KRAS wild-type pancreatic ductal adenocarcinoma

The absence of a KRAS mutation in a pancreatic ductal adenocarcinoma is a signal to look harder. Some cases are misclassified ampullary, distal bile duct or duodenal cancers, some are mismatch repair deficient, and a substantial share carry an alternative driver: fusions of NRG1 (the commonest), NTRK1 to 3, ALK, ROS1, FGFR2, RET, MET or BRAF, BRAF V600E mutations and in-frame BRAF deletions, or less often ERBB2 amplification or GNAS mutation in a cancer arising from an intraductal papillary mucinous neoplasm. Because fusions are missed by DNA panels with limited intron coverage, RNA-based sequencing or a comprehensive panel with fusion detection is recommended for every KRAS wild-type tumour.

Several of these drivers have drugs. Zenocutuzumab, a bispecific antibody blocking HER2 and HER3 that prevents NRG1 from signalling, produced durable responses in the eNRGy trial and was approved in December 2024 for NRG1 fusion-positive pancreatic cancer, the first targeted drug approved for a pancreatic driver. Larotrectinib and entrectinib are approved for NTRK fusions in any tumour, dabrafenib plus trametinib for BRAF V600E in any tumour, and ALK, ROS1, RET and FGFR2 inhibitors are used on the strength of their activity in other cancers; BRAF in-frame deletions respond to MEK inhibitors in case series. Chemotherapy remains the first-line standard while sequencing is arranged, and NOTABLE, a Chinese phase 3, showed that adding the EGFR antibody nimotuzumab to gemcitabine lengthened survival in KRAS wild-type disease, leading to a Chinese approval.

KRAS wild-type tumours also differ in biology: they are less dependent on the MAPK pathway, less likely to carry CDKN2A or SMAD4 loss, and their prognosis with chemotherapy is somewhat better. Open problems are that fusion testing is still not universal, that each driver is too rare for pancreatic-specific trials, and that resistance to the targeted drugs follows the patterns seen in lung cancer.