Fibroblast Growth Factor Receptor Genetic Alterations Research Articles

Abstract 2533: Design and preclinical profile of CH5183284/Debio 1347, a novel orally available and selective FGFR inhibitor acting on a gatekeeper mutant of FGFR2

Abstract The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases (RTKs) comprises four members (FGFR1-4). FGFRs regulate multiple biological processes, such as cell proliferation, migration, apoptosis, and differentiation. Various genetic alterations, as well as overexpression, drive activation of both kinase activity of the receptors and the pathway signaling, which is associated with tumor growth and survival. Therefore, the FGFR family represents an attractive therapeutic target for treating cancer. Here, we report the discovery and the pharmacological profiles of CH5183284/Debio 1347, an orally available and selective inhibitor of FGFR1, 2, and 3. The lead compound CH5183284/Debio 1347 was identified from our original compound library by a high throughput screening program. Chemical modifications, which were guided by 3D-modeling analyses of the lead series and FGFRs, led to identifying an inhibitor that is selective to FGFR1, FGFR2, and FGFR3 (IC50: 9.3 nM, 7.6 nM, and 22 nM), but does not effectively inhibit FGFR4 (IC50: 290 nM), KDR (IC50: 2,100 nM) nor other 34 kinases. To evaluate kinase selectivity further, we used a KINOMEscan panel consisting of 442 kinases including some mutated forms of kinases. At 100 nM, CH5183284/Debio 1347 only bound to 5 kinases in the panel including FGFR1, FGFR2, and FGFR3 (over 80% inhibition to an ATP analog binding). An X-ray crystal structure analysis showed CH5183284/Debio 1347 binding to the ATP-binding site of FGFR1 in DFG-in mode and its interaction with both the hinge region and the backpocket of the protein. CH5183284/Debio 1347 also showed antitumor activity against cancer cell lines harboring genetic alterations in FGFRs in vitro and in xenograft models in mice. In addition, the unique ability of CH5183284/Debio 1347 to inhibit a relevant FGFR2 gatekeeper mutant (V564F) was documented in cellular phosphorylation assays, in vitro cell proliferation assays, and in vivo efficacy studies in a xenograft mouse model. The X-ray crystal structure analysis and modeling studies of the inhibitors, including NVP-BGJ398 and AZD4547, with FGFRs that were used to guide the SAR strategy in the optimization program will be presented and discussed, together with the unique susceptibility of CH5183284/Debio 1347 against a gatekeeper mutant of FGFR2. These findings underline the therapeutic potential of CH5183284/Debio 1347 in patients with FGFR genetic alterations and are the basis for an ongoing early clinical trial in several cancer types. Citation Format: Hirosato Ebiike, Naoki Taka, Yoshito Nakanishi, Nukinori Akiyama, Fumie Sawamura, Kenji Morikami, Masayuki Matsushita, Masayuki Ohmori, Kyouko Takami, Ikumi Hyohdoh, Masami Kohchi, Tadakatsu Hayase, Hiroki Nishii, Nobuya Ishii, Hiroharu Matsuoka. Design and preclinical profile of CH5183284/Debio 1347, a novel orally available and selective FGFR inhibitor acting on a gatekeeper mutant of FGFR2. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2533. doi:10.1158/1538-7445.AM2014-2533

Abstract CT326: Phase I study of BGJ398, a selective pan-FGFR inhibitor in genetically preselected advanced solid tumors

