daraxonrasib (RMC-6236)

P3, N=501, Active, not recruiting, Revolution Medicines, Inc. | Recruiting --> Active, not recruiting

P1/2, N=183, Recruiting, Tango Therapeutics, Inc. | N=133 --> 183

Likewise, a combination of selective inhibitors of KRAS (RMC-6236/daraxonrasib), EGFR family (afatinib), and STAT3 (SD36) induced the complete regression of orthotopic PDAC tumors with no evidence of tumor resistance for over 200 d posttreatment...Of importance, this combination therapy was well tolerated. In sum, these results should guide the development of new clinical trials that may benefit PDAC patients.

P3, N=500, Recruiting, Revolution Medicines, Inc.

These data support RRAS Q87L and RRAS2 Q72L as bona fide lung cancer drivers and nominate RRAS/RRAS2-mutant tumors as candidates for pan-RAS-targeted therapeutics. Our findings provide a biologic rationale and preclinical evidence to inform molecular testing paradigms and to prioritize enrollment of patients with RRAS/RRAS2-mutant NSCLC into future clinical trials of pan-RAS inhibitors.

P1/2, N=754, Recruiting, Revolution Medicines, Inc. | Phase classification: P1 --> P1/2 | Trial completion date: Jun 2026 --> Jul 2027 | Trial primary completion date: May 2026 --> May 2027

Here, we demonstrate that RMC-7977, a preclinical RAS(ON) multi-selective inhibitor representative of the investigational agent daraxonrasib (RMC-6236), was able to elicit potent antitumor immune responses across multiple NRAS-mutant melanoma models. Consistent with these preclinical data, objective clinical responses were observed in two NRAS-mutant melanoma patients treated with daraxonrasib in an ongoing Phase I/Ib clinical trial. Together, these data support the continued clinical evaluation of RAS(ON) multi-selective inhibitors for the treatment of NRAS-mutant melanoma.

Our findings point to the negative impact of KRAS mutations, particularly G12C and G12V, on RC treatment outcomes. Adaptive resistance by upregulation of ERBB genes limits the efficacy of KRAS inhibitors. Combining these with pan-ERBB inhibitors enhances anti-tumor effects in patient-derived cellular RC models, showing its potential as an alternative to the combination with anti-EGFR antibodies.

P1, N=604, Recruiting, Revolution Medicines, Inc. | N=444 --> 604

P1, N=350, Recruiting, Amgen | N=188 --> 350

Selective KRAS G12C inhibitors (e.g., sotorasib, adagrasib) have demonstrated moderate efficacy in clinical trials; however, this mutation is infrequent in PDAC. Emerging therapies targeting KRAS G12D and G12V mutations, such as MRTX1133, PROTACs, and active-state inhibitors, show promise in preclinical studies. Pan-RAS inhibitors like ADT-007, RMC-9805, and RMC-6236 compounds provide broader coverage of mutations...RNA interference technologies have also shown potential in silencing mutant KRAS and reducing tumorigenicity. Future strategies should emphasize the combination of targeted therapies with metabolic or immunomodulatory agents to overcome resistance and enhance survival in KRAS-mutated PDAC.

The recently developed pan-KRAS inhibitor daraxonrasib, also known as RMC-6236, is capable of targeting a wide array of KRAS mutations and shows promise against pancreatic and lung cancers...In osteosarcoma, KRAS inhibition decreased MMP1, MMP9, and AKT/ETS1 signaling. Daraxonrasib is a promising agent for treating osteosarcoma with KRAS mutations.