larotrectinib
Sources réglementaires consultées
Indications approuvées
- Chez les adultes et les patients pédiatriques atteints de tumeurs solides présentant une fusion du gène NTRK, localement avancées ou métastatiques, ou dont la chirurgie entraînerait probablement une morbidité sévère, lorsqu’il n’existe aucune option thérapeutique satisfaisante.
Contre-indications
Absolues
- Hypersensibilité au larotrectinib ou à ses excipients.
Mises en garde cliniques
- Mise en garde majeure · Peut provoquer une hépatotoxicité et une atteinte hépatique médicamenteuse. Contrôler ALT, AST, phosphatase alcaline et bilirubine avant le traitement, toutes les 2 semaines pendant les 2 premiers mois puis chaque mois ; suspendre, réduire ou arrêter selon la gravité. — DailyMed, VITRAKVI set_id 0c8ca614-58b2-4aa4-83d3-0387a8f782fd
- Mise en garde majeure · Peut provoquer des effets neurologiques centraux, notamment vertiges et troubles cognitifs, de l’humeur ou du sommeil. Éviter de conduire ou d’utiliser des machines s’ils surviennent. — DailyMed, VITRAKVI set_id 0c8ca614-58b2-4aa4-83d3-0387a8f782fd
- Mise en garde majeure · Des fractures ont été rapportées, avec une incidence plus élevée en pédiatrie. Évaluer toute douleur ou modification de la mobilité et prendre en charge selon la pratique clinique. — DailyMed, VITRAKVI set_id 0c8ca614-58b2-4aa4-83d3-0387a8f782fd
Interactions médicamenteuses
- SévèreInhibiteurs puissants ou modérés du CYP3A, de la P-gp ou de la BCRP
Mécanisme: Ils peuvent augmenter l’exposition au larotrectinib et sa toxicité.
Recommandation: Éviter l’association ; si un inhibiteur puissant du CYP3A est indispensable, réduire le larotrectinib de 50 % et surveiller la toxicité.
DailyMed, VITRAKVI set_id 0c8ca614-58b2-4aa4-83d3-0387a8f782fdhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0c8ca614-58b2-4aa4-83d3-0387a8f782fd
- SévèreInducteurs puissants ou modérés du CYP3A
Mécanisme: Ils réduisent l’exposition et peuvent diminuer l’efficacité.
Recommandation: Éviter l’association, y compris le millepertuis.
CIMA/AEMPS, ficha técnica VITRAKVI 100 mg, registro 1191385002https://cima.aemps.es/cima/dochtml/ft/1191385002/FT_1191385002.html
- ModéréeSubstrats sensibles du CYP3A à marge thérapeutique étroite
Mécanisme: Le larotrectinib peut augmenter leur exposition.
Recommandation: Éviter l’association ; si elle est indispensable, surveiller étroitement la toxicité et coordonner l’ajustement du substrat avec l’équipe prescriptrice.
DailyMed, VITRAKVI set_id 0c8ca614-58b2-4aa4-83d3-0387a8f782fdhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0c8ca614-58b2-4aa4-83d3-0387a8f782fd
Effets indésirables
Communs (≥1%)
élévation de l’ALT · élévation de l’AST · vomissements · anémie · constipation · diarrhée · nausées · fatigue · vertiges
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 au moins 1 mois après ; ajouter une méthode barrière en cas de contraception hormonale systémique. Ne pas allaiter pendant le traitement ; le profil CIMA exige 3 jours après et le profil FDA 1 semaine après.
