Systemic therapy of advanced/metastatic gastrointestinal stromal tumors: an update on progress beyond imatinib, sunitinib, and regorafenib

Figures & data

Figure 1. Kinome illustrations of imatinib, sunitinib, regorafenib, avapritinib, and ripretinib. Red circle represent various kinases. Avapritinib specifically inhibits PDGFRA D842V. Illustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com)

Figure 2. Schematic illustration of mechanism of action of approved TKIs

Table 1. Overview of ongoing recruiting clinical trials for metastatic or locally advanced GIST with agents in development according to clinicaltrials.gov, date assessed: 6 October 2020

Trial	Mechanism/target of action	Phase	Inclusion criteria in GIST	ClinicalTrials.gov identifier
MEK162 in combination with imatinib	MEK inhibition	1 + 2	Pretreatment with imatinib (phase 1b), untreated or off adjuvant imatinib (phase 2)	NCT01991379
Regorafenib (REGISTRI)	Broad TKI	2	Wild-type, first line	NCT02638766
Ponatinib	Inhibition of KIT, FGFR, PDGFR, VEGFR, FLT3, RET	2	Pretreatment with at least imatinib	NCT03171389
HQP1351 in GIST or other solid tumors	Inhibition of both wild type and mutant KIT kinases	1	Primary imatinib resistance mutation or imatinib plus 1 other TKI	NCT03594422
Lenvatinib versus placebo (LENVAGIST)	Inhibition of VEGFR1-3, FGFR1-4, KIT, RET, PDGFRA	2	Pretreatment with at least imatinib and sunitinib	NCT04193553
Crenolanib versus placebo	Inhibition of PDGFRA D842V	3	PDGFRA D842V mutation, any line	NCT02847429
Spartalizumab in combination with imatinib	Immunotherapy (anti PD-1*)	1 + 2	Pretreatment with imatinib, sunitinib and regorafenib	NCT03609424
Paclitaxel in low P-glycoprotein expressed GIST	Spindle cell inhibitor	2	Pretreatment with imatinib, sunitinib and regorafenib	NCT03944304
Temozolomide	Alkylating agent	2	Advanced SDH-deficient	NCT03556384
DS-6157a in advanced GIST	GPR20*** directed antibody drug conjugate	1	Pretreatment with imatinib	NCT04276415
Ripretinib versus sunitinib	TKI switch pocket inhibitor	3	Pretreatment with imatinib	NCT03673501
Nivolumab versus nivolumab combined with ipilimumab	Anti PD-1* (nivolumab), plus anti CTLA-4**** (ipilimumab)	2	Pretreatment with imatinib	NCT02880020
Axitinib in combination with avelumab	Inhibition of VEGFR 1–3 (axitinib), anti PD-L1** (avelumab)	2	Pretreatment with two or three approved TKIs	NCT04258956
Anlotinib in advanced GIST	Inhibition of VEGFR, FGFR, PDGFR, KIT	2	Pretreatment with imatinib	NCT04106024
Selinexor in combination with imatinib	Selective inhibition of nuclear transport (Selinexor)	1 + 2	Pretreatment with imatinib	NCT04138381
Regorafenib in combination with avelumab (REGOMUNE)	Broad TKI (regorafenib), anti PD-L1** (avelumab)	1 + 2	Pretreatment with imatinib, sunitinib and regorafenib	NCT03475953
Tidutamab in neuroendocrine tumors and GIST	Anti-CD3 and Anti-SSTR2******	1	Pretreatment with imatinib, sunitinib and regorafenib	NCT03411915
TNO155 in advanced solid tumors	Inhibition of SHP2***** (TNO155)	1	Pretreatment with imatinib, sunitinib and regorafenib	NCT03114319
TNO155 in combination with spartalizumab	Inhibition of SHP2***** (TNO155), anti PD-1* (spartalizumab)	1	Pretreatment with imatinib, sunitinib and regorafenib	NCT04000529
Ipilimumab in combination with imatinib	Inhibition of CTLA-4**** (ipilimumab)	1	Pretreatment with imatinib, sunitinib and regorafenib	NCT01738139
Nivolumab in combination with ipilimumab in rare tumors	Anti PD-1* (nivolumab), plus anti CTLA-4**** (ipilimumab)	2	Pretreatment with imatinib, sunitinib and regorafenib	NCT02834013
Pembrolizumab in combination with cyclophosphamide in advanced sarcomas	Immunotherapy anti PD-1* (pembrolizumab), alkylating agent (cyclophosphamide)	2	Pretreatment with imatinib, sunitinib and regorafenib	NCT02406781
LY2880070 in advanced or metastatic cancer	Inhibition of checkpoint kinase 1	1 + 2	Pretreatment with at least one TKI	NCT02632448

*PD-1: programmed death receptor-1

**PD-L1: programmed death-ligand-1

***GPR20: G protein-coupled receptor 20, is a transmembrane receptor, which is highly expressed in GIST.

**** CTLA-4: cytotoxic T-lymphocyte–associated protein 4

*****SHP2: Src homology region 2 domain-containing phosphatase-2

******CD3: T-cell surface antigen, SSTR2: somatostatin receptor 2.