{"entity":{"id":"idea-pdac-ras-inhibitor-combinations-and-sequencing","kind":"idea","name":"RAS inhibitor combinations and sequence: pan-RAS plus G12D-selective, plus chemotherapy, and what to give after progression","aka":[],"tldr":"The first drug against the KRAS protein nearly doubled survival in pancreatic cancer in 2026, but on its own it holds the disease for months, not years. Trials are now testing it in combination with a second RAS drug and with chemotherapy, and earlier in the disease; the open questions are which combination, in which order, and what works when the tumour escapes.","summary":"RASolute 302 (500 patients, second line) gave daraxonrasib a median survival of 13.2 against 6.7 months (hazard ratio 0.40) and approval in August 2026. The chemistry (Holderfield 2024) inhibits active mutant and wild-type RAS together, so the drug is agnostic to allele but carries wild-type-RAS toxicity (rash, stomatitis); the G12D-selective zoldonrasib spares normal tissue and, combined with daraxonrasib, is meant to close the wild-type and secondary-mutation escape routes (the pairing record g12d-plus-pan-ras). The registry now holds RASolute 303 (first line, alone or with gemcitabine and nab-paclitaxel, 900 estimated, primary completion June 2028), RASolute 309 (zoldonrasib plus daraxonrasib against chemotherapy in G12D disease, 400, March 2029), RASolute 304 (adjuvant, 500, May 2029), Incyte's DAWN-303 (G12D inhibitor with chemotherapy, 588, September 2028) and a G12D competitor trial (GFH375). What none of these answers is sequence: whether a patient who progresses on a RAS inhibitor benefits from a different one, whether chemotherapy after RAS inhibition retains its activity, and whether ctDNA clearance can be used to stop or switch early. Resistance through secondary RAS mutations, receptor tyrosine kinase bypass and adaptive feedback is already described in the roadmap's open problems.","asOf":"2026-09-24","links":[{"label":"ClinicalTrials.gov NCT07491445","url":"https://clinicaltrials.gov/study/NCT07491445"},{"label":"ClinicalTrials.gov NCT07805954","url":"https://clinicaltrials.gov/study/NCT07805954"},{"label":"ClinicalTrials.gov NCT07252232","url":"https://clinicaltrials.gov/study/NCT07252232"},{"label":"ClinicalTrials.gov NCT07522073","url":"https://clinicaltrials.gov/study/NCT07522073"},{"label":"Holderfield et al.: concurrent inhibition of oncogenic and wild-type RAS-GTP (Nature 2024)","url":"https://europepmc.org/article/MED/38589574"}],"tags":["pancreatic-evidence"],"related":["g12d-plus-pan-ras","kras-roadmap","idea-ras-inhibitor-neoadjuvant-pdac"],"cancers":["pancreatic","metastatic-pdac","resectable-pdac"],"sections":[],"technologies":["kras-inhibitors","mrd-testing"],"targets":["kras"],"drugs":["daraxonrasib","zoldonrasib","elironrasib","mrtx1133","gemcitabine-nab-paclitaxel","folfirinox"],"companies":["revolution-medicines","incyte"],"institutions":[],"pathways":["ras-mapk"],"terms":["kras-mutation-subtypes","ctdna"],"trials":["rasolute-302","nct07491445","nct07805954","nct07252232","nct07522073","nct07262567"],"people":[],"bottlenecks":["b-resistance","b-combination-space","b-toxicity-qol"],"keyPapers":["paper-daraxonrasib-pancreatic-n-engl-j-med-2026","paper-holderfield-ras-on-multi-selective-inhibitor-nature-2024","paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Combining a G12D-selective inhibitor with a pan-RAS(ON) inhibitor, or a RAS inhibitor with chemotherapy, extends first-line progression-free survival beyond either alone with acceptable added toxicity; and a pre-specified sequencing study shows a second RAS-directed line has activity after progression on the first.","rationale":"Single-agent survival gains are large but not durable; the escape routes are known and each has a drug; the trials are enrolling, and the sequencing question can be answered from their post-progression data if it is collected.","test":"RASolute 303, 309 and 304 and DAWN-303 readouts (2028 to 2029) with mandatory post-progression treatment capture and ctDNA sampling; a randomised sequencing sub-study (switch to a second RAS inhibitor versus chemotherapy at progression).","maturity":"being-tested-at-scale","actor":"industry","cost":"large","horizonYears":4},"route":"/ideas/idea-pdac-ras-inhibitor-combinations-and-sequencing/","neighbours":{"pairing":[{"id":"g12d-plus-pan-ras","kind":"pairing","name":"G12D-selective + pan-RAS(ON) inhibitor (zoldonrasib + daraxonrasib)","route":"/pairings/g12d-plus-pan-ras/"}],"roadmap":[{"id":"kras-roadmap","kind":"roadmap","name":"KRAS roadmap: undruggable → G12C → pan-RAS","route":"/roadmaps/kras-roadmap/"},{"id":"pancreatic-roadmap","kind":"roadmap","name":"Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question","route":"/roadmaps/pancreatic-roadmap/"}],"idea":[{"id":"idea-ras-inhibitor-neoadjuvant-pdac","kind":"idea","name":"RAS(ON) inhibitors to convert unresectable pancreatic cancer to resectable","route":"/ideas/idea-ras-inhibitor-neoadjuvant-pdac/"}],"cancer":[{"id":"metastatic-pdac","kind":"cancer","name":"Metastatic pancreatic ductal adenocarcinoma","route":"/cancers/metastatic-pdac/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"},{"id":"resectable-pdac","kind":"cancer","name":"Resectable pancreatic ductal adenocarcinoma","route":"/cancers/resectable-pdac/"}],"technology":[{"id":"kras-inhibitors","kind":"technology","name":"KRAS & RAS inhibitors","route":"/technologies/kras-inhibitors/"},{"id":"mrd-testing","kind":"technology","name":"MRD / molecular residual disease testing","route":"/technologies/mrd-testing/"}],"target":[{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"}],"drug":[{"id":"daraxonrasib","kind":"drug","name":"Daraxonrasib","route":"/drugs/daraxonrasib/"},{"id":"elironrasib","kind":"drug","name":"Elironrasib","route":"/drugs/elironrasib/"},{"id":"folfirinox","kind":"drug","name":"FOLFIRINOX / mFOLFIRINOX","route":"/drugs/folfirinox/"},{"id":"gemcitabine-nab-paclitaxel","kind":"drug","name":"Gemcitabine + nab-paclitaxel","route":"/drugs/gemcitabine-nab-paclitaxel/"},{"id":"mrtx1133","kind":"drug","name":"MRTX1133","route":"/drugs/mrtx1133/"},{"id":"zoldonrasib","kind":"drug","name":"Zoldonrasib","route":"/drugs/zoldonrasib/"}],"company":[{"id":"incyte","kind":"company","name":"Incyte","route":"/companies/incyte/"},{"id":"revolution-medicines","kind":"company","name":"Revolution Medicines","route":"/companies/revolution-medicines/"}],"pathway":[{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"term":[{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"},{"id":"kras-mutation-subtypes","kind":"term","name":"KRAS mutation subtypes (G12C, G12D, G12V)","route":"/terms/kras-mutation-subtypes/"}],"trial":[{"id":"nct07522073","kind":"trial","name":"A Study to Evaluate Chemotherapy With or Without INCB161734 in Previously Untreated, KRAS G12D-Mutated Metastatic Pancreatic Ductal Adenocarcinoma","route":"/trials/nct07522073/"},{"id":"nct07262567","kind":"trial","name":"Phase III Study to Compare GFH375 and Chemotherapy in Patients With KRAS G12D-Mutant Metastatic Pancreatic Cancer","route":"/trials/nct07262567/"},{"id":"rasolute-302","kind":"trial","name":"RASolute 302","route":"/trials/rasolute-302/"},{"id":"nct07252232","kind":"trial","name":"Study of Daraxonrasib (RMC-6236) in Patients With Resected Pancreatic Ductal Adenocarcinoma (PDAC)","route":"/trials/nct07252232/"},{"id":"nct07491445","kind":"trial","name":"Study of Daraxonrasib and Daraxonrasib + GnP as First-line Treatment in Patients With Metastatic Pancreatic Adenocarcinoma","route":"/trials/nct07491445/"},{"id":"nct07805954","kind":"trial","name":"Study of Zoldonrasib (RMC-9805) Plus Daraxonrasib (RMC-6236) Versus Gemcitabine and Nab-Paclitaxel as First-Line Treatment in Metastatic KRAS G12D-Mut","route":"/trials/nct07805954/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-combination-space","kind":"bottleneck","name":"Too many combinations to test","route":"/bottlenecks/b-combination-space/"},{"id":"b-toxicity-qol","kind":"bottleneck","name":"Toxicity and quality of life are undervalued","route":"/bottlenecks/b-toxicity-qol/"}],"paper":[{"id":"paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023","kind":"paper","name":"CodeBreaK 100: sotorasib in KRAS p.G12C-mutated advanced pancreatic cancer","route":"/key-papers/paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023/"},{"id":"paper-holderfield-ras-on-multi-selective-inhibitor-nature-2024","kind":"paper","name":"Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy","route":"/key-papers/paper-holderfield-ras-on-multi-selective-inhibitor-nature-2024/"},{"id":"paper-daraxonrasib-pancreatic-n-engl-j-med-2026","kind":"paper","name":"Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer","route":"/key-papers/paper-daraxonrasib-pancreatic-n-engl-j-med-2026/"}]}}