Bibliographie récente (PubMed)
Glioblastoma multiforme (GBM) is a WHO grade 4 glioma and the most common malignant primary brain tumour. Recently, there has been outstanding progress in the treatment of GBM. In addition to the newest form of GBM removal using fluorescence, three-dimensional (3D) imaging, tomoradiotherapy, moderate electro-hyperthermia, and adjuvant temozolomide (post-operative chemotherapy), new developments have been made in the fields of immunology, molecular biology, and virotherapy. An unusual and modern treatment has been created, especially for stage 4 GBM, using the latest therapeutic techniques, including immunotherapy and virotherapy. Modern oncological medicine is producing extraordinary and progressive therapeutic methods. Oncological therapy includes individual analysis of the properties of a tumour and targeted therapy using small-molecule inhibitors. Individualised medicine covers the entire patient (tumour and host) in the context of immunotherapy. An example is individualised multimodal immunotherapy (IMI), which relies on individual immunological tumour-host interactions. In addition, IMI is based on the concept of oncolytic virus-induced immunogenic tumour cell death. In this review, we outline current knowledge of the various available treatment options used in the therapy of GBM including both traditional therapeutic strategy and modern therapies, such as tomotherapy, electro-hyperthermia, and oncolytic virotherapy, which are promising treatment strategies with the potential to improve prognosis in patients with GBM. This newest therapy, immunotherapy combined with virotherapy (oncolytic viruses and cancer vaccines), is displaying encouraging signs for combating GBM. Additionally, the latest 3D imaging is compared to conventional two-dimensional imaging.
Triple-negative breast cancer (TNBC) is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival (OS). Taxane and anthracycline-containing chemotherapy (CT) is currently the main systemic treatment option for TNBC, while platinum-based chemotherapy showed promising results in the neoadjuvant and metastatic settings. An early arising of intrinsic or acquired CT resistance is common and represents the main hurdle for successful TNBC treatment. Numerous mechanisms were uncovered that can lead to the development of chemoresistance. These include cancer stem cells (CSCs) induction after neoadjuvant chemotherapy (NACT), ATP-binding cassette (ABC) transporters, hypoxia and avoidance of apoptosis, single factors such as tyrosine kinase receptors (EGFR, IGFR1), a disintegrin and metalloproteinase 10 (ADAM10), and a few pathological molecular pathways. Some biomarkers capable of predicting resistance to specific chemotherapeutic agents were identified and are expected to be validated in future studies for a more accurate selection of drugs to be employed and for a more tailored approach, both in neoadjuvant and advanced settings. Recently, based on specific biomarkers, some therapies were tailored to TNBC subsets and became available in clinical practice: olaparib and talazoparib for BRCA1/2 germline mutation carriers larotrectinib and entrectinib for neurotrophic tropomyosin receptor kinase (NTRK) gene fusion carriers, and anti-trophoblast cell surface antigen 2 (Trop2) antibody drug conjugate therapy for heavily pretreated metastatic TNBC (mTNBC). Further therapies targeting some pathologic molecular pathways, apoptosis, miRNAS, epidermal growth factor receptor (EGFR), insulin growth factor 1 receptor (IGF-1R), and androgen receptor (AR) are under investigation. Among them, phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and EGFR inhibitors as well as antiandrogens showed promisin
Tumor-agnostic, or histology-agnostic, cancer therapy marks a groundbreaking evolution in the realm of precision oncology. In stark contrast to conventional cancer treatments that categorize malignancies based on their tissue of origin (eg, breast, lung, renal cell, etc), tumor-agnostic therapies transcend histologic boundaries, honing in on the genetic and molecular attributes of tumors, regardless of their location. This article offers a comprehensive review of the current landscape of tissue-agnostic cancer therapies and provides clinical insights to empower surgical oncologists with a deeper understanding of these innovative therapeutic approaches.
Advanced cholangiocarcinoma and gene fusions Cholangiocarcinomas (CCAs) are rare digestive tumors classified as intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) CCAs. These tumors are most often diagnosed at an advanced stage, unresectable or metastatic, and associated with a poor prognosis. The identification in recent years of multiple molecular alterations of interest, particularly in iCCA, has nevertheless allowed the development of new targeted therapeutic options for a significant proportion of patients. Gene fusions are among the most frequent alterations, involving FGFR2 in 10-15% of iCCAs in particular, and NTRK genes at a lower frequency (<1%). A dedicated analysis, most often based on RNA sequencing, is required to identify such alterations. Three FGFR inhibitors, pemigatinib, infigratinib and futinatinib, have recently received FDA approval for use in pre-treated patients. These compounds are currently being evaluated as first-line therapy in several phase III trials. Promising results have also been reported with new-generation inhibitors such as RLY-4008, which may soon constitute new therapeutic options. In the case of NTRK fusion, larotrectinib and entrectinib have also demonstrated their efficacy. The objectives of this review are to clarify the specific diagnostic modalities for gene fusions and to summarize the results of the main trials and developments underway for the management of advanced CCA with gene fusions.