tivozanib
Sources réglementaires consultées
Indications approuvées
- Carcinome rénal avancé chez l’adulte après au moins deux traitements systémiques antérieurs.
- Traitement de première ligne du carcinome rénal avancé chez l’adulte, ou après progression sous cytokines sans traitement antérieur par inhibiteur du VEGFR ou de mTOR.
Contre-indications
Absolues
- CIMA : hypersensibilité au tivozanib ou aux excipients et utilisation concomitante de millepertuis ; l’étiquette FDA n’établit aucune contre-indication formelle.
Mises en garde cliniques
- Surveiller la pression artérielle et traiter l’hypertension ; suspendre ou réduire si elle persiste et arrêter en cas de crise hypertensive. — OpenFDA, set_id de77155c-ecf2-4f15-9758-21d271449d83
- Surveiller insuffisance cardiaque, ischémie ou thrombose artérielle, thromboembolie veineuse, hémorragie, protéinurie, perforation ou fistule digestive, fonction thyroïdienne et syndrome d’encéphalopathie postérieure réversible. Suspendre au moins 24 jours avant chirurgie programmée et ne reprendre qu’au moins 2 semaines après chirurgie majeure et cicatrisation adéquate. — OpenFDA, set_id de77155c-ecf2-4f15-9758-21d271449d83
Interactions médicamenteuses
- SévèreInducteurs puissants du CYP3A
Mécanisme: Ils réduisent l’exposition au tivozanib et peuvent diminuer son efficacité.
Recommandation: Éviter l’association.
OpenFDA, set_id de77155c-ecf2-4f15-9758-21d271449d83
Effets indésirables
Communs (≥1%)
fatigue · hypertension · diarrhée · diminution de l’appétit · nausées · dysphonie · hypothyroïdie · toux
Grossesse et allaitement
Peut provoquer une atteinte fœtale. Les femmes, les hommes et leurs partenaires susceptibles de concevoir doivent utiliser une contraception efficace pendant le traitement et pendant 1 mois après ; une contraception hormonale doit être complétée par une méthode barrière. Ne pas allaiter pendant le traitement.
Bibliographie récente (PubMed)
Immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors are cornerstones of first-line treatment for advanced renal cell carcinoma; however, optimal treatment sequencing after progression is unknown. This study aimed to assess clinical outcomes of tivozanib-nivolumab versus tivozanib monotherapy in patients with metastatic renal cell carcinoma who have progressed following one or two lines of therapy in the post-ICI setting. TiNivo-2 is a multicentre, randomised, open-label, phase 3 trial at 190 sites across 16 countries, in Australia, Europe, North America, and South America. Patients with advanced renal cell carcinoma and progression during or after one to two previous lines of therapy (including one ICI) were randomised 1:1 to tivozanib (0·89 mg per day, orally) plus nivolumab (480 mg every 4 weeks, intravenously) or tivozanib (1·34 mg per day, orally). Randomisation was stratified by immediate previous therapy (ICI or non-ICI) and International Metastatic Renal Cell Carcinoma Database Consortium risk category. The primary endpoint was progression-free survival (PFS), defined as the time from randomisation to first documentation of objective progressive disease according to RECIST 1·1 or death from any cause, whichever came first, by independent radiology review. Efficacy was evaluated in the intention-to-treat population, and safety was assessed in patients who received one or more doses of the study drug. This trial was registered on ClinicalTrials.gov (NCT04987203) and is active and not recruiting. From Nov 4, 2021, to June 16, 2023, 343 patients were randomly assigned to tivozanib-nivolumab (n=171) or tivozanib monotherapy (n=172). Median follow-up was 12·0 months. Median PFS was 5·7 months (95% CI 4·0-7·4) with tivozanib-nivolumab and 7·4 months (5·6-9·2) with tivozanib monotherapy (hazard ratio 1·10, 95% CI 0·84-1·43; p=0·49). Among those with an ICI as their immediate previous therapy (n=244), median P
