Efficacy and Safety of KRAS-Targeted Therapy in Locally Advanced or Metastatic Pancreatic Ductal Adenocarcinoma: An Updated Systematic Review and Meta-Analysis of Pooled Proportions.

OBJECTIVES: Kirsten rat sarcoma viral oncogene homolog mutations drive over 90% of pancreatic ductal adenocarcinoma (PDAC). Direct RAS inhibitors have shown early activity, but the only prior meta-analysis pooled early-phase monotherapy cohorts and predates the first phase 3 randomized trial and newer combination regimens. We estimated the objective response rate (ORR), disease control rate (DCR), and safety of Kirsten rat sarcoma viral oncogene homolog-targeted therapy in locally advanced or metastatic PDAC. METHODS: PubMed/MEDLINE, Embase, and SCOPUS were searched from inception through July 2026. Single-arm proportions were pooled using a random-effects generalized linear mixed model; RASolute 302 was analyzed separately. Prespecified subgroups stratified ORR by mechanistic class and line of therapy. RESULTS: A total of 1008 patients from 16 cohorts across 7 trials were included; 15 single-arm cohorts (507 patients) contributed to pooled estimates. Pooled ORR was 38.9% (95% CI: 29.9%-48.8%; I2=75.7%) and varied significantly by mechanism (P<0.0001): combination regimens showed the highest activity (60.5%), followed by G12D-selective (31.0%), pan-RAS(ON) (26.6%), and G12C-selective monotherapy (25.4%). Response declined with successive lines of therapy (P=0.0102), from 72.5% in treatment-naive patients to 32.5% after ≥3 prior lines. Pooled DCR was 87.6% (95% CI: 82.8%-91.2%). Grade ≥3 treatment-related adverse events occurred in 47.3%. In RASolute 302, daraxonrasib nearly doubled median overall survival versus chemotherapy (13.2 vs. 6.6 mo). CONCLUSIONS: Kirsten rat sarcoma viral oncogene homolog-directed therapy produces meaningful antitumor activity in previously treated PDAC, greatest for combination regimens and earlier treatment; the evidence remains heterogeneous and largely early-phase, and randomized trials are needed before routine adoption.