Cyclic disruption of the mitogen-activated protein kinase (MAPK) pathway by the Dual MEK inhibitor, IMM-6-415, enhances PD-1 and CTLA-4 checkpoint blockade in RAS mutant tumors

By November 10, 2022Publications

KRAS is the most frequently altered RAS gene (~85%) and is often mutated in pancreatic ductal adenocarcinoma (PDAC; 95%), non-small cell lung cancer (NSCLC; 40%) and colorectal cancer (CRC; 45%)1. KRAS-G12C inhibitors (sotorasib/adagrasib) have demonstrated single-agent activity in all three tumor types. However, acquired resistance and limited biomarker positive patients (e.g., only 1-3% of PDAC and CRC) limit broader access and overall response to G12C inhibitors, prompting evaluation of combination partners including immune therapies. In contrast to G12C-mutant focused KRAS inhibitors, MEK inhibitors could broaden the potential for immune therapy in RAS-mutant tumors, but they have been largely ineffective in this setting as monotherapy. Here, we demonstrate that the short-lived Dual-MEK inhibitor, IMM-6-415, is active across multiple MAPK-driven tumor models both as a single agent and in combination with checkpoint inhibitors (CPI).

Presented at SITC , November 2022 (Abstract 449)

Brett Hall, Anna Travesa, Amy Yamamura, Amy Axel, Sarah Kolitz, Jason Funt, Kevin D Fowler, Matthew Nord, Praveen Nair, Scott Barrett, Benjamin J Zeskind, Peter J King