Comprehensive review into the challenges of gastrointestinal tumors in the Gulf and Levant countries

Table 1 Monitoring frequency based on risk of recurrence[1]

Risk	Monitoring frequency
High-risk tumors	Every 3 to 6 mo for the first 3 yr of adjuvant therapy
	Every 3 mo for 2 yr after stopping adjuvant imatinib, then every 6 mo for 5 yr, then once a year for 5 yr
Low-risk tumors	Every 6 to 12 mo for 5 yr
Very low-risk tumors	Routine follow-up may not be necessary; however, risk of recurrence is not nil

Table 2 Promising therapeutic agents in development for the treatment of advanced gastrointestinal stromal tumor

Target	Class of agent (specific activity)	Drug(s)	Trial number/ study phase	Results	Ref.
KIT/PDGFRA	Multitargeted TKI (KIT exon 17 D816-mutant kinases)	Ponatinib	NCT01874665 Phase 2	37% CBR at 16 weeks	[78]
	KIT exon 13 resistance mutations	Ponatinib	NCT03171389 Phase 2	Awaited	[79]
	Multitargeted TKI (PDGFRA D842V)	Dasatinib	Phase 2	32% PR; 21% PFS at 6 months	[74]
			NCT01643278 Phase 1 (+ ipilimumab)	Awaited	[80]
	Multitargeted TKI	Crenolanib	NCT01243346 Phase 1/2 study	31% CBR	[81]
	KIT D816V/PDGFRA D842V inhibitor	BLU285	NCT02508532 Phase 1	ORR 84% in PDGFRA D842V GIST and ORR 20% for fourth-line or later; tumor reduction 98% in PDGFRA D842V and 60% in fourth-line or later	[82,83]
	KIT exon 9, 11, 13, 14, 17, and 18 inhibitor	DCC-2618	NCT02571036 Phase 1	ORR 14%, 3-month DCR 22%, mPFS at 24 weeks 56%	[84]
PI3K	PI3K inhibitor	BYL719	NCT01735968 Phase 1	Awaited	[85]
	Selective PI3K catalytic p110α subunit inhibitor	Buparlisib	NCT01468688 Phase 1	Awaited	[86]
BRAF V600E	BRAF inhibitor	Vemurafenib	NCT02304809 Phase 2	Awaited	[87]
MEK	MEK inhibitor	Binimetinib	NCT01991379 Phase 1b/2 (+ imatinib)	33% PR	[88]
MET	Dual MET and KIT small-molecule inhibitor	Cabozantinib	Phase 1	Long-lasting SD as best response	[89]
			NCT02216578 Phase 2	Awaited	[90]
FGFR	Pan-FGFR inhibitor	BGJ398	NCT02257541 Phase 1b/2 (+ imatinib)	Awaited	[91]
IGF1R	IGF1R inhibitor	Linsitinib	NCT01560260 Phase 2	45% CBR; 52% PFS, 80% OS at 9 months	[92]
HSP90	Non-ansamycin HSP90 inhibitor	Onalespib	NCT01560260 Phase 1	36% CBR	[93]
			NCT01294202 Phase 2 (± imatinib)	Awaited	[94]
CTLA4	Anti-CTLA4 antibody	Ipilimumab	NCT01738139 Phase 1 (+ imatinib)	Single PR	[95]
			NCT01643278 Phase 1 (+ dasatinib)	Single durable SD for 59+ weeks	[80]
CDK	CDK4/6 inhibitor	Palbociclib	NCT01907607 Phase 2	Awaited	[96]

CBR: Clinical benefit rate; CDK: Cyclin-dependent kinase; CTLA4: Cytotoxic T-lymphocyte-associated protein 4; DCR: Disease control rate; FGFR: Fibroblast growth factor receptor; GIST: Gastrointestinal stromal tumor; HSP: Heat shock protein; IGF1R: Insulin-like growth factor 1; MEK: Mitogen-activated protein kinase; NCT: ClinicalTrials.gov identifier; ORR: Objective response rate; OS: Overall survival; PDGFRA: Platelet-derived growth factor receptor A; (m)PFS: (Median) progression-free survival; PI3K: Phosphoinositide 3-kinase; PR: Partial remission, SD: Stable disease; TKI: Tyrosine kinase inhibitor.