Abstract Background: Fibroblast growth factor receptors (FGFRs) play a role in cell proliferation and survival. Genetic alterations of FGFRs can lead to deregulated activation in various cancers, including squamous cell carcinoma (SCC) of the lung and urothelial bladder cancer. Here, we report on a phase I study of BGJ398 a potent, selective pan-FGFR inhibitor. Methods: Eligible patients (pts; ≥ 18 years of age) had tumors with any FGFR genetic alteration identified by central or local prescreening. Pts received BGJ398 once or twice daily (qd or bid) in 28-day cycles in escalating cohorts. Dose-limiting toxicities (DLTs) were predefined and included both severe events and those resulting in significant dosing delays. Upon determination of maximum tolerated dose (MTD), 3 expansion arms were treated: arm 1 included FGFR1-amplified SCC of the lung (continuous qd dosing); arms 2 and 3 included FGFR-altered solid tumors given qd continuous doses (arm 2) or qd doses on a 3-weeks-on/1-week-off schedule (arm 3). Results: As of September 24, 2013, 94 pts were enrolled (median age 57.5 years). Pts were treated in qd dose cohorts (5-150 mg; n = 90) or a bid dose cohort (50 mg; n = 4). Arms 1 and 3 are ongoing. Of the 82 pts who discontinued, the most common reasons were disease progression (n = 56), consent withdrawal (n = 12), and adverse events (AEs; n = 10). DLTs during dose escalation were grade 3 aminotransferase increases (1 each at 100 and 125 mg), hyperphosphatemia (125 mg), and grade 1 corneal toxicity (150 mg). The 125-mg qd dose was identified as the MTD. Common treatment-emergent AEs (any grade, suspected to be related) at 125 mg qd (n = 41) include hyperphosphatemia (78%), stomatitis (37%), alopecia (32%), decreased appetite (32%), and fatigue (22%) and were generally mild, with stomatitis (7%) the only grade 3/4 AE occurring ≥ 5%. Elevated serum phosphate levels, a pharmacodynamic marker of FGFR pathway inhibition, could be managed through diet, phosphate lowering therapy, and drug interruptions. Preliminary analysis of efficacy data indicates tumor regressions in pts with various FGFR genetic alterations, including 4 of 5 pts with urothelial cell carcinomas (4 of which originated in the bladder) with FGFR3-activating mutations (with tumor reductions ranging from 27% to 48%). Additionally, 1 pt with FGFR1-amplified SCC lung cancer achieved confirmed partial response (PR) while another pt achieved a PR confirmed after 27 days. Tumor reductions were also observed in cholangiocarcinoma with an FGFR2 gene fusion, and FGFR1-amplified breast cancer. Conclusions: BGJ398 had a tolerable safety profile and demonstrated single-agent activity in pts with FGFR-genetically altered solid tumors. The 3-weeks-on/1-week-off schedule has been chosen for future studies based on its improved safety profile. Clinical activity was observed in multiple tumor types, and pts with FGFR3-mutated bladder cancer may be especially sensitive to BGJ398. Citation Format: Lecia V. Sequist, Phillippe Cassier, Andrea Varga, Josep Tabernero, Jan HM Schellens, Jean-Pierre Delord, Patricia LoRusso, D. Ross Camidge, Manuel Hidalgo Medina, Martin Schuler, Mario Campone, G. Gary Tian, Steven Wong, Jesus Corral, Randi Isaacs, Suman K. Sen, Diana Graus Porta, Swarupa G. Kulkarni, Caroline Lefebvre, Jürgen Wolf. Phase I study of BGJ398, a selective pan-FGFR inhibitor in genetically preselected advanced solid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT326. doi:10.1158/1538-7445.AM2014-CT326

FGFR Genetic Alterations Predict for Sensitivity to NVP-BGJ398, a Selective Pan-FGFR Inhibitor

Patient stratification biomarkers that enable the translation of cancer genetic knowledge into clinical use are essential for the successful and rapid development of emerging targeted anticancer therapeutics. Here, we describe the identification of patient stratification biomarkers for NVP-BGJ398, a novel and selective fibroblast growth factor receptor (FGFR) inhibitor. By intersecting genome-wide gene expression and genomic alteration data with cell line-sensitivity data across an annotated collection of cancer cell lines called the Cancer Cell Line Encyclopedia, we show that genetic alterations for FGFR family members predict for sensitivity to NVP-BGJ398. For the first time, we report oncogenic FGFR1 amplification in osteosarcoma as a potential patient selection biomarker. Furthermore, we show that cancer cell lines harboring FGF19 copy number gain at the 11q13 amplicon are sensitive to NVP-BGJ398 only when concomitant expression of β-klotho occurs. Thus, our findings provide the rationale for the clinical development of FGFR inhibitors in selected patients with cancer harboring tumors with the identified predictors of sensitivity. The success of a personalized medicine approach using targeted therapies ultimately depends on being able to identify the patients who will benefit the most from any given drug. To this end, we have integrated the molecular profiles for more than 500 cancer cell lines with sensitivity data for the novel anticancer drug NVP-BGJ398 and showed that FGFR genetic alterations are the most significant predictors for sensitivity. This work has ultimately endorsed the incorporation of specific patient selection biomakers in the clinical trials for NVP-BGJ398.

Abstract C193: FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a novel orally bioavailable, selective, and potent FGFR inhibitor.

Abstract The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases (RTK) consists of FGFR1, FGFR2, FGFR3 and FGFR4, which are the high affinity receptors for 22 different FGF ligands. These ligand-receptor combinations elicit a broad spectrum of biological activities during development and in adult tissue homeostasis. In contrast, de-regulated FGF signaling has been linked to diseases, most prominently in the pathogenesis of multiple cancers. Epidemiological and molecular studies have revealed a variety of genetic alterations in components of the FGF/FGFR signaling system which result in aberrant receptor activation and thus, enhanced downstream signaling. Hence, on this basis, targeted inhibition of FGFRs can be exploited for therapeutic intervention. In this report we disclose NVP-BGJ398, a novel orally bioavailable, selective and potent kinase inhibitor of the FGFRs currently in Phase I clinical trials. We further describe the identification of patient stratification biomarkers for NVP-BGJ398 by intersecting genome-wide gene expression data with genomic alterations and cell line sensitivity data across an annotated collection of cancer cell lines termed “Cancer Cell Line Encyclopedia”. We show that genetic alterations for selected FGF/FGFR family members predict for sensitivity to NVP-BGJ398 in specific cancer types, thus providing the rationale for clinical trials in well defined subpopulations of cancer patients based upon the presence of these molecular abnormalities. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C193.