Phase 2 VS-7375 oral KRAS G12D (ON/OFF) inhibitor ± EGFR antibody cetuximab in metastatic PDAC.

Verastem, Inc. is running TARGET-D 201 (NCT07644559), an open-label, multicenter Phase 2 study testing VS-7375—an oral, KRAS G12D–selective “ON/OFF” small-molecule inhibitor—given as monotherapy and in combination with cetuximab, an EGFR-directed monoclonal antibody (marketed by Eli Lilly; originally from ImClone/Bristol Myers Squibb). The purpose is to define safety and preliminary efficacy in metastatic pancreatic ductal adenocarcinoma (PDAC) with a confirmed KRAS G12D mutation, including treatment-naïve/near–treatment-naïve patients in a 1L cohort and a separate combination cohort for previously treated (2L) metastatic disease. Scientifically, the commercial angle is “registration-directed” Phase 2 development in a high-unmet, KRAS G12D–driven tumor where EGFR feedback signaling can limit KRAS-pathway suppression—hence the rationale for adding cetuximab. Today’s care for metastatic PDAC is systemic combination chemotherapy up front (modified FOLFIRINOX or gemcitabine + nab-paclitaxel), with subsequent lines often including nanoliposomal irinotecan/5-FU–based regimens and targeted therapy only for small biomarker-defined subsets (e.g., BRCA/PALB2).