Targeted therapy of gastrointestinal stromal tumours

Table 1 Published randomized controlled trials of role of targeted therapy in gastrointestinal tumours

Study	Research question	Sample size	Study arms	Response rates	PFS/RFS	OS	Toxicity (Grades 3-5)	Conclusion
SWOG S0033[14]	Imatinib as first line in metastatic GISTs	746	400 mg daily vs 400 mg twice daily	ORR 45% (CR 5%, PR 40%) vs 45% (CR 3%, PR 42%)	2 yr PFS 41% vs 46% (P = 0.13)	2 yr OS 76% vs 72% (HR = 0.98)	43% vs 63%	400 mg daily is initial dose and consider dose escalation with disease progression
EORTC 62005[13]	Imatinib as first line in metastatic GISTs	946	400 mg daily vs 400 mg twice daily	51% vs 54%	2 yr PFS 56% vs 50% (HR = 0.82, P = 0.026)	2 yr OS 69% vs 74%	32% vs 50%, P < 0.0001	Better PFS in 400 mg twice daily with higher toxicity
Demetri et al[25]	Sunitinib as second line in metastatic GISTs	312	Sunitinib vs placebo	7% vs 0% (SD 58% vs 48%)	Median TTP 27.3 wk vs 6.4 wk (HR = 0.33, P < 0.0001)	Better in Sunitinib arm (HR = 0.49, P = 0.007)	20% vs 5%	Sunitinib is approved as a second line therapy in metastatic GISTs
GRID[29]	Regorafinib as third line in metastatic GISTs	199	Regorafinib vs placebo	4.5% vs 1.5% (SD 71.4% vs 33.3%)	Median PFS 4.8 mo vs 0.9 mo (HR = 0.27, P < 0.0001)	No difference, HR = 0.77	61% vs 14%	Regorafinib is approved third line therapy in metastatic GISTs
ACOSOG Z9001[35]	Imatinib as adjuvant	713	1 yr (400 mg) vs placebo	Not available	1 yr RFS 98% vs 83% (HR = 0.33, P < 0.0001)	1 yr OS 99.2% vs 99.7% (HR = 0.66, P = 0.47)	30.9% in Imatinib arm	1 yr adjuvant Imatinib is effective and safe
SSG XVIII/AIO[36]	Imatinib as adjuvant	400	1 yr vs 3 yr	Not available	5 yr RFS 47.9% vs 65.6% (HR = 0.46, P < 0.001)	5 yr OS 81.7% vs 92% (HR = 0.45, P = 0.02)	20.1% vs 32.8%	3 yr adjuvant Imatinib improved RFS and OS

SWOG: Southwest Oncology Group; GISTs: Gastrointestinal stromal tumours; ORR: Overall response rates; CR: Complete response; PR: Partial response; SD: Stable disease; PFS: Progression free survival; RFS: Recurrence free survival; TTP: Time to tumour progression; OS: Overall survival; HR: Hazard ratio.

Table 2 Current role of targeted therapy in gastrointestinal stromal tumours

Agent	Use	Dose	Duration
Imatinib	First line in metastatic GISTs[13-15]	400 mg once daily (oral)	Till progression or intolerance
	Progression on 400 mg[13-15]	400 mg twice daily (oral)	Till progression or intolerance
	Exon 9 mutation[13-15]	400 mg twice daily (oral)	Till progression or intolerance
	Adjuvant in high risk cases[37]	400 mg daily (oral)	3 yr
	Neoadjuvant setting[29,39,40]	400 mg daily (oral)	6-12 mo
Sunitinib	Second line in metastatic setting[21,24]	50 mg once daily for 4 wk every 6 wk (oral) or 37.5 mg once daily continuously (oral)	Till disease progression or intolerance
Regorafinib	Third line in metastatic setting[26]	160 mg once daily for 3 wk every 4 wk (oral)	Till disease progression or intolerance

GISTs: Gastrointestinal stromal tumours.