Oncogenic RAS signaling has long been recognized as one of the most dominant and therapeutically challenging drivers in solid tumors. Activating mutations in KRAS, NRAS, and HRAS occur in approximately 30% of all human cancers and define the molecular backbone of several aggressive malignancies, including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer, and subsets of non-small cell lung cancer. Despite decades of biological insight, direct RAS inhibition remained elusive until the advent of allele-specific KRAS G12C inhibitors, which validated RAS as a druggable target but left the majority of RAS-mutant tumors unaddressed.
Daraxonrasib (RMC-6236), developed by Revolution Medicines, represents a next-generation approach to RAS targeting. By inhibiting the active, GTP-bound state of RAS, Daraxonrasib is designed to suppress oncogenic signaling across multiple RAS mutation subtypes. This mutation-agnostic strategy has enabled rapid clinical advancement, positioning Daraxonrasib as one of the most clinically mature RAS(ON) inhibitors in development, including late-stage evaluation in pancreatic cancer.
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Mechanism of Action: Targeting Active RAS Signaling
Daraxonrasib is a small-molecule inhibitor engineered to bind selectively to RAS in its signaling-competent, GTP-bound conformation. This approach fundamentally distinguishes it from first-generation KRAS G12C inhibitors, which bind the inactive GDP-bound state and rely on a cysteine residue unique to the G12C mutation.
By directly engaging RAS-GTP, Daraxonrasib disrupts downstream signaling through the RAF–MEK–ERK and PI3K–AKT pathways, resulting in sustained suppression of proliferative and survival signals. Preclinical pharmacodynamic studies demonstrated robust inhibition of ERK phosphorylation across multiple KRAS variants, including G12D, G12V, G13D, and Q61X. This active-state targeting strategy is particularly relevant in tumors with rapid RAS cycling and pathway redundancy, which contribute to intrinsic and adaptive resistance to allele-restricted inhibitors.
Preclinical and Translational Rationale
The translational development of Daraxonrasib was guided by the hypothesis that direct inhibition of active RAS could overcome both intrinsic resistance and feedback reactivation observed with earlier RAS-targeted strategies. In vitro studies showed that Daraxonrasib inhibited proliferation and induced apoptosis in RAS-mutant cancer cell lines, including pancreatic and colorectal cancer models resistant to KRAS G12C inhibition.
In vivo xenograft models further demonstrated dose-dependent tumor growth inhibition and durable pathway suppression. Activity in pancreatic cancer models—where KRAS dependency is nearly universal—provided strong biological justification for prioritizing PDAC in clinical development.
Early-Phase Clinical Development: Phase 1 and 1b Experience
Daraxonrasib entered first-in-human evaluation through a phase 1/1b dose-escalation and expansion program enrolling patients with advanced, refractory RAS-mutant solid tumors. The study population was heavily pretreated and included patients with metastatic PDAC, colorectal cancer, and non-small cell lung cancer.
Safety and Tolerability
Across dose-escalation cohorts, Daraxonrasib demonstrated a manageable and consistent safety profile. The most common treatment-related adverse events included rash, mucositis or stomatitis, diarrhea, nausea, and fatigue. These events were predominantly grade 1–2. Grade ≥3 treatment-related adverse events occurred in approximately one-third of patients but were generally manageable with supportive care and dose modification.
Importantly, no patients discontinued Daraxonrasib due to toxicity. Temporary dose interruptions and reductions were common but effective, allowing patients to remain on therapy. Mean dose intensity across studies remained high (approximately 85–89%), supporting the feasibility of sustained RAS inhibition.
Pharmacokinetics and Pharmacodynamics
Pharmacokinetic analyses demonstrated dose-proportional exposure with oral once-daily dosing. Pharmacodynamic assessments confirmed on-target RAS pathway inhibition, including sustained suppression of ERK phosphorylation in tumor biopsies and peripheral biomarkers, establishing a clear exposure–response relationship.
