KRAS G12C-mutant pancreatic ductal adenocarcinoma

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.

Sotorasib 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.

The 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.