sotorasib + BI 1701963

Sotorasib + BI 1701963 is an investigational combination therapy comprising sotorasib, a small molecule KRAS G12C inhibitor (approved for KRAS G12C-mutated cancers), and BI 1701963, an orally available small molecule SOS1::pan-KRAS inhibitor. Sotorasib covalently and selectively inhibits the KRAS G12C mutant protein, preventing downstream signaling through the MAPK pathway. BI 1701963 binds to the catalytic domain of SOS1, preventing interaction with KRAS and reducing formation of active KRAS; it inhibits MAPK pathway signaling in KRAS-dependent cancers and blocks feedback-driven pathway reactivation, with efficacy across multiple KRAS mutant alleles. The rationale for the combination is the potential for synergistic therapeutic benefit in KRAS-mutated cancers due to dual blockade of the KRAS pathway[1]. Clinical investigation is ongoing in Phase I.