# KRAS wild-type pancreatic ductal adenocarcinoma

Source: https://onco.cc/cancers/kras-wild-type-pdac/  
OnCo record `kras-wild-type-pdac` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-18
- Also known as: KRAS wild-type pancreatic cancer; KRAS-negative PDAC; Fusion-driven pancreatic cancer; BRAF-altered pancreatic cancer
- Tags: subtype-page; gastrointestinal
- Group: gastrointestinal
- Burden: Roughly one in ten pancreatic ductal adenocarcinomas has no KRAS mutation. The group is younger on average and is where most of the gene fusions and BRAF alterations that can be targeted with existing drugs are found.
- Subtypes: NRG1 fusion-positive KRAS wild-type PDAC (zenocutuzumab); NTRK fusion-positive KRAS wild-type PDAC (larotrectinib, entrectinib); BRAF V600E-mutant or BRAF in-frame deletion KRAS wild-type PDAC (BRAF plus MEK or MEK inhibitors); ALK, ROS1, RET or FGFR2 fusion-positive KRAS wild-type PDAC; Mismatch repair deficient KRAS wild-type PDAC (pembrolizumab); KRAS wild-type PDAC without an identified driver (chemotherapy; nimotuzumab in China)
- Biomarkers: KRAS wild-type status on tumour or plasma sequencing (prompts fusion testing); RNA-based or comprehensive fusion testing for NRG1, NTRK, ALK, ROS1, FGFR2, RET, MET and BRAF fusions; BRAF V600E and in-frame deletion status; Mismatch repair immunohistochemistry or microsatellite instability testing; ERBB2 amplification and GNAS mutation (IPMN-derived cancers); Review of histology and site to exclude ampullary, bile duct or duodenal primaries

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/kras-wild-type-pdac/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/kras-wild-type-pdac/#overview [4 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/kras-wild-type-pdac/#what-it-is [6 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/kras-wild-type-pdac/#finding-it [6 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/kras-wild-type-pdac/#treating-it [7 settings, 5 decisions with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/kras-wild-type-pdac/#evidence [5 trials, 8 key papers, 6 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/kras-wild-type-pdac/#science [10 targets, 3 pathways]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/kras-wild-type-pdac/where-you-are/ [32 UK centres]
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/kras-wild-type-pdac/#living-with-it [23 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/kras-wild-type-pdac/coming/ [11 medicines, 5 trials, 1 idea, 4 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/kras-wild-type-pdac/data/ [73 connected records]

## Standard of care

- 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. ([Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [Gene fusion](https://onco.cc/terms/gene-fusion/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/))
- 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. ([FOLFIRINOX / mFOLFIRINOX](https://onco.cc/drugs/folfirinox/), [NALIRIFOX (liposomal irinotecan + oxaliplatin + 5-FU/LV)](https://onco.cc/drugs/nalirifox/), [Gemcitabine + nab-paclitaxel](https://onco.cc/drugs/gemcitabine-nab-paclitaxel/))
- NRG1 fusion: Zenocutuzumab (eNRGy), approved December 2024 for pancreatic cancer with an NRG1 fusion after prior systemic therapy. ([Zenocutuzumab](https://onco.cc/drugs/zenocutuzumab/), [HER3](https://onco.cc/targets/her3/), [HER2](https://onco.cc/targets/her2/))
- NTRK fusion: Larotrectinib or entrectinib, approved for NTRK fusion-positive solid tumours; repotrectinib after resistance. ([Larotrectinib](https://onco.cc/drugs/larotrectinib/), [Entrectinib](https://onco.cc/drugs/entrectinib/), [Repotrectinib](https://onco.cc/drugs/repotrectinib/), [NTRK](https://onco.cc/targets/ntrk/))
- BRAF alteration: Dabrafenib plus trametinib for BRAF V600E (tumour-agnostic approval); MEK inhibitors for BRAF in-frame deletions on case-series evidence. ([Dabrafenib + trametinib](https://onco.cc/drugs/dabrafenib-trametinib/), [BRAF V600E mutation](https://onco.cc/terms/braf-v600-mutation/), [BRAF](https://onco.cc/targets/braf/))
- Other fusions: ALK, ROS1, RET and FGFR2 inhibitors extrapolated from other cancers; mismatch repair deficient tumours receive pembrolizumab. ([Repotrectinib](https://onco.cc/drugs/repotrectinib/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [ALK](https://onco.cc/targets/alk/), [ROS1](https://onco.cc/targets/ros1/), [FGFR2](https://onco.cc/targets/fgfr2/))
- No identified driver: Chemotherapy; nimotuzumab plus gemcitabine approved in China after NOTABLE. ([Nimotuzumab](https://onco.cc/drugs/nimotuzumab/), [NOTABLE (nimotuzumab, KRAS wild-type pancreatic cancer)](https://onco.cc/trials/notable-trial/), [Gemcitabine](https://onco.cc/drugs/gemcitabine/))

