Efficacy and safety signals from early-phase studies of KRAS inhibition in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, driven by KRAS mutations long deemed "undruggable". We conducted a meta-analysis of seven early phase cohorts (n = 695) that evaluated KRAS-targeted therapies in patients with PDAC. The pooled objective response rate was 29% (95% CI 24-35%), indicating promising activity in refractory PDAC, with consistent estimates across studies (I2 = 5.7%). Gastrointestinal toxicities were among the most common adverse events, with pooled incidences of 40% for diarrhea and 41% for nausea in all patients treated with KRAS-targeted agents. These findings validate direct KRAS inhibition as a breakthrough concept in PDAC but are tempered by modest durability, risk of bias, and limitations of early phase designs, underscoring the need for biomarker-guided, rigorously designed clinical trials.