discontinued treatment due to TRAEs.

“Based on [findings from] this study, there has been a randomized phase 3 trial, RASolute 302 [NCT06625320], that has been launched,” Garrido-Laguna said. “It is a global study that is enrolling patients [with PDAC] in the US. It started accrual in…2024, and it is going to include approximately 400 patients. It’s a very promising study based on these data, but we need to wait for completion of the study and follow up on outcomes from those patients. Patients are randomly assigned in the second line after disease progression with first-line chemotherapy to [receive] the multi-RAS inhibitor [daraxonrasib] or standard-of-care chemotherapy.”

References

1. Punekar SR, Velcheti V, Neel BG, Wong KK. The current state of the art and future trends in RAS-targeted cancer therapies. Nat Rev Clin Oncol. 2022;19(10):637-655. doi:10.1038/s41571- 022-00671-9
2. Nokin MJ, Mira A, Patrucco E, et al. RAS-ON inhibition overcomes clinical resistance to KRAS G12C-OFF covalent blockade. Nat Commun. 2024;15(1):7554. doi:10.1038/s41467-024-51828-2
3. Spira AI, Papadopoulos KP, Kim DW, et al. Preliminary safety, antitumor activity, and circulating tumor DNA (ctDNA) changes with RMC-9805, an oral, RAS(ON) G12D-selective tri-complex inhibitor in patients with KRAS G12D pancreatic ductal adenocarcinoma (PDAC) from a phase 1 study in advanced solid tumors. J Clin Oncol. 2025;43(suppl 4):724. doi:10.1200/ JCO.2025.43.4_suppl.724
4. Garrido-Laguna I, Wolpin BM, Park W, et al. Safety, efficacy, and on-treatment circulating tumor DNA (ctDNA) changes from a phase 1 study of RMC-6236, a RAS(ON) multi-selective, tricomplex inhibitor, in patients with RAS mutant pancreatic ductal adenocarcinoma (PDAC). J Clin Oncol. 2025;43(suppl 4):722. doi:10.1200/JCO.2025.43.4_suppl.722