ESMO has issued an Express Update to its Clinical Practice Guideline for pancreatic cancer, providing new recommendations for molecular profiling in unresectable pancreatic ductal adenocarcinoma (PDAC) and second-line treatment in metastatic disease following new efficacy data for the pan-RAS(ON) multi-selective inhibitor daraxonrasib.
The update, titled “ESMO Clinical Practice Guideline Express Update on daraxonrasib in the treatment of metastatic pancreatic cancer,” was published on August 19, 2026, in Annals of Oncology.
Authors: T. Conroy and M. Ducreux, on behalf of the ESMO Guidelines Committee.
On July 22, 2026, Revolution Medicines announced that the US Food and Drug Administration had accepted for review its New Drug Application for daraxonrasib for the treatment of patients with previously treated metastatic pancreatic ductal adenocarcinoma.
Molecular Profiling in Unresectable PDAC
KRAS is the major driver of PDAC tumorigenesis. Approximately 85%-95% of PDACs harbor activating KRAS mutations, predominantly codon 12 substitutions. G12D is reported in 34%-47% of cases, G12V in 27%-36%, G12R in 10%-17%, and G12C in fewer than 2%. Approximately 8%-13% of PDACs are KRAS wild-type.
The guideline describes two types of RAS signaling protein inhibitors: RAS(OFF) and RAS(ON) inhibitors. RAS(OFF) inhibitors bind the inactive, GDP-bound form of RAS, whereas pan-RAS(ON) multi-selective inhibitors target the active, GTP-bound form of wild-type and mutated RAS proteins and block downstream signaling pathways.
Daraxonrasib is an oral RAS(ON) multi-selective inhibitor that targets the active state of mutated and wild-type KRAS, HRAS, and NRAS proteins. ESMO now recommends tumor molecular profiling at diagnosis in all patients with unresectable PDAC to identify clinically actionable genetic alterations such as RAS G12 mutations [II, A; ESCAT I-A].
Early Clinical Data With Daraxonrasib
Daraxonrasib was initially evaluated as monotherapy in a phase I-II study of patients with previously treated metastatic RAS-mutated PDAC. Patients with liver or lung metastases received daraxonrasib at doses ranging from 10 to 400 mg orally once daily. Of 254 patients, 168 who received doses of 300 mg or lower were assessable for safety. Efficacy and toxicity findings supported selection of 300 mg as the phase III dose.
At this dose, grade ≥3 treatment-emergent adverse events occurred in 34% of patients, mostly rash, diarrhea, and mucositis.
Among 38 patients with any RAS mutation who received daraxonrasib 300 mg as second-line therapy, the objective response rate (ORR) was 29% (95% CI, 15%-46%). Median progression-free survival (PFS) was 8.1 months (95% CI, 5.9-10.1), and median overall survival (OS) was 15.6 months (95% CI, 10.9-not evaluable).
RASolute 302: Daraxonrasib Versus Chemotherapy
The randomized phase III RASolute 302 trial further evaluated daraxonrasib in patients with previously treated metastatic PDAC whose tumors had eligible nonsynonymous KRAS, NRAS, or HRAS mutations at codons 12, 13, or 61, or were RASwild-type. Eligible patients were aged 18 years or older, had measurable disease according to RECIST v1.1, and had an ECOG performance status of 0-1.
A total of 500 patients were randomly assigned 1:1 to receive daraxonrasib 300 mg orally once daily (n=248) or investigator’s choice of chemotherapy (n=252). Chemotherapy options included gemcitabine–nab-paclitaxel, modified FOLFIRINOX, FOLFOX, or liposomal irinotecan–5-FU–leucovorin. The primary endpoints were PFS by blinded independent central review and OS in patients with RAS G12-mutated tumors.
Overall, 84.8% of patients had previously received multidrug chemotherapy for metastatic disease, while 15.2% had received prior neoadjuvant or adjuvant therapy and experienced progression or relapse within 6 months. Most patients, 91.8%, had RAS G12-mutated tumors.
Median follow-up was 8.5 months, with a range of 3.2-15.9 months. Median treatment duration was 6.2 months with daraxonrasib and ranged from 1.5 to 3.2 months with chemotherapy.
Overall Survival and Progression-Free Survival
In the RAS G12-mutated population, median OS was 13.2 months (95% CI, 10.0-not reached) with daraxonrasib compared with 6.6 months (95% CI, 5.4-8.2) with chemotherapy, corresponding to an HR of 0.40 (95% CI, 0.30-0.54; P<0.001).