Physiological vascular endothelial cell division and angiogenesis occur during embryonic development, wound healing, in the endometrium during the menstrual cycle, and during placental development. Otherwise, vascular endothelial cells divide less than once per decade. Neoplasms are limited in size (∼ 1.0 mm) owing to a deficiency of oxygen and metabolic fuels. To grow larger, new blood vessels form from pre-existing vasculature by angiogenesis (capillary sprouting). During this process, mature endothelial cells replicate and become incorporated into new capillaries resulting in tumor growth. Angiogenesis results in part from the increased production of vascular endothelial growth factors (VEGFs). The human VEGF family consists of VEGF-A/B/C/D and placental growth factor (PlGF). The VEGF family of receptors consists of three protein-tyrosine kinases (VEGFR1/2/3) and two nonprotein kinase receptors (neuropilin-1 and neuropilin-2). Semaphorins 3A-F/4A-G/5 A/B/6A-G/7 A are regulatory ligands that interact with their neuropilin and plexin receptors (PlxA1-A4/B1-B3/C1/D1) and regulate angiogenesis. Angiopoietin-1/2/4 interact with their Tie1/2 receptor protein-tyrosine kinases to modulate vasculogenesis and angiogenesis. Ephrin ligands (EfnA1/A2/A3/A4/A5/B1/B2/B3) and Ephrin receptors (EphA1/A2/A3/A4/A5/A6/A7/A8/A10/B1/B2/B3/B4/B6/) also contribute to angiogenesis. Platelet-derived growth factors, fibroblast growth factors, hepatocyte growth factor (c-Met), stem cell growth factor (Kit) receptor protein-tyrosine kinases, PKB/Akt, Src, and MAP kinases also participate in angiogenesis. Owing to its importance in tumor progression, the inhibition of angiogenic signaling represents an attractive cancer treatment. Ponatinib, regorafenib, and vandetanib are FDA-approved VEGFR, Tie2, and Ephrin receptor blockers used in the treatment of various malignancies. Other disorders characterized by aberrant angiogenesis include diabetic retinopathies and neovascular age-related macular
The phase III TIVO-3 study demonstrated improvement in progression-free survival (PFS) with tivozanib compared with sorafenib in patients with 2-3 prior systemic regimens for metastatic renal cell carcinoma (mRCC). The TIVO-3 trial enrolled patients with measurable mRCC who had received 2 or more prior systemic therapies, including a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). Patients were stratified by International Metastatic RCC Database Consortium risk score and type of prior treatment and were randomized 1:1 to receive tivozanib or sorafenib. Efficacy was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 criteria, with PFS as the primary endpoint. Safety was evaluated using Common Terminology Criteria for Adverse Events version v4.03, and statistical analyses included Cox regression for overall survival (OS) and descriptive statistics for duration of response (DOR). The current post-hoc long-term follow-up analysis consists of an assessment of OS in the previously stratified subpopulation of patients with prior CPI exposure. Between May 2016, and August 2017, 350 patients were randomized, of which 26% had prior CPI exposure, with final analysis data cut off on June 21, 2021. In patients previously treated with CPIs (n = 91), the median PFS of tivozanib was 7.3 months versus 5.1 months with sorafenib and hazard ratio (HR) of 0.55 (95% CI, 0.32-0.94). The OS HR in the CPI-treated subset was 0.69 (95% CI, 0.43-1.11, P =.0992) favoring tivozanib, although with a median OS of 18.1 and 20.9 months, for tivozanib and sorafenib, respectively. Tivozanib demonstrated a longer median DOR of 20.3 versus 5.7 months for sorafenib in the subset previously treated with CPIs. The safety profile favored tivozanib, with lower rates of VEGF-TKI class-related grade ≥3 adverse events compared with sorafenib. However, in the subset of patients previously treated with CPIs, the incidence of grade ≥3 adverse events was higher, at 58%