Savolitinib (AZD6094, HMPL-504, volitinib)

Agent Description

Savolitinib is a potent and selective small molecule MET kinase inhibitor. Savolitinib is orally bioavailable with good pharmacokinetic properties and consistent exposure. Savolitinib at low nanomolar concentrations (IC50 <5 nM) inhibits both enzymatic activity and phosphorylation of MET, and demonstrates 650-fold selectivity towards MET across a panel of 265 kinases when tested at high concentrations (1 uM). Currently, savolitinib is in phase II clinical trials for papillary renal cell carcinoma (PRCC), non-small cell lung carcinoma (NSCLC) and gastric cancer.

Mechanism of Action

MET kinase inhibition

Classification

MET kinase inhibitor

Molecular Targets

MET

Monograph

In vitro data, including that generated from a panel of ~900 cell lines derived from solid and hematological tumors, suggests that cancer cell lines with MET amplification (constitutive activity) or a HGF/MET autocrine loop (ligand dependent) are sensitive to inhibition with savolitinib. Xenograft models of gastric or lung cancer with MET amplification are sensitive to inhibition by savolitinib. Savolitinib has also been demonstrated to be more potent than crizotinib and 3 other selective MET inhibitors in a highly amplified gastric cell line (GTL16).

Presently, the following studies are being conducted with savolitinib:

Savolitinib in combination with gefitinib in EGFRm 2L+ NSCLC
Savolitinib in combination with osimertinib in EGFR T790M positive or negative 2L+ NSCLC
Savolitinib in combination with durvalumab in clear cell and papillary renal cell cancers
Savolitinib in combination with docetaxel in 2nd line MET amplified gastric cancer
Savolitinib monotherapy in Exon14 NSCLC and MET amplified gastric cancer
Savolitinib monotherapy in 3rd line MET amplified gastric cancer
Savolitinib monotherapy in comparison to sunitinib, crizotinib and cabozantinib in papillary renal cell cancer

Studies of Interest

Areas of interest:

Combination with EGFRi in EGFRi relapsed setting other than in CRC, NSCLC
Monotherapy in MET-driven indications other than in pRCC, gastric cancer, CRPC and pediatric brain tumors
Combination with immunotherapy other than with PD-L1 therapy in RCC
Combination with chemotherapy other than in gastric cancer
Molecular epidemiology studies of prevalence of MET aberrations in underserved indications

Information collaborator would like included in investigator proposals

N/A