Efficacy of TAS-120, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in cholangiocarcinoma patients with FGFR pathway alterations who were previously treated with chemotherapy and other FGFR inhibitors

Introduction: TAS-120, an oral and highly selective, irreversible FGFR1-4 tyrosine kinase inhibitor, has demonstrated inhibition of cancer cell growth in human xenografts of tumors bearing FGFR aberrations. TAS-120 inhibited mutant and wild-type FGFR2 with similar IC50 (wild-type FGFR2, 0.9 nM; V5651, 1-3 nM; N550H, 3.6 nM; E566G, 2.4 nM) and has shown efficacy in cell lines with acquired resistance to FGFR inhibitors. In this Phase I study in patients with advanced solid tumors, TAS-120 was evaluated at 8-24 mg once daily (QD). 20 mg QD was determined as the maximum tolerated dose/recommended Phase II dose, while 24 mg QD had dose-limiting toxicity. Here we report results from cholangiocarcinoma (CCA) patients enrolled in this Phase I study. Methods: Adult patients (≥18 years) with CCA who were treated at 16, 20, and 24 mg QD continuously during the Phase I dose-escalation and expansion phases were included. FGF/FGFR status was evaluated by local institutions or at a commercial laboratory. Patients were treated with TAS-120 until disease progression or unacceptable toxicity. Safety was assessed using CTCAE version 4.03. Tumor response was evaluated by local radiologists using RECIST version 1.1. Results: Forty-five patients with CCA (intra-hepatic n = 41) harboring FGF/FGFR aberrations were treated at 16 mg (n = 24), 20 mg (n = 14), and 24 mg (n = 7) QD. Median age was 53 years (range 29-73), 76% were female, 58% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1, and 42% had an ECOG PS of 0. Twenty-eight patients (62%) had FGFR2 gene fusions and 17 (38%) had other FGF/FGFR aberrations, e.g. mutations, amplifications, and re-arrangements. All patients had received prior systemic therapies and 13 had received at least one prior reversible FGFR inhibitor. Of 28 patients with FGFR2 gene fusions, 20 (71%) experienced tumor shrinkage and seven achieved confirmed partial response (cPR). The objective response rate was 25%. Of the seven responders, six remain on treatment, including one patient with an ongoing cPR of > 1 year. Of 28 patients, 15 patients (54%) experienced stable disease as their best response, with seven still on treatment. The overall disease control rate was 79%. Of 17 patients with other FGF/FGFR aberrations, three had cPR (two with FGFR2 re-arrangement and one with co-expression of FGFR2 re-arrangement and amplification). Median time on treatment was 7.4 months and ongoing. Of the 13 patients who had received prior FGFR inhibitors, four (three with FGFR2 gene fusions and one with FGFR2 amplification) had cPR on TAS-120. The most common treatment-related adverse events (AEs) of all grades in 45 CCA patients were hyperphosphatemia (78%), increased aspartate aminotransferase (29%), dry skin (29%), diarrhea (27%), and dry mouth (27%). Grade ≥3 treatment-related AEs were reported in 23 out of 45 patients (51%); the most common was hyperphosphatemia in 10 patients (22%). Conclusion: TAS-120 demonstrated compelling clinical activity and a manageable AE profile in CCA patients with FGFR2 gene fusions and showed efficacy in patients who progressed on prior FGFR inhibitors. A Phase II study of TAS-120 in CCA patients with FGFR2 gene fusions has been initiated.