Last updated on February 2018

Single Agent Regorafenib in First-line for Metastatic/Unresectable KIT/PDGFR Wild Type GIST

Brief description of study

Evaluate the treatment with regorafenib in patients with metastatic and/or unresectable KIT/PDGFR wild type GIST in the first line setting.

Detailed Study Description

The SDH complex is involved in mitochondrial Krebs cycle and defects in the succinate dehydrogenase (SDH) complex have identified, as previously mentioned, in KIT/PDGFR WT. This complex, SDH, has 4 subunits (A-D) and SDH-A or SDH-B are involved in oxidization succinate to fumarate. Therefore, loss of function owing to mutational inactivation leads to the cytoplasmic accumulation of succinate which downregulates prolyl hydroxylase. This enzyme has a negative regulator role of hypoxia-inducible factor 1 (HIF1) since promotes its proteasomal degradation. Increased levels of HIF1 can enter the nucleus and activate the transcription of vascular endothelial growth factor (VEGFR)24. In fact, the VEGFR expression is higher in KIT/PDGFR WT than in KIT mutant GISTs25.

Approximately 50% of KIT/PDGFR WT show high expression of insulin-like growth factor 1 receptor (IGFR1). This expression may correlate also with the loss of SDH due to IGF autocrine loop26. IGFR signals through both MAPK and PI3K-AKT pathways. As previously mentioned, Regorafenib is able to block MAPK signaling pathway at different levels. Interestingly, early interstitial Cajal cell (ICC) progenitors have a phenotype of KITlowCD44+CD34+IGFR+ while committed lineage of progenitors have KIThighCD44+CD34-IGFR-. Unlike mature or more committed lineage of ICCs, the KITlowCD44+CD34+IGFR+ display resistance to Imatinib in spite of kit signaling pathway activation. Thus Regorafenib could gain advantage over Imatinib for treating KIT/PDGFR WT27,28.

On the other hand, other subsets within of KIT/PDGFR WT as B-RAF mutants or NF1-associated GIST could also be sensitive to Regorafenib. In this later subset, protein expression of phospho-MAPK was seen in 92% of cases in a series of 25 patients29.

Theoretically Regorafenib could also act blocking STAT3, which is activated by RET proto-oncogen, through RET inhibition. STAT3 is implicated as downstream pathway signal in GIST30.

Taken together, the previous data suggests Regorafenib could play a relevant role as upfront treatment of metastatic or unresectable locally advanced KIT/PDGFR WT GIST.

Clinical Study Identifier: NCT02638766

Find a site near you

Start Over