Abstract

Fibroblast growth factor (FGF) and fibroblast growth factor receptor (FGFR) are important regulators of a variety of biologic functions, including cellular proliferation, differentiation, migration, angiogenesis, wound healing, and survival. The FGF protein family comprises 18 ligands that signal through four transmembrane tyrosine kinase receptors (FGFR1-4). A fifth receptor, FGFR5 (or FGFRL1), can bind FGF, but it lacks a tyrosine kinase domain. Dysregulation of FGFR has been implicated in the development of many neoplasms and can occur through a variety of mechanisms, including gain-of-function mutations with constitutive kinase activation, chromosomal translocations with ligand-independent signaling, altered splicing, and gene amplification, which leads to receptor overexpression. Abnormalities in FGF and the FGFR pathway have been associated with progression of a wide spectrum of malignancies including myeloma, breast, endometrial, genitourinary, and gastric cancers. For example, amplification of the 8p12 loci which codes FGFR1 is detected in approximately 10% of breast cancers, FGFR2-activating mutations and amplifications are seen in 12% of endometrial cancers, and FGFR3 mutations can be seen in approximately 12% of bladder cancers. In addition, FGFs have been implicated in tumor angiogenesis and may mediate drug resistance to both conventional chemotherapy and anti–vascular endothelial growth factor (VEGF) therapy. Initial efforts in targeting FGFRs with small-molecule tyrosine kinase inhibitors (TKIs) have been tempered by challenges in the drug development process, which illustrates the complexities of developing drugs that target uncommon genomic alterations in tumors, as well as poor tolerability mainly related to nonspecificity and off-target effects. Multiple pharmaceutical companies are at different stages of pursuing FGFR blockade, mostly using small-molecule TKIs, but other approaches using monoclonal anti-FGFR antibodies and FGF trapping molecules are also being investigated. Early trials involved nonselective multitargeted TKIs that exhibit only modest bioactivity against FGFR and have wide-spectrum off-target inhibition against other tyrosine kinases, including VEGF receptors (VEGFRs). For example, dovitinib (TKI258) showed activity against FGFR1-3, VEGFR1-3, PDGFR-B, FLT-3, KIT, RET, and CSF1R, and lucitanib (E3810) is a potent inhibitor of VEGFR1-3, FGFR1-2, and CSF1R. Other nonselective FGFR inhibitors have been investigated (eg, nintedanib [BIBF1120], ponatinib [AP24534], brivanib [BMS-582664], lenvatinib [E7080], ENMD-2076, and orantinib [TSU-68]) and although they have some bioactivity against FGFR, their toxicity profiles (eg, hypertension and proteinuria) have been largely related to VEGFR inhibition. More recently, selective potent FGFR TKIs (eg, JNJ42756493, BGJ398, AZD4547, LY287445, and TAS120) are being investigated with high in vitro kinase activity and specificity against FGFR1, FGFR2, and FGFR3 (enzymatic concentration that causes 50% inhibition [IC50], 10 nmol/L) in the hope of having a more tolerable safety profile by reducing off-target effects. Of interest, selective FGFR inhibitors cause blockade of FGF23 release from the bone, acting as an on-target effect in normal tissues. The resultant modulations of serum phosphate, FGF23, and vitamin D could potentially be used as biomarkers of effective FGFR inhibition. The multitude of companies investigating FGFR inhibition need to be put in context with the difficulties of identifying patients with FGFR aberrations. In an early trial of dovitinib, molecular screening failure rates were high, and of the 243 patients with breast cancer who had their tumor samples analyzed for FGFR1 aberrations, only 25 were eligible for the FGFR1 amplified cohort. Similarly, in a study by Helsten et al that used Clinical Laboratory Improvement Amendments–approved next generation sequencing, only 343 of 4,853 patients who underwent molecular screening carried FGFR aberrations, primarily amplifications and activating missense mutations. Given limited resources and patients, the early drug development pathway for uncommon molecular aberrations should be scrutinized to determine whether multiple competing first-generation compounds should even be developed or whether investigation of this pathway should move forward only when more selective and potent lead candidates with minimal offtarget effects are identified. Having multiple first-generation compounds that ultimately undergo attrition is an inefficient process for advancing targeted therapeutics. It is in this context that Tabernero et al reported the results of a phase I trial of the selective FGFR inhibitor JNJ-42756493 in patients with advanced solid tumors. JNJ-42756493 is a potent, oral, panFGFR inhibitor with IC50 values in the low nanomolar ranges against FGFR1-4 that exhibits minimal activity against other kinases, including VEGFR. Although the initial recommended phase II dose (RP2D) of single-agent JNJ-42756493 was 9 mg per day, the authors declared 10 mg administered on an intermittent schedule (7 days on/7 days off) as the ultimate RP2D on the basis of its more favorable toxicity profile and the attainment of biologic relevance via pharmacokinetic simulation of preclinical efficacy data. Although blood-based pharmacodynamic assessment (eg, hyperphosphatemia) supported their RP2D, these are not validated biomarkers of target inhibition in the tumor or JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 30 OCTOBER 2

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