Clinical Activity in Previously Treated Metastatic PDAC
Long-term follow-up data in patients with RAS-mutant metastatic PDAC treated in the second-line or later setting provided compelling evidence of clinical activity.
In 83 patients with RAS-mutant ≥2L metastatic PDAC treated with Daraxonrasib 300 mg once daily, objective responses and durable disease control were observed. Objective response rates approached 30–35%, with disease control rates exceeding 90% across RAS mutation subgroups. Median progression-free survival was approximately eight months, and median overall survival ranged from 13 to over 15 months, depending on mutation subgroup and follow-up duration. These outcomes compare favorably with historical benchmarks in refractory PDAC, where response rates are typically below 10% and median progression-free survival is often limited to two to four months.
Activity in First-Line Metastatic PDAC
Encouraging signals were also observed when Daraxonrasib was evaluated earlier in the disease course.
Daraxonrasib Monotherapy
In treatment-naïve patients with RAS-mutant metastatic PDAC receiving Daraxonrasib monotherapy at 300 mg once daily, objective responses approached 50%, with disease control rates near 90%. At the time of data cutoff, most patients remained on treatment, suggesting durable benefit and manageable tolerability.
Daraxonrasib Plus Gemcitabine and Nab-Paclitaxel
Combination therapy with Daraxonrasib and standard gemcitabine plus nab-paclitaxel produced even higher response rates, exceeding 50%, with disease control observed in approximately 90% of evaluable patients. Importantly, no new safety signals emerged with the combination, and dose intensity remained high, supporting the feasibility of integrating Daraxonrasib into frontline chemotherapy regimens.
RASolute 303: Phase III Registrational Evaluation in PDAC
The accumulated clinical data provided the foundation for RASolute 303, a global, randomized, phase III registrational trial evaluating Daraxonrasib in newly diagnosed metastatic PDAC.
Patients enrolled in RASolute 303 must have metastatic disease, no prior systemic therapy for metastatic PDAC, and an ECOG performance status of 0–1. Enrollment is permitted regardless of specific RAS mutation subtype, reflecting the mutation-agnostic activity of RAS(ON) inhibition.
Participants are randomized in a 1:1:1 ratio to Daraxonrasib monotherapy, Daraxonrasib in combination with gemcitabine and nab-paclitaxel, or standard-of-care chemotherapy alone. The primary endpoints are progression-free survival and overall survival assessed per RECIST v1.1, with secondary endpoints including objective response rate, duration of response, safety, and patient-reported quality-of-life outcomes.
RASolute 303 is ongoing, and no efficacy results have yet been formally reported. The trial reflects a high level of clinical confidence in the mechanism and early activity of Daraxonrasib but should not yet be interpreted as definitive evidence of benefit.
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Positioning Daraxonrasib in the Evolving RAS Therapeutic Landscape
Daraxonrasib occupies a distinct position among emerging RAS-targeted therapies. Unlike allele-specific inhibitors, it offers broad mutation coverage and direct suppression of active RAS signaling. Compared with upstream pathway modulators, Daraxonrasib provides direct target engagement, potentially reducing feedback reactivation and resistance.
For clinicians, Daraxonrasib represents one of the most advanced investigational strategies aimed at directly addressing the central oncogenic driver of pancreatic cancer and other RAS-driven solid tumors.
Conclusion
Daraxonrasib exemplifies a new generation of RAS-targeted therapeutics designed to translate decades of biological insight into clinically meaningful benefit. Across early- and mid-phase studies, Daraxonrasib has demonstrated substantial response rates, durable disease control, and a safety profile that allows patients to remain on therapy in one of the most challenging malignancies in oncology.
The initiation of the phase III RASolute 303 trial marks a pivotal moment in the clinical development of Daraxonrasib and in the broader effort to directly target RAS in solid tumors. While definitive survival data are awaited, current evidence positions Daraxonrasib as a high-promise investigational therapy with the potential to reshape treatment paradigms in RAS-driven cancers.