Although FGFR pathway deregulation has been identified frequently in NSCLC, clinical activity of FGFR inhibitors has been considered disappointing and modest, at best, to date.
1as well as in driving carcinogenesis and maintenance, of the malignant phenotype viatumor proliferation.
Among human cancers,FGFRsare the most frequently mutated kinase genes and alterations in the FGFR pathway and are found in many cancers including lung cancer.2Although FGFR pathway deregulation has been identified frequently in NSCLC, (FGFR2mutations at 3%; FGFR1 amplification in SCC in 19%; and SCLCFGFR1amplification in 6%) clinical activity of FGFR inhibitors has been considered disappointing and modest, at best, to date.3
First-line FGFR Inhibitors
A review study published inJournal of Thoracic Oncologyfocuses on the role of EGFR pathway, specifically its role in lung cancer. The authors have systematically reviewed and analyzed the literature on FGFR, FGF, NSCLC, squamous cell lung cancer and therapeutics between 1990 and 2015, and have provided a comprehensive list of all FGFR inhibitors in clinical development and their targets.4
The first class of agents to be studied as FGFR inhibitors were multikinase compounds that had initially been developed to target vascular endothelial growth factor receptor (VEGFR). With the emergence of FGFR as an important target for cancer therapy, however, these agents were repositioned as FGFR inhibitors and studied for their FGFR-inhibitory activity. These agents include brivanib, cediranib, dovitinib, lucitanib, and nintedanib.5
A number of potent and specific second-generation inhibitors, listed below, have been introduced.
A selective inhibitor of FGFR1, FGFR2 and FGFR3 tyrosine kinases, AZD4547 has shown potent antitumor activity against FGFR-deregulated tumors in preclinical models.
Although AZD4547 did not meet its prespecified efficacy endpoint for overall response rate to warrant continuation in a phase IB open-label multicenter study of AZD4547 in 15 patients with advanced solid tumors, increase in serum phosphate indicated that AZD4547 at doses of 80 mg twice daily causes FGFR inhibition.6
A three-part phase I study of AZD4547 conducted in patients with advanced solid tumors determined a continuous tolerable dose to be 80 mg orally twice daily. Dose-limiting toxicities included elevated liver enzymes, stomatitis, renal failure, and hyperphosphatemia. In the dose expansion phase, 21 patients with FGFR1- or FGFR2-amplified tumors showed prolonged periods of disease stabilization (>24 weeks) in 4 patients. Studies on patients with squamous NSCLC and gastric cancer are ongoing.7,8
A potent inhibitor of FGFR1, FGFR2, and FGFR3, BGJ398 has shown single-agent activity in patients with FGFR aberrations. Preliminary efficacy data in a phase I study of BGJ398 in 94 patients with advanced solid tumors with FGFR genetic alterations showed tumor regression in 4 of 5 patients with urothelial cancer with FGFR3-activating mutations (tumor reductions ranging from 27%-48%) and a partial response in one patient with FGFR1-amplified squamous cell cancer. The maximum tolerated dose was 125 mg, with the most common adverse effects (AEs) being hyperphosphatemia (78%), stomatitis (37%), alopecia (32%), and decreased appetite (32%).9Three phase I studies and one phase II study of oral BGJ398 are currently recruiting patients with advanced solid tumors with alterations in FGFR.
Is a pan-FGFR inhibitor that has shown prolonged target inhibition in preclinical models with FGFR genetic aberrations. A multipart phase I study was conducted to evaluate the safety, efficacy, and antitumor activity of JNJ-42756493 in patients with advanced solid tumors with FGFR aberrations. Interim data on 28 patients treated at five dose levels (0.5, 2, 4, 6, and 9 mg daily continuously) revealed linear pharmacokinetics and a half-life of 50 to 60 hours. The most common AEs were hyperphosphatemia (57%), asthenia (46%), and dry mouth (32%).10
Is a potent small molecule pan-FGFR inhibitor that exhibits a 6- to 9-fold higher selectivityin vitroandin vivoinhibition of FGF than does VEGF-mediated targeted signaling in mice.11A total of 36 patients were treated with escalating doses (2-10 mg/d or 8-24 mg 2x/d) of LY2874455, in the phase I multicenter, nonrandomized, open-label, dose escalation study of oral LY2874455. The most common AEs were gastrointestinal side effects (3). Pharmacokinetic studies revealed that the plasma area under the curve increased 1.1- to 2.3-fold with twice daily administration, and the half-life was relatively short, with no evidence of drug accumulation from a single dose. The starting dose for the dose expansion cohort was selected as 16 mg orally twice daily.12
Is a soluble FGF receptor 1 Fc fusion protein that traps FGF ligands by means of high affinity binding, thereby preventing FGF-dependent angiogenesis and tumor growth. FP-1039 selectively blocks mitogenic FGFs (FGF1 through FGF10, FGF16 through FGF18, FGF20, and FGF22) without binding the hormonal FGFs (FGF19, FGF21, and FGF23), which require a membrane anchored coreceptor klotho for high-affinity binding and signaling. This limits the side-effect profile preventing development of hyperphosphatemia due to inhibition of FGF23. FP-1039 has been shown to inhibit tumor growth in preclinical models withFGFR1gene amplification13,14. A multiarm, nonrandomized, open label phase IB study is currently recruiting patients to evaluate the safety and preliminary efficacy of FP-1039. The study plan calls for administering FP-1039 as a 30-minute intravenous infusion once a week in a 21-day cycle. The starting dose will be 5 mg/kg and will be escalated until the maximum tolerated dose or maximum feasible dose in combination with chemotherapy is achieved.15
While inhibiters of EGFR tyrosine kinase, ALK and ROS yield response rates in range of 40% or more in lung cancer patients, the response rates to FGFR inhibitors is very low. The authors attribute the low response rates to the low frequency of activating mutations in theFGFRgene in NSCLC. They also attribute the nonuniform degrees of gene amplification among the clinical trials patient populations as the underlying second cause for poor response rates.