Background
Narrative review of KRAS wild-type pancreatic ductal adenocarcinoma (PDAC). KRAS-WT PDAC represents ~5-10% of cases and is enriched for targetable alterations including RET, NRG1, NTRK, ALK, and BRAF. Discusses FDA-approved targeted therapies and emerging precision-oncology approaches.
Interventions and follow up
Design: Review and case series of KRAS-WT PDAC with targetable fusions (RET, NRG1, NTRK) treated with selpercatinib, repotrectinib, larotrectinib, or zenocutuzumab
Primary focus: Objective responses reported in case reports and small series
Median follow up: Variable across cited reports, NR
Primary focus: Objective responses reported in case reports and small series
Median follow up: Variable across cited reports, NR
Results
RET-fusion response: Case reports describe responses to selpercatinib in RET-rearranged PDAC; repotrectinib active against RET/NTRK/ROS1 fusions including resistance mutations
Approved agents: Selpercatinib FDA-approved (tissue-agnostic) for RET fusion-positive solid tumors; larotrectinib for NTRK fusions; zenocutuzumab for NRG1 fusion-positive tumors
Caveat: No head-to-head randomized data in PDAC; evidence is from small series and basket trials, NR for formal ORR in PDAC subset
Approved agents: Selpercatinib FDA-approved (tissue-agnostic) for RET fusion-positive solid tumors; larotrectinib for NTRK fusions; zenocutuzumab for NRG1 fusion-positive tumors
Caveat: No head-to-head randomized data in PDAC; evidence is from small series and basket trials, NR for formal ORR in PDAC subset
Adverse events
Selpercatinib: hypertension (20-30%), diarrhea (15-25%), transaminase elevation; manageable with dose adjustment
Larotrectinib/repotrectinib: dizziness, fatigue, and neurologic effects; generally manageable with supportive care and dose modification
Larotrectinib/repotrectinib: dizziness, fatigue, and neurologic effects; generally manageable with supportive care and dose modification
Conclusions
Comprehensive genomic profiling is essential in PDAC to identify fusion-driven disease (enriched in KRAS-WT tumors). Targeted therapies offer a precision approach for select fusions, and germline BRCA/ATM testing improves access to PARP inhibitors and platinum therapy.
Key Limitations
Narrative review, not a prospective trial; evidence base limited to case reports and small basket-trial subsets; rare alteration frequencies mean limited generalizability; no randomized comparison versus standard chemotherapy in PDAC.
Clinical Context
Supports tissue-agnostic precision oncology in PDAC: routine next-generation sequencing to detect RET/NTRK/NRG1 fusions and germline testing for homologous-recombination defects. ESMO precision-medicine guidance endorses broad molecular profiling in advanced PDAC, enabling use of FDA-approved tissue-agnostic targeted agents in fusion-positive disease.