Defactinib (DB12282): A Comprehensive Monograph on a First-in-Class FAK Inhibitor for KRAS-Mutated Ovarian Cancer

I. Executive Summary

Defactinib is an orally bioavailable, small molecule, dual inhibitor of Focal Adhesion Kinase (FAK) and the closely related Proline-rich Tyrosine Kinase 2 (Pyk2).[1] As a second-generation FAK inhibitor developed by Verastem Oncology, it represents a significant advancement in targeting the complex signaling networks that drive tumor progression, survival, and resistance to therapy.[3]

The drug's clinical development culminated in a landmark achievement in May 2025 with the U.S. Food and Drug Administration (FDA) granting Accelerated Approval to the Avmapki Fakzynja Co-pack, a combination therapy of defactinib and the RAF/MEK clamp avutometinib.[5] This approval is for the treatment of adult patients with recurrent,

KRAS-mutated low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy, marking the first-ever FDA-approved treatment specifically for this disease.[1] The regulatory decision was underpinned by compelling efficacy data from the Phase 2 RAMP 201 trial, which demonstrated a confirmed overall response rate (ORR) of 44% in this molecularly defined patient population—a substantial improvement over historical standards of care.[8]

The strategic rationale for the combination therapy is grounded in a sophisticated understanding of tumor biology. Inhibition of the MAPK pathway with avutometinib can trigger a compensatory, FAK-mediated adaptive resistance mechanism; the concurrent inhibition of FAK by defactinib effectively blocks this escape pathway, leading to a more profound and durable anti-tumor response.[8] This synergistic mechanism was key to overcoming the resistance often seen in MAPK-driven tumors.