What this research found
Pancreatic ductal adenocarcinoma (PDAC) is almost universally RAS-driven, yet the approved covalent inhibitors only act on the KRAS G12C allele. This clinician-facing tumor-board brief quantifies who the pan-RAS inhibitor daraxonrasib could actually treat, pooling 6,697 tissue-genotyped PDAC cases across five continents and mapping every allele to the drug classes that address it. Eligibility rises from 1.4% under G12C-selective drugs to 89.6% under daraxonrasib.
- Across 6,697 tissue-genotyped PDAC cases, 89.6% carry a RAS alteration addressable by daraxonrasib against 1.4% eligible for the G12C-selective drugs sotorasib and adagrasib — an incremental gain of 88.2 percentage points.
- KRAS G12D, not G12C, is the dominant single hotspot in pancreatic cancer at 38% of cases, which is why covalent G12C inhibitors reach so few patients in this disease.
- The Phase 3 RASolute-302 readout reported a hazard ratio of 0.40 for overall survival against chemotherapy, with median overall survival of 13.2 months versus 6.7 months.
- Allele frequencies do differ by continent — Q61X enriched in North America, G12D in Asia, G13D in Europe, each surviving false-discovery-rate correction — but the effect sizes are small, with Cramer's V below 0.1, and the brief concludes the differences do not change practice.
- A survey of 137 RAS-targeted trials identified six Phase 3 studies in pancreatic cancer, three of daraxonrasib and three of G12D-selective agents, alongside seven patient groups still left uncovered, among them RAS wild-type disease, atypical variants, frail patients, and central nervous system metastases.
How it was done
Mutation prevalence was pooled from 21 pancreatic studies in cBioPortal plus six literature cohorts, giving a tissue-only denominator of 6,697 cases that deliberately excludes circulating-tumour-DNA cohorts, whose lower sensitivity would inflate the apparent wild-type fraction. Every allele was assigned an explicit coverage class — addressable by G12C drugs only, by daraxonrasib only, or uncovered — and cross-continent differences were tested with chi-squared and Fisher-Freeman-Halton exact tests under Benjamini-Hochberg correction, with effect sizes reported as Cramer's V and odds ratios. The trial landscape was pulled live from the ClinicalTrials.gov v2 interface using 64 search terms across eight drug classes, returning 137 studies. The result is a 19-page brief with eight figures, a triage decision tree, and 39 verified references.
Data sources
- cBioPortal — 21 pancreatic ductal adenocarcinoma studies, accessed May 2026
- Six published PDAC genomic cohorts, pooled to a tissue-only denominator of 6,697 cases across Asia, Europe, North America, Oceania, and South America
- ClinicalTrials.gov — 137 RAS-targeted trials retrieved May 2026
- Phase 3 RASolute-302 daraxonrasib results as announced by Revolution Medicines
- 39 verified references including Wolpin (NEJM 2026), Wasko (Nature 2024), Kim (Nature 2024), Canon (Nature 2019), and Strickler (NEJM 2023)
Limitations
The headline Phase 3 survival result comes from a company announcement rather than a peer-reviewed publication, which was expected in the second half of 2026. South American prevalence rests on a single 122-patient cohort with correspondingly wide confidence intervals, and the European G13D enrichment involves rare alleles (1.1% versus 0.4%) that could reflect sequencing-panel coverage rather than biology.
Figures from this analysis
How this research was produced
K-Dense Web planned and ran this cancer biology investigation end to end — gathering the sources, carrying out the analysis, producing the figures, and drafting the report. The full session transcript, including every intermediate step, is available to view.
