Table 2.
Pivotal clinical trials of TKIs with European Medicines Agency (EMA) approval for the treatment of unresectable or metastatic GISTs.
| First Author, Publication Information | Number of Patients, Patient Population |
Clinical Phase | Intervention | Molecular Analysis Performed |
Primary Endpoint | Response Evaluation Criteria |
Results |
|---|---|---|---|---|---|---|---|
| Demetri et al., NEJM 2002 [76] | 147 Advanced GISTs |
2 | Imatinib 400 mg/d vs. imatinib 600 mg/d | No | ORR | Southwest Oncology Group criteria [105] |
ORR: 49.3% (400 mg) vs. 58.1% (600 mg) Estimated 1 y OS: 88%. |
| Verweij et al., Lancet 2004 [24] |
946 Metastatic or unresectable GISTs |
3 | Imatinib 400 mg/d vs. imatinib 800 mg/d | No | PFS | RECIST 1.0 | PFS longer in the group with 800 mg vs. 400 mg, HR 0.82, p = 0.026 1 y OS: 85% (400 mg) vs. 86% (800 mg) ORR: 50.1% (400 mg) vs. 54.3% (800 mg) |
| Blanke et al., JCO 2008 [75] | 746 Metastatic or unresectable GISTs |
3 | Imatinib 400 mg/d vs. imatinib 800 mg/d | No | PFS and OS | RECIST 1.0 | Median PFS: 18 m (400 mg) vs. 20 m (800 mg), p = 0.13 Median OS: 55 m (400 mg) vs. 51 m (800 mg), p = 0.83 No difference in RR between the two arms |
| Demetri et al., Lancet 2006 [86] | 312 Advanced GISTs resistant or intolerant to imatinib |
3 | Sunitinib 50 mg vs. placebo | No | TTF | RECIST 1.0 or WHO (WHO Handbook for Reporting Results of Cancer Treatment) |
Median TTP: 6.3 m (sunitinib) vs. 1.5 m (placebo), HR 0.33, p < 0.0001 Median PFS: 5.5 m (sunitinib) vs. 1.4 m (placebo), HR 0.33, p < 0.0001 Median OS: not reached. HR 0.49, p = 0.007 ORR: 7% (sunitinib) and 0% (placebo), p = 0.006 |
| George et al., EJC 2009 [106] | 60 Patients with unresectable GISTs resistant or intolerant to imatinib |
2 | Sunitinib 37.5 mg/d | No | DCR | RECIST 1.0 |
DCR: 53% Median PFS: 7.8 m Median OS: 24.6 m ORR: 13% 1 y survival rate: 70% |
| Demetri et al., Lancet 2013 [92] | 199 Metastatic or unresectable GISTs resistant to imatinib and sunitinib |
3 | Regorafenib 160 mg/d vs. placebo | Yes * | PFS | Modified RECIST 1.1 [92] | Median PFS 4.8 m (regorafenib) vs. 0.9 m (placebo), HR 0.27, p < 0.0001 HR OS: 0.77, p = 0.199 DCR 52.6% (regorafenib) vs. 9.1% (placebo) |
| Blay et al., Lancet Oncol 2020 [89] | 129 Advanced GISTs with resistance or intolerance to imatinib, sunitinib, and regorafenib |
3 | Ripretinib 150 mg/d + BSC vs. placebo + BSC | Yes (112/129) |
PFS | Modified RECIST 1.1 [92] | Median PFS: 6.3 m (ripretinib) vs. 1.0 m (placebo), HR: 0.15, p < 0.0001 Median OS: 15.1 m (ripretinib) vs. 6.6 m (placebo), HR 0.36 1 y estimated OS: 65.4% (ripretinib) vs. 25.9% (placebo) ORR: 9% |
| Heinrich et al. Lancet Oncol 2020 [90] | 56 Unresectable PDGFRA D842V-GISTs, regardless of previous therapy |
1 | Avapritinib 300/400 mg/d | Yes (56/56) |
ORR | Modified RECIST 1.1 [92] | ORR: 91% CBR: 98% Median DOR: 27.6 m Median PFS: 34.0 m |
*—number not provided; ORR—objective response rate, OS—overall survival, PFS—progression-free survival, RECIST—response evaluation in solid tumors, TTF—time to treatment failure, WHO—World Health Organization, DCR—disease control rate, CBR—clinical benefit rate, d—day, m—months, y—year, HR—hazard ratio.