{"entity":{"id":"kras-g12c-pdac","kind":"cancer","name":"KRAS G12C-mutant pancreatic ductal adenocarcinoma","aka":["KRAS G12C pancreatic cancer","KRAS p.G12C PDAC","G12C-mutant pancreatic adenocarcinoma"],"tldr":"KRAS G12C pancreatic cancer is the small slice of pancreatic cancer whose KRAS mutation happens to be the one that the first KRAS drugs were built for. Sotorasib and adagrasib, approved for lung cancer, shrink a share of these tumours after chemotherapy and are listed as options, and newer inhibitors such as elironrasib, olomorasib and the pan-RAS drug daraxonrasib are being tested in this group.","summary":"KRAS is mutated in more than nine out of ten pancreatic ductal adenocarcinomas, but the covalent inhibitors that reached the clinic first bind only the cysteine of the G12C variant, which is rare in the pancreas. The G12C subgroup otherwise resembles other KRAS-mutant pancreatic cancers in its presentation, its TP53, CDKN2A and SMAD4 co-alterations and its response to chemotherapy; it is found only by tumour or plasma sequencing, which is why guidelines ask for it at diagnosis in advanced disease.\n\nSotorasib in the pancreatic cohort of CodeBreaK 100 (2023) and adagrasib in KRYSTAL-1 (2023) produced responses in a minority of previously treated patients with disease control in most, durable for some months. Both are NCCN-listed options after first-line chemotherapy and are used off label or through access schemes, since neither has a pancreatic indication. Resistance arises through secondary KRAS mutations, amplification and bypass through receptor tyrosine kinases, and pancreatic tumours appear to depend more on wild-type RAS and on EGFR-family signalling than lung tumours do, which is the rationale for combining G12C inhibitors with EGFR antibodies or with pan-RAS drugs.\n\nThe pan-RAS inhibitor daraxonrasib, active against G12C alongside the other variants, lengthened survival in RASolute 302 and is approved after first-line chemotherapy regardless of KRAS subtype, so G12C-mutant patients now have a RAS inhibitor with pancreatic-specific evidence. Elironrasib (a RAS(ON) G12C-selective inhibitor) is being combined with daraxonrasib, olomorasib is in a pancreatic cohort, glecirasib has a pancreatic phase 2 in China, and divarasib, garsorasib and FMC-376 are in earlier studies. Open questions are whether a G12C-selective drug adds anything to a pan-RAS inhibitor, how to sequence them with chemotherapy, and whether responses in the pancreas can be made as deep as in the lung.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/KRAS","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/KRAS"},{"label":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}],"tags":["subtype-page","gastrointestinal"],"related":["metastatic-pdac","kras-wild-type-pdac","locally-advanced-pdac","brca-palb2-pdac","kras-g12c-nsclc","kras-g12c-colorectal","kras-roadmap"],"cancers":[],"sections":[],"technologies":["kras-inhibitors","cgp","liquid-biopsy","cytotoxic-chemotherapy"],"targets":["kras","egfr"],"drugs":["sotorasib","adagrasib","daraxonrasib","elironrasib","olomorasib","glecirasib","divarasib","garsorasib","folfirinox","gemcitabine-nab-paclitaxel"],"companies":["amgen","bms","revolution-medicines","eli-lilly","jacobio-pharmaceuticals","roche-genentech"],"institutions":[],"pathways":["ras-mapk","pancreatic-cancer-signalling","rtk-activation"],"terms":["kras-mutation-subtypes","driver-mutation","oncogene","resistance","ca19-9"],"trials":["rasolute-302","nct06128551","nct04956640","nct06008288","nct06244771","nct07491445"],"people":["kevan-shokat","frank-mccormick","tanios-bekaii-saab","eileen-oreilly","andrew-aguirre"],"bottlenecks":[],"keyPapers":["paper-ostrem-kras-g12c-nature-2013","paper-codebreak-200-lancet-2023"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 1 to 2 percent of pancreatic ductal adenocarcinomas carry KRAS G12C, far fewer than the G12D, G12V and G12R mutations that make up most of the rest, so it is a small group even in a common cancer.","subtypes":["KRAS G12C PDAC after first-line chemotherapy (sotorasib or adagrasib listed; daraxonrasib approved)","KRAS G12C PDAC in trials of G12C-selective inhibitors (elironrasib, olomorasib, glecirasib, divarasib)","KRAS G12C PDAC with acquired resistance (secondary KRAS mutations, bypass signalling)","KRAS G12C PDAC treated first line with chemotherapy as for other KRAS-mutant disease"],"biomarkers":["KRAS G12C by