ESMO Guidelines Express Update Recommends Daraxonrasib for RAS G12–Mutated Metastatic PDAC

The European Society for Medical Oncology (ESMO) has issued a Clinical Practice Guideline Express Update recommending the oral RAS(ON) multi-selective inhibitor daraxonrasib (RMC-6236) as monotherapy after progression on chemotherapy in previously treated patients with RAS G12–mutated metastatic pancreatic ductal adenocarcinoma (PDAC) and an ECOG performance status of 0 or 1, according to an update published in Annals of Oncology.¹

The recommendation follows the readout of data from the randomized phase 3 RASolute 302 trial (NCT06625320), in which daraxonrasib elicited a median overall survival (OS) of 13.2 months (n = 228; 95% CI, 10.0-not reached) compared with 6.6 months (95% CI, 5.4-8.2) with investigator’s choice of chemotherapy (n = 231) in the population of patients with RAS G12–mutated disease (HR, 0.40; 95% CI, 0.30-0.54; P < .5.9 x 10^–10).²

Notably, daraxonrasib is not yet approved by the European Medicines Agency or FDA.¹

The express update also reaffirms that tumor molecular profiling should be performed at the time of diagnosis in all patients with unresectable PDAC to identify actionable alterations, such as RAS G12 mutations.

What prompted the ESMO Clinical Practice Guideline Express Update for PDAC?

KRAS is the principal oncogenic driver of PDAC, mutated in more than 90% of early precursor lesions. Additionally, approximately 85% to 95% of PDAC tumors harbor activating KRAS mutations. KRAS codon 12 substitutions predominate (G12D, 34%-47%; G12V, 27%-36%; G12R, 10%-17%; and G12C, < 2%) and account for roughly 90% of KRAS-mutated PDAC tumors. Moreover, 8% to 13% of PDAC tumors are KRAS wild-type. Two inhibitor classes have emerged that differ by the conformational state of RAS they engage: RAS(OFF) mutation-selective inhibitors, which bind the inactive, GDP-bound form, and pan-RAS(ON) multiselective inhibitors, which target the active, GTP-bound state of wild-type and mutated RAS to overcome the resistance mechanisms that have limited RAS(OFF) agents.

Daraxonrasib was first evaluated as monotherapy in a phase 1/2 study (NCT05379985) of patients with previously treated metastatic RAS-mutated PDAC, which supported 300 mg once daily as the phase 3 dose.³ Among 38 patients with any RAS mutation who received 300 mg in the second-line setting, the objective response rate (ORR) was 29% (95% CI, 15%-46%), with a median progression-free survival (PFS) of 8.1 months (95% CI, 5.9-10.1) and a median OS of 15.6 months (95% CI, 10.9-not evaluable [NE]).

How was the RASolute 302 trial designed?

RASolute 302 randomly assigned 500 adult patients 1:1 to receive daraxonrasib at 300 mg orally once daily (n = 248) or investigator’s choice of chemotherapy (n = 252).² Eligible patients had previously treated RAS-mutated or RAS wild-type metastatic PDAC and an ECOG performance status of 0 or 1. The dual primary end points were PFS and OS in the RAS G12–mutated population.

What additional efficacy and patient-reported outcomes were reported in RASolute 302?

The OS benefit with daraxonrasib was consistent in the overall population, at 13.2 months (95% CI, 10.0-NE) vs 6.7 months (95% CI, 5.8-8.0) with chemotherapy (HR, 0.40; 95% CI, 0.30-0.53; P < .4.6 x 10^–11). In the RAS G12–mutated population, the median PFS was 7.3 months (95% CI, 6.3-8.1) with daraxonrasib vs 3.5 months (95% CI, 2.9-3.8) with chemotherapy (HR, 0.45; 95% CI, 0.34-0.59; P < 3.2 x 10^–9), with a comparable overall-population median PFS of 7.2 months (95% CI, 5.7-7.5) vs 3.6 months (95% CI, 2.9-4.2), respectively (HR, 0.49; 95% CI, 0.38-0.64; P < 5.2 x 10^–8). The ORRs in the RAS G12–mutated population were 33.2% with daraxonrasib vs 11.8% with chemotherapy (P < .0001).

Daraxonrasib also delayed time to deterioration (TTD) of patient-reported outcomes. The median time to aggravation of pain was 9.2 months with daraxonrasib vs 3.8 months with chemotherapy in the RAS G12–mutated population (HR, 0.51; 95% CI, 0.37-0.71; P < .0001), and the median TTD of global health status/quality of life was 5.7 months vs 2.6 months, respectively (HR, 0.60; 95% CI, 0.46-0.79; P = .0002).

Notably, in July 2026, the FDA accepted a new drug application seeking the approval of daraxonrasib for the treatment of patients with previously treated PDAC.⁴

What is the safety profile of daraxonrasib, and what questions remain regarding the potential use of this agent in PDAC?

The most common treatment-related adverse effects (TRAEs) with daraxonrasib were rash (85%), diarrhea (58%), stomatitis (53%), nausea (46%), and vomiting (37%).² Grade 3 or higher rash (14%) and stomatitis (12%) were more frequent with daraxonrasib, whereas grade 3 or higher neutropenia (28%), anemia (16%), and fatigue (6%) were more frequent with chemotherapy. Serious TRAEs occurred in 10.8% vs 18.7% of patients, respectively. The guideline authors characterized the principal toxicity as cutaneous, with rash distribution, particularly involving the scalp, that differs from that seen with anti-EGFR agents.¹

The authors also flagged unresolved questions. RASolute 302 was not powered or stratified to assess rarer genotypes, and in the subgroup of patients with RAS G13–mutated, RAS G61–mutated, or RAS wild-type tumors, no PFS benefit was demonstrated with daraxonrasib (HR, 1.38; 95% CI, 0.60-3.17). The tolerability of daraxonrasib in patients with an ECOG performance status of 2 likewise remains uncharacterized, and the authors concluded that the strongest evidence supports the agent’s use in RAS G12–mutated tumors with an ECOG performance status of 0 or 1.

References

1. Conroy T, Ducreux M; on behalf of the ESMO Guidelines Committee. ESMO Clinical Practice Guideline Express Update on daraxonrasib in the treatment of metastatic pancreatic cancer. Ann Oncol. Published online 2026. doi:10.1016/j.annonc.2026.08.003
2. Wolpin BM, Wainberg ZA, Hendifar AE, et al. Daraxonrasib, a RAS(ON) multi-selective inhibitor vs chemotherapy in previously treated metastatic pancreatic adenocarcinoma (mPDAC): primary and final analysis from the phase 3 RASolute 302 study. J Clin Oncol. 2026;44(suppl 17):LBA5. doi:10.1200/JCO.2026.44.17_suppl.LBA5
3. Wolpin BM, Park W, Garrido-Laguna I, et al. Daraxonrasib in previously treated advanced RAS-mutated pancreatic cancer. N Engl J Med. 2026;394(18):1790-1802. doi:10.1056/NEJMoa2505783
4. Revolution Medicines’ new drug application for daraxonrasib accepted for review by US FDA for previously treated metastatic pancreatic cancer. News release. Revolution Medicines. July 22, 2026. Accessed August 19, 2026. https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-new-drug-application-daraxonrasib-accepted