Table 1.

Current application and perspectives in targeted therapies in pediatric GISTs treatment.

Drug Substance	Molecular Target	Comments	Reference
Imatinib	PDGF, SCF, KIT, C-KIT, ABL (including BCR-ABL fusion)	First-line treatment after R1 surgery (including high-risk group); if needed- neoadjuvant treatment	[2,38,39,40,41]
Sunitinib	PDGFR-α, PDGFR-β, VEGFR1, VEGFR2, VEGFR3, KIT, FLT3, CSF-1R, RET	Usually the second-line treatment of imatinib-resistant GIST; leads to the tumor stabilization	[1,45,46,47,48,49,50]
Regorafenib	VEGF-1, VEGF-2, VEGF-3, VEGFR-1, VEGFR-2, VEGFR-3, TIE-2, KIT, RET, RAF-1, B-RAF, PDGFR(-β), FGFR-1, EGFR	Beneficial for KIT-mutated and PDGFR-mutated GIST, including radio- and chemosensitization in vitro; anti-angiogenic effect (limited data)	[52,53,54,55,56,57]
Nilotinib	BCR-ABL, KIT, LCK, EPHA3, EPHA8, DDR1, DDR2, PDGFRB, MAPK11, ZAK	Less effective in adult GIST than imatinib without evidence in the pediatric population	[58]
Vandetanib	VEGFR-2, VEGFR-3 (weak interaction), VEGF, EGFR(-3), EGF, RET	No meaningful changes observed after application so far	[59]
Larotrectinib	TRK A, B, C	High and durable clinical response rate, good toleration of treatment	[60,61]
Entrectinib	TRK A, B, C, ROS1, ALK	High and durable clinical response rate, well-tolerated	[60,61]
Sorafenib	RAF kinases (C-RAF > B-RAF), PDGFR kinases, PDGFRβ, VEGFR-1, VEGFR-2, VEGFR-3, FLT-3, C-KIT, RET, induction of autophagy	Effective in adult GIST treatment but ineffective in V600E BRAF mutation, no evidence of efficacy in pediatric GIST	[40,62,63,64,69]
Avapritinib	KIT, PDGFRA mutant (such as D816 V KIT and D842 V PDGFRA)	Effective in adult GIST treatment, no evidence of efficacy in pediatric GIST treatment, ongoing NCT03862885 trial with early access for avapritinib in patients >16 years old with locally advanced unresectable or metastatic GIST	[65,66,67]
Ponatinib	ABL (BCR-ABL mutants), VEGFR, PDGFR, EGFR, SRC kinase, KIT, RET, FLT3	Effective in adult GIST treatment, no evidence of efficacy in pediatric GIST treatment yet	[68,77]
Ipilimumab	CTLA-4	Good safety, limited data about the treatment efficacy in combination with other multikinase inhibitors, ongoing NCT01738139 trial in patients >15 years old	[42,43,44]
Ripretinib	KIT and PDGFRA kinases	Effective inhibition of a wide range of KIT mutants in patients with drug-resistant GISTs (preclinical models, phase III trial finished)	[70]