A Phase 2 Study of Sitravatinib in Combination With PD-(L)1 Checkpoint Inhibitor Regimens in Patients With Advanced or Metastatic Urothelial Carcinoma

Sitravatinib is an orally-available, small molecule inhibitor of a closely related

spectrum of receptor tyrosine kinases (RTKs) including MET, Axl, MERTK, VEGFR family,

PDGFR family, KIT, FLT3, Trk family, RET, DDR2 and selected Eph family members. Nivolumab

is a human IgG monoclonal antibody that binds to the programmed cell death-1(PD-1)

receptor and blocks its interaction with programmed cell death ligand-1 (PD-L1) and

PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response including

anti-tumor immune response. Combining an immunotherapeutic PD-L1 checkpoint inhibitor

with an agent that has both immune modulatory and antitumor properties could enhance the

antitumor efficacy observed with either agent alone. Sitravatinib selectively inhibits

key molecular and cellular pathways strongly implicated in checkpoint inhibitor

resistance and therefore represents a rational strategy to enhance or restore anti-tumor

immunity when combined with nivolumab, a checkpoint inhibitor therapy.

Pembrolizumab is a humanized IgG4 monoclonal antibody that binds to the PD-1 receptor and

selectively blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated

inhibition of the immune response, including the anti-tumor immune response. Enfortumab

vedotin (enfortumab) is an investigational ADC that is comprised of a fully human

anti-Nectin-4 IgG1 monoclonal antibody conjugated to MMAE via a protease-cleavable

linker. Enfortumab binds to cells that express Nectin-4 with high affinity, triggering

the internalization and release of MMAE in target cells, inducing cell cycle arrest and

apoptotic cell death. Early efficacy results from enfortumab in combination with

pembrolizumab in frontline cisplatin-ineligible urothelial carcinoma in the ongoing

EV-103 study have demonstrated encouraging activity with a safety profile that appears

manageable and tolerable. Addition of sitravatinib to this combination might further

augment clinical activity by selectively inhibiting key molecular and cellular pathways

strongly implicated in checkpoint inhibitor resistance.