tissue or plasma next-generation sequencing (about 1 to 2 percent of pancreatic adenocarcinomas)","Co-alterations in TP53, CDKN2A and SMAD4","Acquired KRAS mutations, KRAS amplification or receptor tyrosine kinase bypass at progression","CA 19-9 for response monitoring","Liver enzymes on a G12C inhibitor"],"standardOfCare":[{"setting":"First line","approach":"Chemotherapy as for other pancreatic adenocarcinoma: modified FOLFIRINOX, NALIRIFOX or gemcitabine plus nab-paclitaxel; G12C inhibitors are not approved first line.","refs":["folfirinox","nalirifox","gemcitabine-nab-paclitaxel","kras-mutation-subtypes"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"After first-line chemotherapy","approach":"Daraxonrasib (RASolute 302, approved for pancreatic cancer irrespective of KRAS subtype); sotorasib or adagrasib as NCCN-listed options on the CodeBreaK 100 and KRYSTAL-1 cohorts.","refs":["daraxonrasib","rasolute-302","sotorasib","adagrasib","kras-inhibitors"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Clinical trials","approach":"Elironrasib with daraxonrasib, olomorasib, glecirasib and other G12C-selective inhibitors alone or with chemotherapy or EGFR antibodies.","refs":["elironrasib","nct06128551","olomorasib","nct04956640","glecirasib","nct06008288"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}}],"stateOfArt":["Sotorasib and adagrasib give responses in a minority and disease control in most previously treated patients, and are guideline-listed options.","Daraxonrasib gives the G12C group, like every other KRAS subgroup, an approved RAS inhibitor with pancreatic phase 3 evidence.","RAS(ON) G12C-selective inhibitors such as elironrasib are being combined with pan-RAS inhibition to deepen responses."],"history":[{"year":1988,"title":"KRAS mutations found in almost all pancreatic adenocarcinomas (Almoguera and Perucho)","refs":["kras","oncogene"]},{"year":2013,"title":"Ostrem and Shokat show the G12C cysteine can be trapped by a covalent inhibitor","refs":["kevan-shokat","paper-ostrem-kras-g12c-nature-2013"]},{"year":2021,"title":"Sotorasib approved for KRAS G12C lung cancer, the first KRAS inhibitor","refs":["sotorasib","amgen"]},{"year":2023,"title":"CodeBreaK 100 pancreatic cohort (sotorasib) and KRYSTAL-1 (adagrasib) report activity in previously treated pancreatic cancer","refs":["sotorasib","adagrasib","tanios-bekaii-saab"]},{"year":2026,"title":"RASolute 302: daraxonrasib, active against all RAS variants, lengthens survival after chemotherapy","refs":["rasolute-302","daraxonrasib"]}],"pipeline":["elironrasib","nct06128551","olomorasib","nct04956640","glecirasib","nct06008288","divarasib","garsorasib","nct06244771","daraxonrasib","nct07491445"],"openProblems":["Responses to G12C-selective inhibitors are shallower and shorter in the pancreas than in the lung.","Neither sotorasib nor adagrasib has a pancreatic indication, so access depends on off-label use and trials.","Whether adding a G12C-selective drug to a pan-RAS inhibitor improves on the pan-RAS drug alone is untested.","The group is too small for large randomised trials of its own."],"parent":"pancreatic"},"route":"/cancers/kras-g12c-pdac/","neighbours":{"cancer":[{"id":"borderline-resectable-pdac","kind":"cancer","name":"Borderline resectable pancreatic ductal adenocarcinoma","route":"/cancers/borderline-resectable-pdac/"},{"id":"brca-palb2-pdac","kind":"cancer","name":"BRCA or PALB2-mutant pancreatic ductal adenocarcinoma","route":"/cancers/brca-palb2-pdac/"},{"id":"kras-g12c-colorectal","kind":"cancer","name":"KRAS G12C-mutant colorectal cancer","route":"/cancers/kras-g12c-colorectal/"},{"id":"kras-g12c-nsclc","kind":"cancer","name":"KRAS G12C-mutant non-small-cell lung cancer","route":"/cancers/kras-g12c-nsclc/"},{"id":"kras-wild-type-pdac","kind":"cancer","name":"KRAS wild-type pancreatic ductal adenocarcinoma","route":"/cancers/kras-wild-type-pdac/"},{"id":"locally-advanced-pdac","kind":"cancer","name":"Locally advanced unresectable pancreatic ductal adenocarcinoma","route":"/cancers/locally-advanced-pdac/"},{"id":"metastatic-pdac","kind":"cancer","name":"Metastatic pancreatic ductal adenocarcinoma","route":"/cancers/metastatic-pdac/"},{"id":"msi-high-pdac","kind":"cancer","name":"Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma","route":"/cancers/msi-high-pdac/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"}],"roadmap":[{"id":"kras-roadmap","kind":"roadmap","name":"KRAS roadmap: