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Lung Cancer Treatments and Mutations · Journal article
Nature Medicine · August 11, 2026
Encouraging direction, but not yet definitive.
This Phase 1/2 mechanistic analysis identifies acquired resistance to daraxonrasib monotherapy in RAS-mutant pancreatic cancer through circulating tumor DNA sequencing, revealing that 59% of patients develop treatment-emergent RAS pathway alterations, most commonly KRAS amplification (36%). Preclinical models confirm these mechanisms and suggest that combination strategies targeting KRAS amplification, RTKs, or DNA damage response, or adding the G12D inhibitor zoldonrasib, may overcome resistance and warrant evaluation in the Phase 3 RASolute 302 trial.
Phase 1/2 trial with post-hoc circulating tumor DNA resistance mechanistic analysis. Previously treated patients with RAS-mutant metastatic pancreatic adenocarcinoma (PDAC) enrolled in Phase 1/2 daraxonrasib monotherapy trial.. Intervention: Daraxonrasib monotherapy at clinically active dose levels.. n = 44.
Treatment-emergent genomic alterations in RAS signaling pathway in 59% (26 of 44) of Phase 1/2 patients. Mutant KRAS amplifications detected in 36% (16 of 44) of patients at end of daraxonrasib treatment. RTK pathway alterations in 9% (4 of 44), MAPK alterations in 25% (11 of 44), and PI3K alterations in 9% (4 of 44) of patients.
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These mechanistic findings provide a rationale for prospective combination strategies in pancreatic cancer, but efficacy data are limited to Phase 1/2 monotherapy and preclinical models. Clinicians should await Phase 3 RASolute 302 results and specific trials of the proposed combinations before adoption.
Mechanistic analysis of acquired resistance in a Phase 1/2 trial, identifying actionable pathways and guiding rational combination strategies, but requiring confirmatory evidence from the ongoing Phase 3 trial.
As stated by the source record.
Quoted from the source exactly as published.
These mechanistic findings provide a rationale for prospective combination strategies in pancreatic cancer, but efficacy data are limited to Phase 1/2 monotherapy and preclinical models. Clinicians should await Phase 3 RASolute 302 results and specific trials of the proposed combinations before adoption.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Abstract Daraxonrasib is an orally bioavailable RAS(ON) multi-selective tri-complex inhibitor of the oncogenic mutant and wild-type variants of N, H and KRAS. We previously reported encouraging efficacy in a phase 1/2 clinical trial evaluating daraxonrasib monotherapy at clinically active dose levels in patients with previously treated, RAS mutant metastatic pancreatic adenocarcinoma (PDAC), providing the basis for confirmatory evaluation in the randomized phase 3 RASolute 302 clinical trial. Here we report mechanisms of acquired resistance to daraxonrasib monotherapy observed through targeted sequencing of over 800 genes in paired pretreatment and end of treatment circulating tumor DNA samples from 44 patients in the phase 1/2 clinical trial. Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (26 of 44; 59%) of these patients, including, most notably, mutant KRAS amplifications in one-third (16 of 44; 36%), as well as alterations in receptor tyrosine kinase (RTK) (4 of 44; 9%), MAPK (11 of 44; 25%) and PI3K (4 of 44; 9%) pathways. Notably, no acquired secondary KRAS mutations were observed, distinct from resistance profiles of mutant-selective KRAS G12C(OFF) inhibitors. To corroborate these clinical findings, we found, or mechanistically established, concordant mechanisms of daraxonrasib resistance in human and murine preclinical models of PDAC, including mutant KRAS and MYC amplification and RTK upregulation, with these alterations guiding various combination therapy concepts. Notably, daraxonrasib combined with agents targeting DNA damage response, RTKs or the mutant-selective RAS(ON) G12D inhibitor zoldonrasib averted resistance in preclinical models. Collectively, these results show that most daraxonrasib genomic resistance mechanisms drive reactivation of RAS pathway signaling and guide potential combination strategies in PDAC for further investigation.
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