erdafitinib
Sources réglementaires consultées
Indications approuvées
- Chez l’adulte atteint d’un carcinome urothélial localement avancé ou métastatique avec altérations génétiques sensibles de FGFR3, dont la maladie a progressé pendant ou après au moins une ligne de traitement systémique antérieur. Sélectionner au moyen d’un diagnostic compagnon approuvé par la FDA. Non recommandé chez les patients éligibles à un inhibiteur de PD-1 ou PD-L1 qui n’en ont pas encore reçu.
Mises en garde cliniques
- Mise en garde majeure · Peut provoquer une choriorétinopathie séreuse centrale ou un décollement de l’épithélium pigmentaire rétinien et des déficits du champ visuel. Réaliser un examen ophtalmologique chaque mois pendant les 4 premiers mois, puis tous les 3 mois et en urgence en cas de symptômes visuels ; inclure acuité visuelle, lampe à fente, fond d’œil et OCT. Utiliser des larmes artificielles si nécessaire. — DailyMed, BALVERSA set_id 2a8aa5c0-6c92-4566-8c45-e8f4d1fc20ee
- Mise en garde majeure · L’hyperphosphatémie peut entraîner une minéralisation des tissus mous, une calcinose cutanée, une calciphylaxie non urémique et une calcification vasculaire. Surveiller le phosphate pendant tout le traitement, limiter les apports et utiliser chélateurs et modifications de dose selon le taux et la durée. — DailyMed, BALVERSA set_id 2a8aa5c0-6c92-4566-8c45-e8f4d1fc20ee
- Mise en garde majeure · La sécurité et l’efficacité ne sont pas établies en pédiatrie. Des épiphysiolyses, fractures, glissements de l’épiphyse fémorale supérieure et une croissance linéaire accélérée ont été rapportés chez des patients pédiatriques exposés. — DailyMed, BALVERSA set_id 2a8aa5c0-6c92-4566-8c45-e8f4d1fc20ee
Interactions médicamenteuses
- SévèreInhibiteurs modérés du CYP2C9 ou puissants du CYP3A4
Mécanisme: Ils augmentent l’exposition à l’erdafitinib et peuvent accroître la toxicité.
Recommandation: Préférer une alternative ; si l’association est inévitable, surveiller étroitement et modifier la dose selon la toxicité.
DailyMed, BALVERSA set_id 2a8aa5c0-6c92-4566-8c45-e8f4d1fc20eehttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2a8aa5c0-6c92-4566-8c45-e8f4d1fc20ee
- SévèreInducteurs puissants ou modérés du CYP3A4
Mécanisme: Ils réduisent l’exposition et peuvent diminuer l’activité de l’erdafitinib.
Recommandation: Éviter les inducteurs puissants. Si un inducteur modéré est indispensable dès le début, administrer 9 mg/jour ; après son arrêt, maintenir la dose en l’absence de toxicité.
DailyMed, BALVERSA set_id 2a8aa5c0-6c92-4566-8c45-e8f4d1fc20eehttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2a8aa5c0-6c92-4566-8c45-e8f4d1fc20ee
- SévèreMédicaments modifiant le phosphate sérique
Mécanisme: Ils peuvent interférer avec le taux de phosphate utilisé pour décider de l’augmentation initiale de dose.
Recommandation: Éviter l’association pendant les jours 14 à 21, avant de décider de l’augmentation initiale.
DailyMed, BALVERSA set_id 2a8aa5c0-6c92-4566-8c45-e8f4d1fc20eehttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2a8aa5c0-6c92-4566-8c45-e8f4d1fc20ee
- ModéréeSubstrats de la P-gp à marge thérapeutique étroite
Mécanisme: L’erdafitinib peut augmenter leur concentration et leur toxicité.
Recommandation: Espacer l’administration d’au moins 6 heures avant ou après l’erdafitinib.
DailyMed, BALVERSA set_id 2a8aa5c0-6c92-4566-8c45-e8f4d1fc20eehttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2a8aa5c0-6c92-4566-8c45-e8f4d1fc20ee
Effets indésirables
Communs (≥1%)
hyperphosphatémie · atteintes unguéales · stomatite · diarrhée · élévation de la créatinine · élévation de la phosphatase alcaline · élévation de l’ALT · anémie · hyponatrémie · élévation de l’AST · fatigue · sécheresse buccale · sécheresse cutanée · hypophosphatémie · diminution de l’appétit · dysgueusie · constipation · hypercalcémie · sécheresse oculaire · érythrodysesthésie palmo-plantaire · hyperkaliémie · alopécie · choriorétinopathie séreuse centrale
Rares mais graves
calcification vasculaire
Grossesse et allaitement
Peut provoquer une toxicité embryofœtale. Vérifier la grossesse avant de commencer. Les femmes et les hommes ayant une partenaire susceptible d’être enceinte doivent utiliser une contraception efficace pendant le traitement et pendant 1 mois après. Peut altérer la fertilité féminine. Ne pas allaiter pendant le traitement ni pendant 1 mois après.
Bibliographie récente (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.