undruggable → G12C → pan-RAS","route":"/roadmaps/kras-roadmap/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"cytotoxic-chemotherapy","kind":"technology","name":"Cytotoxic chemotherapy","route":"/technologies/cytotoxic-chemotherapy/"},{"id":"kras-inhibitors","kind":"technology","name":"KRAS & RAS inhibitors","route":"/technologies/kras-inhibitors/"},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"}],"drug":[{"id":"adagrasib","kind":"drug","name":"Adagrasib","route":"/drugs/adagrasib/"},{"id":"daraxonrasib","kind":"drug","name":"Daraxonrasib","route":"/drugs/daraxonrasib/"},{"id":"divarasib","kind":"drug","name":"Divarasib","route":"/drugs/divarasib/"},{"id":"elironrasib","kind":"drug","name":"Elironrasib","route":"/drugs/elironrasib/"},{"id":"folfirinox","kind":"drug","name":"FOLFIRINOX / mFOLFIRINOX","route":"/drugs/folfirinox/"},{"id":"garsorasib","kind":"drug","name":"Garsorasib","route":"/drugs/garsorasib/"},{"id":"gemcitabine-nab-paclitaxel","kind":"drug","name":"Gemcitabine + nab-paclitaxel","route":"/drugs/gemcitabine-nab-paclitaxel/"},{"id":"glecirasib","kind":"drug","name":"Glecirasib","route":"/drugs/glecirasib/"},{"id":"nalirifox","kind":"drug","name":"NALIRIFOX (liposomal irinotecan + oxaliplatin + 5-FU/LV)","route":"/drugs/nalirifox/"},{"id":"olomorasib","kind":"drug","name":"Olomorasib","route":"/drugs/olomorasib/"},{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"}],"company":[{"id":"amgen","kind":"company","name":"Amgen","route":"/companies/amgen/"},{"id":"bms","kind":"company","name":"Bristol Myers Squibb","route":"/companies/bms/"},{"id":"eli-lilly","kind":"company","name":"Eli Lilly (incl. Loxo)","route":"/companies/eli-lilly/"},{"id":"jacobio-pharmaceuticals","kind":"company","name":"Jacobio Pharmaceuticals","route":"/companies/jacobio-pharmaceuticals/"},{"id":"revolution-medicines","kind":"company","name":"Revolution Medicines","route":"/companies/revolution-medicines/"},{"id":"roche-genentech","kind":"company","name":"Roche / Genentech","route":"/companies/roche-genentech/"}],"pathway":[{"id":"pancreatic-cancer-signalling","kind":"pathway","name":"Pancreatic cancer (KEGG map)","route":"/pathways/pancreatic-cancer-signalling/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"},{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"}],"term":[{"id":"ca19-9","kind":"term","name":"CA 19-9","route":"/terms/ca19-9/"},{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"kras-mutation-subtypes","kind":"term","name":"KRAS mutation subtypes (G12C, G12D, G12V)","route":"/terms/kras-mutation-subtypes/"},{"id":"oncogene","kind":"term","name":"Oncogene","route":"/terms/oncogene/"}],"trial":[{"id":"nct06008288","kind":"trial","name":"A Phase II Study Evaluating JAB-21822 Monotherapy in Adult Patients With Pancreatic Cancer and Other Solid Tumors Harboring the KRAS p.G12C Mutation.","route":"/trials/nct06008288/"},{"id":"nct06244771","kind":"trial","name":"A Study Evaluating FMC-376 in Participants With KRAS G12C Mutated Solid Tumors","route":"/trials/nct06244771/"},{"id":"rasolute-302","kind":"trial","name":"RASolute 302","route":"/trials/rasolute-302/"},{"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":"nct06128551","kind":"trial","name":"Study of Elironrasib and Daraxonrasib as Monotherapies and Combination Therapy in Participants With Advanced KRAS G12C Mutant Solid Tumors","route":"/trials/nct06128551/"},{"id":"nct04956640","kind":"trial","name":"Study of LY3537982 in Cancer Patients With a Specific Genetic Mutation (KRAS G12C)","route":"/trials/nct04956640/"}],"person":[{"id":"andrew-aguirre","kind":"person","name":"Andrew J. Aguirre","route":"/people/andrew-aguirre/"},{"id":"eileen-oreilly","kind":"person","name":"Eileen M. O'Reilly","route":"/people/eileen-oreilly/"},{"id":"frank-mccormick","kind":"person","name":"Frank McCormick","route":"/people/frank-mccormick/"},{"id":"kevan-shokat","kind":"person","name":"Kevan M. Shokat","route":"/people/kevan-shokat/"},{"id":"tanios-bekaii-saab","kind":"person","name":"Tanios Bekaii-Saab","route":"/people/tanios-bekaii-saab/"}],"paper":[{"id":"paper-codebreak-200-lancet-2023","kind":"paper","name":"CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug","route":"/key-papers/paper-codebreak-200-lancet-2023/"},{"id":"paper-ostrem-kras-g12c-nature-2013","kind":"paper","name":"Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable","route":"/key-papers/paper-ostrem-kras-g12c-nature-2013/"}]}}