SAR405838 + pimasertib

A small-molecule combination therapy of the **MDM2–p53 interaction antagonist** SAR405838 and the **MEK1/2 inhibitor** pimasertib, investigated for advanced solid tumors with wild-type TP53 and RAS or RAF mutations. The regimen was evaluated in a Phase 1, open-label, dose-escalation study (NCT01985191) to determine safety, pharmacokinetics/pharmacodynamics, and preliminary efficacy. The study identified an MTD of SAR405838 200 mg once daily plus pimasertib 45 mg twice daily, showed no significant drug–drug interaction, and observed one confirmed partial response and a high rate of stable disease. Development of this combination by Sanofi was subsequently stopped before RP2D expansion enrollment. Mechanistically, SAR405838 reactivates p53 signaling by blocking MDM2, while pimasertib inhibits the MAPK pathway via MEK1/2; preclinical models demonstrated synergistic induction of apoptosis and cell-cycle arrest in TP53 wild-type cancer cells.[3][1][6][7][8]

Other names

HDM2 inhibitor SAR405838 + MEK1/2 inhibitor pimasertib