erdafitinib
Regulatory sources consulted
Approved indications
- In adults with locally advanced or metastatic urothelial carcinoma with susceptible FGFR3 genetic alterations whose disease progressed during or after at least one prior systemic therapy. Select using an FDA-approved companion diagnostic. It is not recommended for patients eligible for a PD-1 or PD-L1 inhibitor who have not yet received one.
Clinical warnings
- Major warning · It can cause central serous retinopathy or retinal pigment epithelial detachment and visual field defects. Perform monthly ophthalmic examinations for the first 4 months, every 3 months thereafter, and urgently for visual symptoms; include visual acuity, slit-lamp examination, fundoscopy, and OCT. Use ocular demulcents as needed. — DailyMed, BALVERSA set_id 2a8aa5c0-6c92-4566-8c45-e8f4d1fc20ee
- Major warning · Hyperphosphatemia can cause soft-tissue mineralization, cutaneous calcinosis, non-uremic calciphylaxis, and vascular calcification. Monitor phosphate throughout treatment, restrict intake, and apply binders and dose modifications according to level and duration. — DailyMed, BALVERSA set_id 2a8aa5c0-6c92-4566-8c45-e8f4d1fc20ee
- Major warning · Safety and effectiveness are not established in pediatric patients. Epiphysiolysis, fractures, slipped capital femoral epiphysis, and accelerated linear growth have been reported in exposed pediatric patients. — DailyMed, BALVERSA set_id 2a8aa5c0-6c92-4566-8c45-e8f4d1fc20ee
Drug interactions
- HighModerate CYP2C9 or strong CYP3A4 inhibitors
Mechanism: They increase erdafitinib exposure and may increase toxicity.
Recommendation: Prefer alternatives; if unavoidable, monitor closely and modify the dose according to toxicity.
DailyMed, BALVERSA set_id 2a8aa5c0-6c92-4566-8c45-e8f4d1fc20eehttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2a8aa5c0-6c92-4566-8c45-e8f4d1fc20ee
- HighStrong or moderate CYP3A4 inducers
Mechanism: They reduce exposure and may decrease erdafitinib activity.
Recommendation: Avoid strong inducers. If a moderate inducer is unavoidable from treatment start, give 9 mg/day; after it is stopped, keep the same dose if there is no toxicity.
DailyMed, BALVERSA set_id 2a8aa5c0-6c92-4566-8c45-e8f4d1fc20eehttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2a8aa5c0-6c92-4566-8c45-e8f4d1fc20ee
- HighSerum phosphate-altering medicines
Mechanism: They may interfere with the phosphate level used to determine the initial dose increase.
Recommendation: Avoid the combination during Days 14–21 before deciding the initial dose increase.
DailyMed, BALVERSA set_id 2a8aa5c0-6c92-4566-8c45-e8f4d1fc20eehttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2a8aa5c0-6c92-4566-8c45-e8f4d1fc20ee
- ModerateP-gp substrates with a narrow therapeutic index
Mechanism: Erdafitinib may increase their concentration and toxicity.
Recommendation: Separate administration by at least 6 hours before or after erdafitinib.
DailyMed, BALVERSA set_id 2a8aa5c0-6c92-4566-8c45-e8f4d1fc20eehttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2a8aa5c0-6c92-4566-8c45-e8f4d1fc20ee
Adverse events
Common (≥1%)
hyperphosphatemia · nail disorders · stomatitis · diarrhea · increased creatinine · increased alkaline phosphatase · increased ALT · anemia · hyponatremia · increased AST · fatigue · dry mouth · dry skin · hypophosphatemia · decreased appetite · dysgeusia · constipation · hypercalcemia · dry eye · palmar-plantar erythrodysesthesia · hyperkalemia · alopecia · central serous retinopathy
Rare but serious
vascular calcification
Pregnancy and lactation
It can cause embryo-fetal harm. Verify pregnancy before starting. Females and males with partners who can become pregnant must use effective contraception during treatment and for 1 month afterward. It may impair female fertility. Do not breastfeed during treatment or for 1 month afterward.
