Milea Timbergen

40 DTF patients studied the effect of sunitinib (Table 2). George et al. did not detect a response to sunitinib in the single DTF patient that was included in their study 85 . In contrast, a study by Jo et al. showed a 2-year PFS of 75% in nineteen patients with advanced DTF 86 . A phase 1 study, investigating the use of sorafenib in paediatric solid malignancies, of which two patients had DTF, showed a partial response on sorafenib in one patient 87 . Recently published results from the phase 3 clinical trial (NCT02066181; sorafenib versus placebo for advanced and refractory DTF) showed a 2-year PFS rate of 81% (95% confidence interval [CI] 69-96) with an objective response rate (ORR) of 33% (95% CI, 20-48) in the sorafenib group versus 2-year PFS of 36% (95% CI, 22-57) and an ORR of 20% (95% CI, 8-38) in the placebo group 88 . The biological mechanisms underlying the activity of sorafenib in DTF remain unclear because sorafenib targets multiple tyrosine kinases thereby affecting multiple pathways. The use of imatinib, sunitinib and sorafenib, led to study the tyrosine kinase inhibitor (TKI) pazopanib in the setting of DTF. Pazopanib targets the VEGFR1-3, PDGFR-ɑ and PDGFR-ß, amongst others. A retrospective study by Szucs et al., described a partial response in three out of eight patients with DTF and stable disease in five out of eight patients with a median PFS of 13.5 months 128 . Another retrospective study in adolescents and young adults with DTF by Agresta et al. reported tumour reduction after pazopanib use with only mild toxicities (Table 2) 129 . One clinical trial is currently ongoing to investigate TKIs in the setting of DTF: pazopanib (NCT01876082, phase 2 study) (Table 3) 130 . Table 3. Overview of ongoing clinical trials with targeted drugs in DTF Drug Ref. NCT number Setting Current status PI3 kinase/AKT/ mTOR signalling pathway Receptor Tyrosin Kinase inhibitor Imatinib + vactosertib 131 NCT03802084 Phase 1/2 clinical trial Not yet recruiting mTOR inhibitor Sirolimus 132 NCT01265030 Phase 1 clinical trial Phase 2 clinical trial (children and young adults) Recruiting Notch signalling pathway Notch inhibitor PF-03084014 133 NCT01981551 Phase 2 clinical trial Active, not recruiting 134 NCT03785964 Phase 3 clinical trial Not yet recruiting Growth regulatory signalling pathway PDGF-ɑ /PDGF-ß /VEGFR Pazopanib 130 NCT01876082 Phase 2 clinical trial Recruiting NCT, national clinical trial 2