R Bahleda1, F Meric-Bernstam2, L Goyal3, B Tran4, Y He5, I Yamamiya5, K A Benhadji5, I Matos6, H-T Arkenau7. 1. Early Drug Development Department (DITEP), Gustave Roussy Cancer Center, Villejuif, France. Electronic address: rastilav.bahleda@gustaveroussy.fr. 2. Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, USA. 3. Department of Medical Oncology, Massachusetts General Hospital Cancer Center, Boston, USA. 4. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia. 5. Taiho Oncology, Inc., Princeton, USA. 6. Department of Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. 7. Medical Oncology, Sarah Cannon Research Institute and Cancer Institute University College London, London, UK.
Abstract
BACKGROUND: Futibatinib is an oral, irreversible, highly selective fibroblast growth factor receptor (FGFR)1-4 inhibitor with potent preclinical activity against tumors harboring FGFR aberrations. This first-in-human, phase I dose-escalation trial (NCT02052778) evaluates the safety and pharmacokinetics/pharmacodynamics of futibatinib in advanced solid tumors. PATIENTS AND METHODS: Following a standard 3+3 dose-escalation design, eligible patients with advanced solid tumors refractory to standard therapies received 8-200 mg futibatinib three times a week (t.i.w.) or 4-24 mg once daily (q.d.). RESULTS: A total of 86 patients were enrolled in the nine t.i.w. (n = 42) and five q.d. cohorts (n = 44); 71 patients (83%) had tumors harboring FGF/FGFR aberrations. Three of nine patients in the 24-mg q.d. cohort experienced dose-limiting toxicities, including grade 3 increases in alanine transaminase, aspartate transaminase, and blood bilirubin (n = 1 each). The maximum tolerated dose (MTD) was determined to be 20 mg q.d.; no MTD was defined for the t.i.w. schedule. Across cohorts (n = 86), the most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (59%), diarrhea (37%), and constipation (34%); 48% experienced grade 3 TEAEs. TEAEs led to dose interruptions, dose reductions, and treatment discontinuations in 55%, 14%, and 3% of patients, respectively. Pharmacokinetics were dose proportional across all q.d. doses but not all t.i.w. doses evaluated, with saturation observed between 80 and 200 mg t.i.w. Serum phosphorus increased dose dependently with futibatinib on both schedules, but a stronger exposure-response relationship was observed with q.d. dosing, supporting 20 mg q.d. as the recommended phase II dose (RP2D). Overall, partial responses were observed in five patients [FGFR2 fusion-positive intrahepatic cholangiocarcinoma (n = 3) and FGFR1-mutant primary brain tumor (n = 2)], and stable disease in 41 (48%). CONCLUSIONS: Futibatinib treatment resulted in manageable safety, pharmacodynamic activity, and preliminary responses in patients with advanced solid tumors. The results of this phase I dose-escalation trial support 20 mg q.d. futibatinib as the RP2D. CLINICAL TRIAL REGISTRATION: FOENIX-101 (ClinicalTrials.gov, NCT02052778).
BACKGROUND:Futibatinib is an oral, irreversible, highly selective fibroblast growth factor receptor (FGFR)1-4 inhibitor with potent preclinical activity against tumors harboring FGFR aberrations. This first-in-human, phase I dose-escalation trial (NCT02052778) evaluates the safety and pharmacokinetics/pharmacodynamics of futibatinib in advanced solid tumors. PATIENTS AND METHODS: Following a standard 3+3 dose-escalation design, eligible patients with advanced solid tumors refractory to standard therapies received 8-200 mg futibatinib three times a week (t.i.w.) or 4-24 mg once daily (q.d.). RESULTS: A total of 86 patients were enrolled in the nine t.i.w. (n = 42) and five q.d. cohorts (n = 44); 71 patients (83%) had tumors harboring FGF/FGFR aberrations. Three of nine patients in the 24-mg q.d. cohort experienced dose-limiting toxicities, including grade 3 increases in alanine transaminase, aspartate transaminase, and blood bilirubin (n = 1 each). The maximum tolerated dose (MTD) was determined to be 20 mg q.d.; no MTD was defined for the t.i.w. schedule. Across cohorts (n = 86), the most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (59%), diarrhea (37%), and constipation (34%); 48% experienced grade 3 TEAEs. TEAEs led to dose interruptions, dose reductions, and treatment discontinuations in 55%, 14%, and 3% of patients, respectively. Pharmacokinetics were dose proportional across all q.d. doses but not all t.i.w. doses evaluated, with saturation observed between 80 and 200 mg t.i.w. Serum phosphorus increased dose dependently with futibatinib on both schedules, but a stronger exposure-response relationship was observed with q.d. dosing, supporting 20 mg q.d. as the recommended phase II dose (RP2D). Overall, partial responses were observed in five patients [FGFR2 fusion-positive intrahepatic cholangiocarcinoma (n = 3) and FGFR1-mutant primary brain tumor (n = 2)], and stable disease in 41 (48%). CONCLUSIONS:Futibatinib treatment resulted in manageable safety, pharmacodynamic activity, and preliminary responses in patients with advanced solid tumors. The results of this phase I dose-escalation trial support 20 mg q.d. futibatinib as the RP2D. CLINICAL TRIAL REGISTRATION: FOENIX-101 (ClinicalTrials.gov, NCT02052778).
Authors: Qibiao Wu; Yuanli Zhen; Lei Shi; Phuong Vu; Patricia Greninger; Ramzi Adil; Joshua Merritt; Regina Egan; Meng-Ju Wu; Xunqin Yin; Cristina R Ferrone; Vikram Deshpande; Islam Baiev; Christopher J Pinto; Daniel E McLoughlin; Charlotte S Walmsley; James R Stone; John D Gordan; Andrew X Zhu; Dejan Juric; Lipika Goyal; Cyril H Benes; Nabeel Bardeesy Journal: Cancer Discov Date: 2022-05-02 Impact factor: 38.272
Authors: Sameer Farouk Sait; Stephen W Gilheeney; Tejus A Bale; Sofia Haque; Marc J Dinkin; Stephanie Vitolano; Marc K Rosenblum; Katarzyna Ibanez; Daniel E Prince; Krisoula H Spatz; Ira J Dunkel; Matthias A Karajannis Journal: JCO Precis Oncol Date: 2021-05-20
Authors: Jose J G Marin; Paula Sanchon-Sanchez; Candela Cives-Losada; Sofía Del Carmen; Jesús M González-Santiago; Maria J Monte; Rocio I R Macias Journal: Cancers (Basel) Date: 2021-05-13 Impact factor: 6.639
Authors: Julie Bolcaen; Shankari Nair; Cathryn H S Driver; Tebatso M G Boshomane; Thomas Ebenhan; Charlot Vandevoorde Journal: Pharmaceuticals (Basel) Date: 2021-06-29