MEK inhibitor-based genomically matched combinatorial targeted therapies in metastatic pancreatic adenocarcinoma with KRAS alterations.

Pancreatic Ductal Adenocarcinoma (PDAC) is often caused by mutations in multiple genes including KRAS (activating the Ras-Raf-MEK-ERK pathway). This study evaluated the role of MEK inhibitor (MEKi)-based combinatorial targeted therapies in patients with PDAC. Methods. This is a retrospective/prospective observational, single institution study, including 29 patients with metastatic PDAC with KRAS alterations, treated with MEKi therapies between 2022-2024. Ten patients had KRAS G12R (34.5%), ten G12D (34.5%), and nine G12V (31%). Majority of patients received MEKi therapy as third-line and beyond (KRAS G12R/G12D/G12V 60%/50%/78%, respectively). Median overall survival from MEKi initiation for KRAS G12R/G12D/G12V was 8.2/5.1/4.7 months (P = 0.5), respectively, and median progression-free survival was 4.4/2.3/1.4 months (P = 0.11). Six (21%) patients discontinued at least one drug in the treatment combination due to toxicity. MEKi-based combinatorial therapies had modest disease control in patients with KRAS G12R, and minimal disease control in patients with KRAS G12D/V in the late-line setting.