Multicenter Phase I Study of Erdafitinib (JNJ-42756493), Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients with Advanced or Refractory Solid Tumors

Abstract

Purpose: Here, we report results of the first phase I study of erdafitinib, a potent, oral pan-FGFR inhibitor. Patients and Methods: Patients age !18 years with advanced solid tumors for which standard antineoplastic therapy was no longer effective were enrolled (NCT01703481). Parts 2 to 4 employed molecular screening for activating FGFR genomic alterations. In patients with such alterations, two selected doses/schedules identified during part 1 doseescalation [9 mg once daily and 10 mg intermittently (7 days on/7 days off), as previously published (Tabernero JCO 2015;33:3401-8)] were tested. Results: The study included 187 patients. The most common treatment-related adverse events were hyperphosphatemia (64%), dry mouth (42%), and asthenia (28%), generally grade 1/2 severity. All cases of hyperphosphatemia were grade 1/2 except for 1 grade 3 event. Skin, nail, and eye changes were observed in 43%, 33%, and 28% of patients, respectively (mostly grade 1/2 and reversible after temporary dosing interruption). Urothelial carcinoma and cholangiocarcinoma were most responsive to erdafitinib, with objective response rates (ORR) of 46.2% (12/26) and 27.3% (3/11), respectively, in response-evaluable patients with FGFR mutations or fusions. All patients with urothelial carcinoma and cholangiocarcinoma who responded to erdafitinib carried FGFR mutations or fusions. Median response duration was 5.6 months for urothelial carcinoma and 11.4 months for cholangiocarcinoma. ORRs in other tumor types were <10%. Conclusions: Erdafitinib shows tolerability and preliminary clinical activity in advanced solid tumors with genomic changes in the FGFR pathway, at two different dosing schedules and with particularly encouraging responses in urothelial carcinoma and cholangiocarcinoma.

Molecular targeted therapies: Ready for “prime time” in biliary tract cancer

“…129,130,133,142 Many FGFR inhibitors are currently being developed, most of which have already shown adequate safety in phase I trials and early efficacy in phase II studies in patients with refractory iCCA (Table 1). 139,140,[145][146][147][148][149][150][151][152][153][154] Activated FGFR FGF P JAK-STAT…”

“…Data extracted from. 139,140,[145][146][147][148][149][150][151][152][153][154] IC50 data also extracted from. 162 AEs, adverse events; CCA, cholangiocarcinoma; CR, complete response; DCR, disease control rate; FGFR, fibroblast growth factor receptor; GBC, gallbladder cancer; IC50, half maximal inhibitory concentration; iCCA, intrahepatic cholangiocarcinoma; LFTs, liver function tests; mDOR, median duration of response; mPFS, median progression-free survival; PDGFR, platelet-derived growth factor receptor; PR, partial response; ORR, objective response rate; TEAEs, treatment-emergent adverse events; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor.…”

“…152 @ Updated data CCA cohort. 154 Multiple phase I/II clinical trials have reported a consistently high partial response rate (varying between 20.7% and 35.5%) for heavily pretreated patients with iCCA harbouring an FGFR2 fusion, [145][146][147][148][149][150][152][153][154] with a median PFS of around 6 months. 139,[145][146][147]150,154 For the majority of compounds under development, responses have been homogeneously absent for patients with other FGFR aberrations.…”

“…139,[145][146][147]150,154 For the majority of compounds under development, responses have been homogeneously absent for patients with other FGFR aberrations. 139,140,145,146,151,153,154 Together with the development of FGFR inhibitors and their assessment in the clinic, research is happening in parallel to understand mechanisms of resistance to these compounds and potential ways to overcome them. Goyal and colleagues reported the first evidence of acquired resistance to FGFR inhibition in CCA.…”

Detection of Fusion Genes Using a Targeted RNA Sequencing Panel in Gastrointestinal and Rare Cancers

“…FGFR fusions with multiple partners have been described in numerous cancer types. After the rst report of FGFR3-TACC3 fusion in glioblastoma, these fusions were [20,21]. RET fusions have been described in up to one-third of papillary thyroid cancers and in 2% of lung adenocarcinoma cases; CCDC6-RET and NCOA4-RET are the most commonly identified RET fusions [22,23].…”