The ESMO update described this as an unprecedented OS benefit in metastatic PDAC. A similar benefit was reported in the overall population, in which median OS was 13.2 months with daraxonrasib versus 6.7 months with chemotherapy (HR, 0.40; 95% CI, 0.30-0.53; P<0.001).
At the time of analysis, follow-up remained short. Overall, 51% of patients in the daraxonrasib group and 52% in the chemotherapy group had experienced disease progression or death from any cause. In the RAS G12-mutated population, median PFS was 7.3 months (95% CI, 6.3-8.1) with daraxonrasib compared with 3.5 months (95% CI, 2.9-3.8) with chemotherapy (HR, 0.45; 95% CI, 0.34-0.59; P<0.001). In the overall population, median PFS was 7.2 months versus 3.6 months, respectively (HR, 0.49; 95% CI, 0.38-0.64; P<0.001).
Response Rates
Investigator-assessed ORR was significantly higher with daraxonrasib than with chemotherapy. Among patients with RAS G12-mutated tumors, ORR was 33.2% with daraxonrasib versus 11.8% with chemotherapy(P<0.001). In the overall population, the respective ORRs were 31.6% and 11.2% (P<0.001).
Pain and Quality of Life
Daraxonrasib also significantly delayed the time to deterioration of pain and global health status/quality of life compared with chemotherapy. In the RAS G12-mutated population, median time to deterioration of pain was 9.0 months with daraxonrasib versus 3.7 months with chemotherapy. The HR was 0.51 (95% CI, 0.37-0.71; P<0.001), with similar results reported in the overall population.
Median time to deterioration in global health status/quality of life was 5.6 months with daraxonrasib versus 2.4 months with chemotherapy in the RAS G12-mutated population (HR, 0.60; 95% CI, 0.45-0.80; P<0.001). In the overall population, the corresponding medians were 5.7 months and 2.6 months (HR, 0.60; 95% CI, 0.46-0.79; P<0.001).
Safety
The most commonly reported treatment-related adverse events with daraxonrasib were rash in 85.5% of patients, diarrhea in 58.1%, stomatitis in 53.1%, nausea in 46.5%, and vomiting in 36.9%.
Grade ≥3 rash occurred in 13.7% of patients receiving daraxonrasib, while grade ≥3 stomatitis occurred in 12.0%. Grade ≥3 neutropenia, anemia, and fatigue were more frequent with chemotherapy, occurring in 27.6%, 16.4%, and 5.6% of patients, respectively. Serious treatment-related adverse events occurred in 10.8% of patients in the daraxonrasib group compared with 18.7%in the chemotherapy group.
The guideline identifies cutaneous toxicity as the main toxicity associated with daraxonrasib, manifesting as rashes whose frequency and areas of involvement, particularly the scalp, differ from those observed with agents such as anti-EGFR therapies.
Uncertainty in Other RAS Subgroups
The ESMO guideline authors noted differing opinions regarding the use of daraxonrasib, when available, in patients with RAS wild-type, RAS G13-mutated, or RAS G61-mutated tumors.
In the final PFS subgroup analyses, treatment benefit with daraxonrasib was generally consistent across patient and tumor characteristics, except in the small subgroup with RAS G13-mutated, RAS G61-mutated, or RAS wild-type tumors. No PFS benefit was demonstrated in this subgroup (HR, 1.38; 95% CI, 0.60-3.17).
Results for the 16 patients with RAS wild-type tumors were not reported. The RASolute 302 trial was not powered or stratified to answer the question of daraxonrasib efficacy in these less common molecular subsets. The guideline authors also noted unexplained discrepancies in this small subgroup between a significant OS benefit and a potential detrimental effect on PFS.
Further data and analyses are needed to establish the tolerability and magnitude of benefit across these rare subsets, as well as tolerability in patients with ECOG PS 2. According to the update, the strongest evidence for daraxonrasib currently applies to patients with RAS G12-mutated tumors and ECOG PS 0-1.
Updated ESMO Recommendation
Based on the available evidence, ESMO recommends daraxonrasib monotherapy after failure of chemotherapy in previously treated patients with RAS G12-mutated tumors and ECOG PS 0-1 [I, A].
The guideline specifies that daraxonrasib is not approved by the European Medicines Agency (EMA) or Food and Drug Administration (FDA). The Express Update also provides a new recommendation for molecular profiling in unresectable PDAC and an updated management algorithm for metastatic pancreatic cancer.
The full update is available in the Annals of Oncology.
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