Table 1.
Summary of main Phase II and III clinical trials of tyrosine kinase inhibitors in differentiated thyroid cancer
| Drug (commercial name) | Molecular target | Dose | Design | Number of patients | Primary outcome | Other outcomes | Side effects | Reference | |
|---|---|---|---|---|---|---|---|---|---|
| Phase III trials | |||||||||
| Sorafenib (Nexavar) | RET, VEGFR1-3, FLT3, c-Kit, and BRAF | 400 mg BID | Multicenter, double blind RCT | 417 | PFS 10.8 mo vs 5.8 mo (HR 0.58, 95% CI 0.45–0.75; P<0.0001) | ORR 12.2% vs 0.5% (P<0.0001), disease control rate 54.1% vs 33.8% (P<0.0001). OS (HR 0.80, 95% CI 0.54–1.19; P=0.14) | Hand–foot skin reaction (76.3%), diarrhea (68.6%), alopecia (67.1%), desquamation (50.2%) | Brose et al48 | |
| Lenvatinib | VEGFR1-3, RET, FGFR1-4, c-kit, PDGFR α/β | 24 mg daily | Multicenter, double blind RCT | 392 | PFS 18.3 mo vs 3.6 mo (HR 0.21, 95% CI 0.14–0.31; P<0.0001) | ORR (CR, PR), OS CRs 1.5% vs 0%; PRs 63.2% vs 1.5% | Hypertension (68%), diarrhea (59%), appetite decreased (50%), weight loss (46%), nausea (41%) | Schlumberger et al66 | |
| Phase II trials | |||||||||
| Sunitinib (Sutent) | VEGFR1-3, PDGFR α/β, FLT3, RET | 37.5 mg daily | Single arm/center | 33 | ORR 31% (95% CI 16%–47%) | SUV change: −11.7% in ORR, −13.9% in SD (P=0.03) | Fatigue (11%), neutropenia (34%), hand/foot syndrome (17%), diarrhea (17%), and leukopenia (31%) | Carr et al54 | |
| 50 mg daily | 37 | PR 13%, SD 68%, PD 10%, and NE 13% | Fatigue (79%), diarrhea (56%), palmar-plantar erythrodysesthesia (53%), neutropenia (49%), and hypertension (42%) | Cohen et al53 | |||||
| Motesanib | VEGFR1-3, PDGFR, and c-Kit | 125 mg daily | Single arm | 93 | ORR 14%; SD 67% | Response duration 24 wk in 35%; PFS 40 weeks (95% CI, 32%–50%); Tg concentration decrease in 81% | Diarrhea (59%), hypertension (56%), fatigue (46%), and weight loss (40%) | Sherman et al57 | |
| Axitinib (Inlyta) | VEGFR1-3, PDGFR | 5 mg BID | Single arm, multicenter | 45 | PR 31%, SD 42% | Median PFS 18.1 mo (DTC and MTC) | Hypertension (12%), fatigue (5%), proteinuria (5%) | Cohen et al60 | |
| Pazopanib (Votrient) | VEGFR1-3, FGFR1-3, PDGFR-α and -β, KIT | 800 mg daily | Single arm, multicenter | 37 | PR 49%, 95% CI 35%–68% | PFS 11.7 mo | Fatigue (74%), skin and hair hypopigmentation (72%), diarrhea (69%), and nausea (69%) | Bible et al62 | |
| Selumetinib | MEK1/MEK2 | 100 mg BID | Single arm, multicenter | 39 | PR 3%, SD 54%, PD 28% | PFS 23 wk | Rash (59%), diarrhea (44%), fatigue (41%), peripheral edema (31%), elevated liver enzymes (23%) | Hayes et al88 | |
| Everolimus (Affintor) | mTOR | 10 mg daily | Single arm, multicenter | 40 | PR 5%, SD 76% | PFS 47 wk | Mucositis (84%), anorexia (44%), elevated liver enzymes (26%) | Lim et al77 | |
Abbreviations: BID, Twice a day; CI, confidence interval; c-Kit, stem cell factor receptor; DTC, differentiated thyroid cancer; FGFR, fibroblast growth factor receptor; FLT3, FMS like tyrosine kinase 3; HR, hazards ratio; MEK, MAPK/ERK kinase; MTC, medullary thyroid cancer; mTOR, Mammalian target of rapamycin; OS, overall survival; PD, progressive disease; PDGFR, platelet-derived growth factor receptor; PFS, progression-free survival; PR, partial response; RCT, randomized controlled trial; RET, rearranged during transfection; SD, stable disease; VEGFR, vascular endothelial growth factor receptor; SUV, standardized uptake values; CR, complete response; NE, not estimable; ORR, objective response rate; mo, month; Tg, thyroglobulin; wk, week; CI, confidence interval.