Abstract CT111: Preliminary results from a phase 1/2 study of INCB054828, a highly selective fibroblast growth factor receptor (FGFR) inhibitor, in patients with advanced malignancies
Authors: Saleh Mansoor , Gutierrez Martin E. , Subbiah Vivek , Smith David C. , Asatiani Ekaterine , Lihou Christine F. , Zhen Huiling , Yeleswaram Swamy , Ji Tao , Nemunaitis John 
Published: July 2017

Abstract
Background: FGFR inhibitors are effective against malignancies with FGFR pathway activation. INCB054828 is a selective FGFR1, 2, and 3 inhibitor (AACR 2015; Abstract 771). This phase 1/2 study evaluated INCB054828 alone or combined with other agents for refractory advanced malignancies; preliminary safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of INCB054828 alone are reported.
Methods: In this open-label, 3-part study (NCT02393248), eligible adults had advanced solid tumors (parts 1 and 3) or tumors with FGF/FGFR alteration (part 2), Eastern Cooperative Oncology Group performance status ≤1 (part 1) or ≤2 (parts 2 and 3), were refractory to prior therapy, and had no further effective standard therapy available to them. Patients received INCB054828 orally QD on a 21-day cycle (2-weeks on/1-week off). In part 1 (dose escalation), the first 3 cohorts (1-4 mg QD) evaluated single patients and subsequently a 3+3 design was used (6-20 mg QD). In part 2 (dose expansion), patients with FGFR activation started on 9 mg QD and increased to 13.5 mg QD; this regimen was also used in combination with standard therapies in part 3 (dose-finding and expansion).
Results: As of the data cutoff (October 12, 2016), 22 and 17 patients were enrolled in parts 1 and 2, respectively. In part 1, one DLT (grade 3 mucositis) was observed at 20 mg. MTD was not reached; the recommended phase 2 dose (RP2D) was 13.5 mg QD. Among all 39 patients in parts 1 and 2 (median age, 57 [range, 21-77] years; men, 46%), 28 (72%) discontinued therapy, mainly due to disease progression (46%). Most frequent all-cause, all-grade treatment-emergent adverse events (TEAEs) were hyperphosphatemia (51%; all at doses ≥6 mg), fatigue (49%), dry mouth (28%), alopecia (23%), and stomatitis (21%); most frequent grade ≥3 TEAEs were pneumonia (10%), fatigue (8%), and hyponatremia (8%). Hyperphosphatemia was managed with phosphate binders, diet and/or dose interruption. In part 2 (FGFR pathway activation), most common tumors were cholangiocarcinoma (CCA; n=4), esophageal (n=3), and breast (n=3). In part 2, 1 patient with FGFR1-activated myeloproliferative neoplasm had complete cytogenetic response (9 mg QD; duration of response, 3.5 mo); 1 patient with CCA and FGFR2-CCDC6 translocation had partial response (PR: 9 mg QD; ongoing at cutoff). Terminal half-life was approximately 15 h; pFGFR2 was inhibited by 64% and 82% from baseline at steady-state trough after 9 and 13.5 mg QD, respectively.
Conclusions: INCB054828 was generally well tolerated; hyperphosphatemia was the most common TEAE. Preliminary efficacy in patients with FGFR pathway activation was also observed. PK/PD data support once-daily dosing and sustained inhibition of FGFR signaling at doses &gt;9 mg. Enrollment in parts 2 and 3 is ongoing; updated data will be presented.
Citation Format: Mansoor Saleh, Martin E. Gutierrez, Vivek Subbiah, David C. Smith, Ekaterine Asatiani, Christine F. Lihou, Huiling Zhen, Swamy Yeleswaram, Tao Ji, John Nemunaitis. Preliminary results from a phase 1/2 study of INCB054828, a highly selective fibroblast growth factor receptor (FGFR) inhibitor, in patients with advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT111. doi:10.1158/1538-7445.AM2017-CT111