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Oncogenesis and Metastasis
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Tyrosine kinases: subgroup (family) of protein kinases.Alterations can upregulate growth factor pathway activities → promote tumorigenesis.Examples: FGFR3 (Fibroblast Growth Factor Receptor 3) is upregulated and/or mutated in bladder cancer, while Pan-FGFR inhibitor (FDA approved Erdafitinib) is used to treat advanced bladder cancer.
Bladder Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Approximately 15–20% of patients with metastatic urothelial cancer harbor mutations of amplifications in FGFR2 or FGFR3. A molecularly targeted phase II study of the FGFR2/3 inhibitor, erdafitinib, has reported a 40% ORR and median duration of overall survival of 13.8 months in mutation carriers and has now entered phase III testing.128
Optimizing outcomes and managing adverse events in locally advanced or metastatic urothelial cancer: a clinical pharmacology perspective
Published in Expert Review of Clinical Pharmacology, 2023
Pratap Singh, Anand Rotte, Anthony A. Golsorkhi, Sandhya Girish
Erdafitinib was evaluated in mUC patients with FGFR alterations and who had a history of disease progression while receiving or after at least 1 course of chemotherapy or within 12 months after neoadjuvant or adjuvant chemotherapy, in an open-label, multicenter, phase-2 trial. The study reported that the rate of confirmed response was 40% including a complete response of 3% and partial response of 37%. Median PFS in the patients was 5.5 months and median OS was 13.8 months [76]. The most common adverse events (seen in ≥ 20% patients) in patients receiving erdafitinib include stomatitis, fatigue, creatinine increased, diarrhea, dry mouth, onycholysis, dysgeusia, dry skin, dry eye, alopecia, palmar-plantar erythrodysesthesia syndrome, constipation, abdominal pain, calcium increased, decreased appetite, nausea, and musculoskeletal pain. Common laboratory abnormalities reported with erdafitinib treatment include elevated phosphate, alanine aminotransferase, alkaline phosphatase, and aspartate aminotransferase, and decreased sodium, magnesium, phosphate, albumin, and hemoglobin [summarized from erdafitinib package insert].
Metabolism and disposition in rats, dogs, and humans of erdafitinib, an orally administered potent pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor
Published in Xenobiotica, 2021
Ellen Scheers, Carine Borgmans, Chi Keung, Hilde Bohets, Inneke Wynant, Italo Poggesi, Filip Cuyckens, Laurent Leclercq, Rao N. V. S. Mamidi
Erdafitinib has demonstrated potent inhibition of cell proliferation with IC50 values ranging from 0.06 nM to 75 nM in FGFR pathway-activated cancer cell lines including squamous non-small cell lung, gastric, breast, endometrial, bladder, and hepatocellular cancer, multiple myeloma, and acute myeloid leukaemia (Dieci et al., 2013; Hallinan et al., 2016; Perera et al., 2017; Tabernero et al., 2015; Verstraete et al., 2015). In human tumour cell lines, erdafitinib demonstrated greater than 50-fold selectivity for FGFR over vascular endothelial growth factor receptor when compared to first-generation FGFR inhibitors and thus can be useful for determining the dependency of FGFR-driven oncogenic pathways and may reduce the risk of off-target adverse events (Karkera et al., 2017; Perera et al., 2017).
An evaluation of the efficacy and safety of erdafitinib for the treatment of bladder cancer
Published in Expert Opinion on Pharmacotherapy, 2020
Jones T. Nauseef, Dario M. Villamar, Justin Lebenthal, Panagiotis J. Vlachostergios, Scott T. Tagawa
As the first oral therapy for metastatic urothelial carcinoma, and the first with molecular selection, FDA approval of erdafitinib represents notable progress forward in targeted therapy in urothelial cancer. The approval of erdafitinib comes after a protracted interval with few advances in the development of targeted agents for UC. Although FGFR activating events, including mutations, amplifications, and fusions are well described in UC as important oncogenic drivers [11,12], early studies failed to show a clinical benefit either due to lack of patient selection, reliable targeting, or/and use of less potent inhibitors [19]. Thus, erdafitinib marks a new era of biomarker-driven drug discovery in UC, in which targeted DNA sequencing plays a key role. To wit, FDA approval was granted concurrently to the therascreen FGFR RGQ RT-PCR kit developed by Qiagen as a companion diagnostic test [40], though it is likely that any CLIA approved test would suffice for patient selection. Beyond the significance of the availability of a new treatment modality for a historically difficult to treat disease, promise lies in additional mechanisms of disease treatment suggested in the data.