## State of the art

- Zenocutuzumab is the first drug approved for a pancreatic cancer driver mutation, for NRG1 fusions.
- Tumour-agnostic approvals for NTRK fusions and BRAF V600E cover the other common actionable drivers.
- Guidelines now ask for fusion testing in every KRAS wild-type pancreatic cancer.
- NOTABLE gave KRAS wild-type disease its first positive phase 3 of an EGFR antibody, in China.

## Open problems

- Fusion testing is still missed when DNA panels are used alone, so many actionable tumours go unrecognised.
- Each driver is too rare for pancreatic-specific randomised trials; evidence is extrapolated from lung cancer and basket studies.
- Resistance to fusion-targeted drugs follows lung cancer patterns and second-line options are thin.
- Some KRAS wild-type cases are misclassified periampullary cancers, which confounds every series.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Pancreatic_cancer
- Wikipedia: https://en.wikipedia.org/wiki/Pancreatic_cancer
- NCCN Guidelines: Pancreatic Adenocarcinoma: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455

## Connected records

- cancers: [Ampullary cancer (ampulla of Vater)](https://onco.cc/cancers/ampullary/), [Biliary tract cancer (cholangiocarcinoma)](https://onco.cc/cancers/cholangiocarcinoma/), [BRCA or PALB2-mutant pancreatic ductal adenocarcinoma](https://onco.cc/cancers/brca-palb2-pdac/), [Intraductal papillary mucinous neoplasm and other pancreatic cystic precursors](https://onco.cc/cancers/ipmn-cystic-precursors/), [KRAS G12C-mutant pancreatic ductal adenocarcinoma](https://onco.cc/cancers/kras-g12c-pdac/), [Locally advanced unresectable pancreatic ductal adenocarcinoma](https://onco.cc/cancers/locally-advanced-pdac/), [Metastatic pancreatic ductal adenocarcinoma](https://onco.cc/cancers/metastatic-pdac/), [Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma](https://onco.cc/cancers/msi-high-pdac/), [Pancreatic acinar cell carcinoma](https://onco.cc/cancers/pancreatic-acinar-cell-carcinoma/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- technologies: [Bispecific antibodies](https://onco.cc/technologies/bispecific-antibody/), [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/)
- targets: [ALK](https://onco.cc/targets/alk/), [BRAF](https://onco.cc/targets/braf/), [EGFR](https://onco.cc/targets/egfr/), [FGFR2](https://onco.cc/targets/fgfr2/), [HER2](https://onco.cc/targets/her2/), [HER3](https://onco.cc/targets/her3/), [KRAS](https://onco.cc/targets/kras/), [NTRK](https://onco.cc/targets/ntrk/), [ROS1](https://onco.cc/targets/ros1/)
- drugs: [Dabrafenib + trametinib](https://onco.cc/drugs/dabrafenib-trametinib/), [Entrectinib](https://onco.cc/drugs/entrectinib/), [FOLFIRINOX / mFOLFIRINOX](https://onco.cc/drugs/folfirinox/), [Gemcitabine](https://onco.cc/drugs/gemcitabine/), [Gemcitabine + nab-paclitaxel](https://onco.cc/drugs/gemcitabine-nab-paclitaxel/), [Larotrectinib](https://onco.cc/drugs/larotrectinib/), [NALIRIFOX (liposomal irinotecan + oxaliplatin + 5-FU/LV)](https://onco.cc/drugs/nalirifox/), [Nimotuzumab](https://onco.cc/drugs/nimotuzumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Repotrectinib](https://onco.cc/drugs/repotrectinib/), [Zenocutuzumab](https://onco.cc/drugs/zenocutuzumab/)
- companies: [Bristol Myers Squibb](https://onco.cc/companies/bms/), [Merck & Co. (MSD)](https://onco.cc/companies/merck/), [Pfizer (incl. Seagen)](https://onco.cc/companies/pfizer/), [Roche / Genentech](https://onco.cc/companies/roche-genentech/)
- pathways: [Pancreatic cancer (KEGG map)](https://onco.cc/pathways/pancreatic-cancer-signalling/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/), [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/)
