daraxonrasib (RMC-6236)

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.

Recent advances in mutation-specific inhibitors (e.g., sotorasib for KRASG12C) have demonstrated clinical efficacy but face limitations in tumor types like PDAC, where KRASG12C mutations are rare. Broad-spectrum pan-RAS inhibitors (e.g., RMC-7977, RMC-6236, ADT-007/ADT-1004) now offer promise by targeting active GTP-bound or nucleotide-free RAS across isoforms and mutations...Challenges remain in achieving a therapeutic index due to RAS's role in normal tissue homeostasis, but tumor-specific drug accumulation and rapid normal tissue recovery may mitigate risks. Ongoing trials are evaluating combination strategies with immunotherapy and chemotherapy, positioning pan-RAS inhibitors as transformative agents for RAS-driven cancers.

Robust antitumor activity of AOH1996 in combination with RMC-6236 was observed in PDAC tumoroids. In vivo , the combination of AOH1996 with sotorasib or MRTX1133 reduced tumor growth rates compared to single-agent therapy, with no impact on mouse body weight. Residual tumor analysis showed sustained pERK and Myc inhibition in the combination arm. In conclusion, combination of AOH1996 with KRAS inhibitors is a promising therapeutic strategy for KRAS-driven PDAC, warranting further clinical investigation.

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.