daraxonrasib (RMC-6236)

We evaluated KRAS G12D -specific (MRTX1133) and pan-KRAS inhibitor (RMC-6236) in KRAS mut organoid and orthotopic PDX models of AA. Additionally, KRAS inhibition remodels TME and may enhance innate immune signaling. These findings support continued clinical development of KRAS inhibitors in AA and provide a rationale for combination strategies targeting resistance pathways and stromal remodeling.

We report the case of a patient with metastatic foot melanoma enrolled in a clinical trial of the anti-RAS agent RMC-6236 who developed chronic bilateral corneal epithelial defects and thinning, likely secondary to the systemic effects of targeted therapy. This case highlights the ocular surface toxicity associated with systemic anticancer therapies affecting rapidly dividing cells and the overall importance of multidisciplinary medical management of these systemic therapeutics.

While these pathways can be broadly inhibited using the pan-RAS-ON inhibitor RMC-6236, cells remained capable of developing acquired resistance where cell proliferation is uncoupled from RAS signaling...Finally, concurrent inhibition of KRAS with either CDK4/6 or CDK2 yields durable tumor control in vivo in xenografts derived from acquired resistant models. In conclusion, our findings identify sustained cell cycle activity as a defining feature of resistance to KRAS-directed therapies and establish cell cycle co-targeting as an effective strategy to overcome KRAS/RAS inhibitor resistance.

P2, N=260, Not yet recruiting, Bristol-Myers Squibb

P3, N=900, Recruiting, Revolution Medicines, Inc.

As such, the BCL-2 inhibitor venetoclax further enhanced RMC-6236-mediated killing by disrupting RMC-6236 enhanced BIM:BCL-2 complexes. RMC-6236 is a clinically relevant drug that can successfully target the MAPK pathway in these cancers. This study supports expanded clinical testing of this novel therapy to this important subset of neuroblastoma.

P1/2, N=130, Recruiting, Revolution Medicines Inc.

P1/2, N=534, Recruiting, Revolution Medicines, Inc. | Phase classification: P1 --> P1/2 | N=210 --> 534 | Trial completion date: Nov 2026 --> Jun 2029 | Trial primary completion date: Nov 2026 --> Dec 2028

This article examines the clinical and translational application of specific next-generation blood-brain barrier penetrant KRASG12C inhibitors, such as sotorasib, adagrasib, olomorasib, RMC-6236, and D3S-001, and their rational integration with radiation therapy, targeted therapies, and immunotherapies to overcome therapeutic resistance in patients with NSCLC brain metastases. This review summarizes recent advances aimed at enhancing intracranial tumor control and overall survival in patients with NSCLC brain metastases through the use of next-generation KRASG12C inhibitors and multimodal therapies.

Further, the addition of KO-2806 rescued sensitivity of progressing tumors to the pan-RAS inhibitor RMC-6236. These results establish mTORC1 as an important mediator of escape from RAS inhibition and highlight KO-2806 as a promising RAS companion inhibitor in patients with prior RAS inhibitor exposure.

RRASQ87L and RRAS2Q72L are recurrent, oncogenic, and potentially actionable drivers in NSCLC. Our study supports the inclusion of RRAS/RRAS2 into routine molecular diagnostic panels for precision oncology and provides preclinical rationale for investigating the potential therapeutic utility of pan-RAS inhibitors for patients with RRASQ87L/RRAS2Q72L-mutant lung cancers.

RAS inhibitors MRTX1133 and RMC-6236 alter Switch-I/II conformations, thereby blocking SKP assembly more effectively than they disrupt preformed complexes. This MRAS mutant can form an SMP complex, but MRTX1133 blocks its assembly, demonstrating the feasibility of dual SKP and SMP targeting. Overall, our findings define isoform-specific differences in SHOC2-RAS-PP1C complex formation and support a strategy to prevent both SKP and SMP assemblies to overcome resistance in RAS-driven cancers.