Sitravatinib (MGCD516): A Comprehensive Monograph on a Spectrum-Selective Kinase Inhibitor for Immuno-Oncology

Executive Summary

Sitravatinib, also known by its code designation MGCD516, is an orally bioavailable, small molecule investigational drug developed as a spectrum-selective receptor tyrosine kinase (RTK) inhibitor.[1] Its core scientific rationale was centered on its potential as an immuno-oncology agent. The primary mechanism of action involves the potent and selective inhibition of a specific constellation of RTKs, most notably the TAM family (TYRO3, AXL, MerTK) and the split-kinase domain family (including VEGFR and KIT).[3] This targeted inhibition was designed to reverse the immunosuppressive tumor microenvironment (TME), thereby overcoming resistance to immune checkpoint inhibitors (CPIs) such as nivolumab, and augmenting anti-tumor immune responses.

The clinical development program for sitravatinib progressed through multiple phases, showing initial promise. Early Phase I/Ib studies established a manageable safety profile and a recommended Phase 2 dose, with modest signals of clinical activity in heavily pretreated patients with solid tumors.[6] Subsequent Phase II investigations, particularly the MRTX-500 study in non-small cell lung cancer (NSCLC), generated significant interest. While the study did not meet its primary endpoint of objective response rate, an exploratory analysis revealed an encouraging median overall survival of 14.9 months in the target population of CPI-experienced patients, providing the justification for advancing to a pivotal trial.[8]