Table 1.
Clinical trials evaluating the effects of multitarget tyrosine kinase inhibitors, acting also on FGFR, in patients with NENs.
| Ref | Therapy and dose | Molecular target | Study design (Trial name) | Tumors | Number of patients(placebo) | Median follow- up(placebo) | Primary outcome | Results | Main AE (%) |
|---|---|---|---|---|---|---|---|---|---|
| (70) | Surufatinib 300 mg/day | VEGFR 1,2,3 FGFR1 CSF-1R |
Randomised, double-blind, placebo-controlled, phase 3 (SANET-EP) |
Advanced extrapancreatic NETs (G1-G2) | 129 (69) |
13.8 months (16.6 months) |
PFS | Median PFS: 9.2 months (surufatinib) vs. 3.8 months (placebo) | Hypertension (36%); proteinuria (19%) |
| (71) | Surufatinib 300 mg/day |
VEGFR 1,2,3 FGFR1 CSF-1R |
Randomised, double-blind, placebo-controlled, phase 3 (SANET-P) |
Advanced pancreatic NETs (G1-G2) | 113 (59) |
19.3 months (11.1 months) | PFS | Median PFS: 10.9 months (surufatinib) vs. 3.7 months (placebo) | Hypertension (38%); proteinuria (10%); hypertriglyceridemia (7%) |
| (72) | Surufatinib 300 mg/day |
VEGFR 1,2,3 FGFR1 CSF-1R |
Dose escalation/expansion study | Heavily pre-treated progressive NETs | 32 | 19 weeks | ORR | 9.4% | Hypertension, fatigue, diarrhea |
| (73) | Surufatinib 300 mg/day |
VEGFR 1,2,3 FGFR1 CSF-1R |
Phase 2, open label, two stage design study | Advanced MTC | 27 | – | ORR | 22.2% | hypertension (20.3%), proteinuria (11.9%), hypertriglyceridemia (5.1%)* |
| (74) | Lenvatinib 24 mg/day |
VEGFR 1-3 FGFR1-4 | Prospective multicohort phase 2 (TALENT) |
Advanced pancreatic and gastrointestinal NETs (G1-G2) | 111 | 19 months | ORR | 42.3% pancreatic 16.3% gastrointestinal |
Hypertension (22%); fatigue (11%); diarrhea (11%) |
| (75) | Lenvatinib 24 mg/day |
VEGFR 1-3 FGFR1-4 | Phase 2, multicenter, open-label, single-arm clinical trial | Unresectable or metastatic progressive MTC | 59 | – | ORR | 36% (all PR) |
Diarrhea (14%); hypertension (7%); decreased appetite (7%) |
| (76) | Lenvatinib 24 mg/day |
VEGFR 1-3 FGFR1-4 | Nonrandomized, open-label, multicenter, phase 2 study | Progressive MTC | 9 | 9.6 months | Safety | 100% of patients ≥1 AE; 1.7% of patients AE leading to discontinuation | Decreased appetite (100%); hypertension (89%); palmar-plantar erythrodysesthesia (89%) |
| (77) | Lenvatinib 24 mg/day |
VEGFR 1-3 FGFR1-4 | Prospective, post-marketing observational study | UnresectableMTC | 28 | 12 months | Safety | 100% pts ≥1 AE | Hypertension; proteinuria; palmar-plantar erythrodysesthesia |
| (78) | Nintedanib | VEGFR 1,2,3 FGFR2 | Multicenter phase 2 study | Advanced progressing carcinoid on stable dose SSA for ≥3 months | 30 | 16 weeks | PFS | PFS at 16 weeks 86.7% in 26 pts | Diarrhea (18%); increase in GGT (18%); lymphopenia (18%) |
| (79) | Anlotinib 12 mg/day |
VEGFR 2-3 FGFR1-4 | Single-arm phase 2 study | Advanced or metastatic MTC | 58 | 9.8 months | PFS | PFS at 48 weeks 84.5% | Hand-foot syndrome (79.3%); hypertriglyceridemia (46.5%); elevated cholesterol levels (43.1%) |
| (80) | Anlotinib 12 mg/day |
VEGFR 2-3 FGFR1-4 | Multicenter, randomized, double-blind, placebo-controlled phase IIB trial (ALTER01031) |
Advanced or metastatic MTC | 62 (29) |
– | PFS | Median PFS: 20.67 months (anlotinib) vs 11.07 months (placebo) | Hand-foot syndrome; hypertension; hypertriglyceridemia |
AE, adverse events; FGFR, fibroblast growth factor receptor; MTC, medullary thyroid carcinoma; NET, neuroendocrine tumor; ORR, overall response rate; PFS, progression free survival; pts, patients; SSA, somatostatin analogs; VEGFR, Vascular Endothelial Growth Factor Receptor.
*data reported for the overall population (differentiated thyroid cancer and MTC).