- terms: [BRAF V600E mutation](https://onco.cc/terms/braf-v600-mutation/), [Classical versus basal-like (squamous) subtypes of pancreatic cancer, and GATA6](https://onco.cc/terms/classical-vs-basal-like/), [Driver mutation](https://onco.cc/terms/driver-mutation/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Gene fusion](https://onco.cc/terms/gene-fusion/), [KRAS mutation subtypes (G12C, G12D, G12V)](https://onco.cc/terms/kras-mutation-subtypes/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [Pancreatic cancer drugs in England: NICE appraisals and the Cancer Drugs Fund (September 2026)](https://onco.cc/terms/pancreatic-cancer-uk-drug-access/)
- trials: [A Study of Zenocutuzumab (MCLA-128) in Patients With Solid Tumors Harboring an NRG1 Fusion (eNRGy)](https://onco.cc/trials/nct02912949/), [Binimetinib in Patients With BRAF Fusion-positive Low-grade Glioma or Pancreatic Cancer (Perfume)](https://onco.cc/trials/nct06159478/), [DETERMINE Trial Treatment Arm 07: Dabrafenib in Combination With Trametinib in Adult, Paediatric and Teenage/Young Adult Patients With BRAF V600 Mutation-Positi](https://onco.cc/trials/nct07440290/), [NOTABLE (nimotuzumab, KRAS wild-type pancreatic cancer)](https://onco.cc/trials/notable-trial/), [Studying Chemotherapy With or Without Panitumumab for Unresectable, Locally Advanced, or Metastatic Pancreatic Cancer Without KRAS Mutations](https://onco.cc/trials/nct06998940/)
- people: [Anirban Maitra](https://onco.cc/people/anirban-maitra/), [Eileen M. O'Reilly](https://onco.cc/people/eileen-oreilly/), [Eric Van Cutsem](https://onco.cc/people/eric-van-cutsem/), [Lin Shen](https://onco.cc/people/shen-lin/)
- key papers: [eNRGy: efficacy of zenocutuzumab in NRG1 fusion-positive cancer](https://onco.cc/key-papers/paper-enrgy-zenocutuzumab-nrg1-fusion-positive-cancer-nejm-2025/), [Heining 2018: NRG1 fusions in KRAS wild-type pancreatic cancer](https://onco.cc/key-papers/paper-heining-nrg1-fusions-kras-wild-type-pancreatic-cancer-discov-2018/), [Identification of targetable ALK rearrangements in pancreatic ductal adenocarcinoma](https://onco.cc/key-papers/paper-singhi-alk-rearrangements-pancreatic-jnccn-2017/), [Integrated genomic characterization of pancreatic ductal adenocarcinoma](https://onco.cc/key-papers/paper-tcga-pancreatic-integrated-characterisation-cancer-cell-2017/), [Jones 2019: NRG1 gene fusions are recurrent, clinically actionable rearrangements in KRAS wild-type pancreatic ductal adenocarcinoma](https://onco.cc/key-papers/paper-jones-nrg1-fusions-recurrent-actionable-kras-wild-type-pdac-ccr-2019/), [Molecular characterization of KRAS wild-type tumors in patients with pancreatic adenocarcinoma](https://onco.cc/key-papers/paper-philip-kras-wild-type-pancreatic-ccr-2022/), [Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers](https://onco.cc/key-papers/paper-singhi-targeted-genome-profiling-3594-pdac-gastroenterology-2019/), [Tumour response to TRK inhibition in a patient with pancreatic adenocarcinoma harbouring an NTRK gene fusion](https://onco.cc/key-papers/paper-oreilly-hechtman-ntrk-fusion-pancreatic-larotrectinib-ann-oncol-2019/)
- ideas: [Automatic germline testing for every cancer type where it changes care](https://onco.cc/ideas/idea-prev-reflex-germline-testing/)
- biomarkers: [ALK fusion (ALK-positive)](https://onco.cc/biomarkers/alk-fusion/), [NTRK1/2/3 gene fusion](https://onco.cc/biomarkers/ntrk-fusion/)

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JSON: https://onco.cc/api/v1/entities/kras-wild-type-pdac.json