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10 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.
KRAS wild-type pancreatic cancer is the one in ten pancreatic cancers without the KRAS mutation that drives the rest. Instead many carry a different switched-on gene, often a fusion involving NRG1, NTRK, ALK, ROS1, FGFR2 or RET, or a BRAF change, and several of these have approved pills or antibodies, so these tumours must be sequenced with a test that detects fusions.
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.
| Setting | Approach | Guideline |
|---|---|---|
| Diagnosis | Comprehensive genomic profiling with fusion detection (RNA sequencing where DNA panels are negative) for every KRAS wild-type tumour; pathology review to exclude a periampullary primary. | not mapped |
| First line | Chemotherapy as for other pancreatic adenocarcinoma while sequencing is completed; a targeted drug first line only for NTRK or NRG1 fusions where the patient is unfit for chemotherapy. | not mapped |
| NRG1 fusion | Zenocutuzumab (eNRGy), approved December 2024 for pancreatic cancer with an NRG1 fusion after prior systemic therapy. | not mapped |
| NTRK fusion | Larotrectinib or entrectinib, approved for NTRK fusion-positive solid tumours; repotrectinib after resistance. | not mapped |
| BRAF alteration | Dabrafenib plus trametinib for BRAF V600E (tumour-agnostic approval); MEK inhibitors for BRAF in-frame deletions on case-series evidence. | not mapped |
| Other fusions | ALK, ROS1, RET and FGFR2 inhibitors extrapolated from other cancers; mismatch repair deficient tumours receive pembrolizumab. | not mapped |
| No identified driver | Chemotherapy; nimotuzumab plus gemcitabine approved in China after NOTABLE. | not mapped |