Recent literature (PubMed)
Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) inhibitor approved for the treatment of locally advanced or metastatic urothelial carcinoma in adults with susceptible FGFR3/2 alterations who have progression after platinum-containing chemotherapy. The effects of erdafitinib in patients with FGFR-altered metastatic urothelial carcinoma who have progression during or after treatment with checkpoint inhibitors (anti-programmed cell death protein 1 [PD-1] or anti-programmed death ligand 1 [PD-L1] agents) are unclear. We conducted a global phase 3 trial of erdafitinib as compared with chemotherapy in patients with metastatic urothelial carcinoma with susceptible FGFR3/2 alterations who had progression after one or two previous treatments that included an anti-PD-1 or anti-PD-L1. Patients were randomly assigned in a 1:1 ratio to receive erdafitinib or the investigator's choice of chemotherapy (docetaxel or vinflunine). The primary end point was overall survival. A total of 266 patients underwent randomization: 136 to the erdafitinib group and 130 to the chemotherapy group. The median follow-up was 15.9 months. The median overall survival was significantly longer with erdafitinib than with chemotherapy (12.1 months vs. 7.8 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.47 to 0.88; P = 0.005). The median progression-free survival was also longer with erdafitinib than with chemotherapy (5.6 months vs. 2.7 months; hazard ratio for progression or death, 0.58; 95% CI, 0.44 to 0.78; P<0.001). The incidence of grade 3 or 4 treatment-related adverse events was similar in the two groups (45.9% in the erdafitinib group and 46.4% in the chemotherapy group). Treatment-related adverse events that led to death were less common with erdafitinib than with chemotherapy (in 0.7% vs. 5.4% of patients). Erdafitinib therapy resulted in significantly longer overall survival than chemotherapy among patients with metastatic urothelial carcinoma and FGFR altera
FGFR alterations are reported across various malignancies and might act as oncogenic drivers in multiple histologies. Erdafitinib is an oral, selective pan-FGFR tyrosine kinase inhibitor with activity in FGFR-altered advanced urothelial carcinoma. We aimed to evaluate the safety and activity of erdafitinib in previously treated patients with FGFR-altered advanced solid tumours. The single-arm, phase 2 RAGNAR study was conducted at 156 investigative centres (hospitals or oncology practices that are qualified oncology study centres) across 15 countries. The study consisted of four cohorts based on tumour histology and patient age; the results reported in this Article are for the primary cohort of the study, defined as the Broad Panel Cohort, which was histology-agnostic. We recruited patients aged 12 years or older with advanced or metastatic tumours of any histology (except urothelial cancer) with predefined FGFR1-4 alterations (mutations or fusions according to local or central testing). Eligible patients had disease progression on at least one previous line of systemic therapy and no alternative standard therapy available to them, and an Eastern Cooperative Oncology Group performance status of 0-1 (or equivalent for adolescents aged 12-17 years). Patients received once-daily oral erdafitinib (8 mg/day with provision for pharmacodynamically guided up-titration to 9 mg/day) on a continuous 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was objective response rate by independent review committee according to Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, or Response Assessment In Neuro-Oncology (RANO). The primary analysis was conducted on the treated population of the Broad Panel Cohort. This ongoing study is registered with ClinicalTrials.gov, number NCT04083976. Patients were recruited between Dec 5, 2019, and Feb 15, 2022. Of 217 patients treated with erdafitinib, 97 (45%) patients were female and 120 (55%
Fibroblast growth factor (FGF) signalling via FGF receptors (FGFR1-4) orchestrates fetal development and contributes to tissue and whole-body homeostasis, but can also promote tumorigenesis. Various agents, including pan-FGFR inhibitors (erdafitinib and futibatinib), FGFR1/2/3 inhibitors (infigratinib and pemigatinib), as well as a range of more-specific agents, have been developed and several have entered clinical use. Erdafitinib is approved for patients with urothelial carcinoma harbouring FGFR2/3 alterations, and futibatinib and pemigatinib are approved for patients with cholangiocarcinoma harbouring FGFR2 fusions and/or rearrangements. Clinical benefit from these agents is in part limited by hyperphosphataemia owing to off-target inhibition of FGFR1 as well as the emergence of resistance mutations in FGFR genes, activation of bypass signalling pathways, concurrent TP53 alterations and possibly epithelial-mesenchymal transition-related isoform switching. The next generation of small-molecule inhibitors, such as lirafugratinib and LOXO-435, and the FGFR2-specific antibody bemarituzumab are expected to have a reduced risk of hyperphosphataemia and the ability to overcome certain resistance mutations. In this Review, we describe the development and current clinical role of FGFR inhibitors and provide perspective on future research directions including expansion of the therapeutic indications for use of FGFR inhibitors, combination of these agents with immune-checkpoint inhibitors and the application of novel technologies, such as artificial intelligence.
Bladder cancer is a heterogeneous malignancy and is responsible for approximately 3.2% of new diagnoses of cancer per year (Sung et al., 2021). Fibroblast Growth Factor Receptors (FGFRs) have recently emerged as a novel therapeutic target in cancer. In particular, FGFR3 genomic alterations are potent oncogenic drivers in bladder cancer and represent predictive biomarkers of response to FGFR inhibitors. Indeed, overall ∼50% of bladder cancers have somatic mutations in the FGFR3 -coding sequence (Cappellen et al., 1999; Turner and Grose, 2010). FGFR3 gene rearrangements are typical alterations in bladder cancer (Nelson et al., 2016; Parker et al., 2014). In this review, we summarize the most relevant evidence on the role of FGFR3 and the state-of-art of anti-FGFR3 treatment in bladder cancer. Furthermore, we interrogated the AACR Project GENIE to investigate clinical and molecular features of FGFR3-altered bladder cancers. We found that FGFR3 rearrangements and missense mutations were associated with a lower fraction of mutated genome, compared to the FGFR3 wild-type tumors, as also observed in other oncogene-addicted cancers. Moreover, we observed that FGFR3 genomic alterations are mutually exclusive with other genomic aberrations of canonical bladder cancer oncogenes, such as TP53 and RB1. Finally, we provide an overview of the treatment landscape of FGFR3-altered bladder cancer, discussing future perspectives for the management of this disease.