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Fibroblast growth factor (FGFR) receptors 1–4 (FGFR1–FGFR4) kinase inhibitor (also binds: RET, CSF1R, PDGFRA, PDGFRB, FLT4 (VEGFR3), KIT, and VEGFR-2)
Erdafitinib is a kinase inhibitor with activity against FGFR receptors 1–4 (IC50 = 1.2, 2.5, 3, and 5.7 nM, respectively; Kd = 0.24–2.2 nM) and RET (Kd = 0.94 nM).108 At clinically relevant concentrations erdafitinib also binds CSF1R, PDGFRA, PDGFRB, FLT4 (VEGFR3), KIT, and VEGFR-2.38,108–110 Erdafitinib is the first agent to win FDA approval for an FGFR-dysregulated cancer, but in the U.S. it was preceded to market by four other multikinase inhibitors with activity against one or more FGFRs (lenvatinib [for thyroid cancer], nintedanib [for pulmonary fibrosis], pazopanib [for renal cell carcinoma and soft tissue sarcoma], regorafenib [for colorectal cancer, gastrointestinal stromal tumors, and hepatocellular carcinoma], and burosumab [an anti-FGF23 antibody, indicated for the treatment of X-linked hypophosphatemia]).
Urothelial carcinoma is the sixth most common cancer in the U.S.111 Historical treatment for patients with locally advanced or metastatic urothelial carcinoma has resulted in a low response rate (∼10%) and a typical survival of only 7–9 months.112 On the basis of an overall tumor response rate of 32.2% among 87 patients treated in a multicenter, open-label, single-arm trial (NCT02365597),108,113 orally administered erdafitinib received accelerated approval as a breakthrough therapy for locally advanced or metastatic urothelial carcinoma in patients with susceptible FGFR2 or FGFR3 genetic alterations114 (as determined by a companion diagnostic)27 and disease progression after platinum-based chemotherapy.38 Results comparing urothelial carcinoma survival rates associated with erdafitinib versus standard of care (NCT03390504)115 are expected in late 2020.111
FGFRs are nearly ubiquitous transmembrane tyrosine kinase receptors. FGFR inhibition is an area of intense pharmacological research, and as a result, FGFR gene alterations are well characterized in association with urothelial carcinoma and a variety of other cancers.108,109,114 FGFR signaling modulates multiple vital physiologic processes through RAS/RAF/MEK, PI3K–AKT, JAK–STAT, and other pathways.116–118 Aberrant FGFR signaling is found in association with a wide variety of both malignant and nonmalignant human diseases.111,117,119–121 In cancers, FGFR-mediated signaling plays a role in tumor cell growth, survival, migration, and angiogenesis.110,111,116,121 Through inhibition of FGFR-mediated phosphorylation and downstream intracellular signaling, erdafitinib exerts antiproliferative and antisurvival effects in FGFR overexpressing tumors and also causes potentially serious toxicities that are largely predictable from the pharmacology of FGFR inhibition of vital physiologic processes.108–110 Most notable among the latter is hyperphosphatemia due to inhibition of renal FGF23/klotho–mediated phosphate wasting in the renal tubules (occurred in 75.9% of study subjects and may be severe enough to require phosphate binders).38,108 Ocular toxicities, including central serous retinopathy and chorioretinopathy, keratitis, and other unwanted eye effects, require intermittent eye examinations, frequent patient monitoring, prophylactic use of ocular lubricants when indicated, and discontinuation of therapy when warranted.38,108,122 Other notable treatment-emergent side effects have included anorexia, asthenia, constipation, diarrhea, dry mouth, dry skin, elevated creatinine, elevated hepatic enzymes, fatigue, hyponatremia, onycholysis, palmar-plantar erythrodysaesthesia syndrome, paronychia, and stomatitis.108–110,114,120 Due to the potential for adverse developmental outcomes, erdafitinib should not be used by breastfeeding or pregnant women. A preclinical signal for the development of arrhythmias was detected but has not been clinically validated.108 In short, patients receiving erdafitinib must be closely monitored to maximize drug efficacy and minimize serious toxicities.119
Erdafitinib is administered orally and continued until disease progression or unacceptable toxicity occurs.38 Dosing is guided by serum phosphate measurements and patient tolerability. The recommended dose is 8 mg once daily for the first 14–21 days, and in the absence of toxicity, increased to 9 mg once daily thereafter in patients with serum phosphate levels <5.5 mg/dL.38 A schedule of dosing adjustments for treatment-emergent toxicities is provided in the product labeling.38 Erdafitinib is >99% protein bound, primarily to alpha-1-acid glycoprotein, and the mean effective half-life is 59 hours.38,108 Erdafitinib is primarily metabolized by CYP2C9 and CYP3A4 with excretion in feces (69%) and urine (19%).108 It is an inhibitor and inducer of CYP3A4, a substrate and inhibitor of P-gp, and an inhibitor of OCT2.38 Systemic exposure is predicted to be 50% higher in subjects with the CYP2C9*3/*3 genotype, and noteworthy drug-drug interactions should be anticipated with CYP2C9 and CYP3A4 inhibitors and inducers, CYP3A4 substrates, OCT2 substrates, P-gp substrates, and agents that alter serum phosphate levels.38 The chemical structure of erdafitinib is shown in Figure P1–2. Erdafitinib and more than 25 other FGF-related drug candidates (including small molecule inhibitors, FGFR antibodies, and FGF ligand traps) currently are in development.109,110,114,116,117,120,122–124 Potential mechanisms of tumor resistance to FGFR inhibitors have been described, and strategies to counter resistance, including combining FGFR and PD-1 inhibitors, are under investigation.118,121,125
Chapter 67. Pathway-Targeted Therapies: Monoclonal Antibodies, Protein Kinase Inhibitors, and Various Small Molecules
eChapter 2018: The Goodman & Gilman Year in Review New and Noteworthy FDA Approvals