entrectinib
Sources réglementaires consultées
Indications approuvées
- Chez les adultes et les patients pédiatriques âgés de plus de 1 mois atteints de tumeurs solides avec fusion du gène NTRK, localement avancées ou métastatiques, ou dont la chirurgie entraînerait probablement une morbidité sévère, sans traitement antérieur par inhibiteur de NTRK et sans option satisfaisante.
- Chez l’adulte atteint d’un cancer bronchique non à petites cellules avancé ROS1 positif n’ayant jamais reçu d’inhibiteur de ROS1.
Contre-indications
Absolues
- Hypersensibilité à l’entrectinib ou à ses excipients.
Mises en garde cliniques
- Mise en garde majeure · Peut provoquer une insuffisance cardiaque congestive. Évaluer la fraction d’éjection avant le traitement chez les patients à risque ou symptomatiques et surveiller les signes cliniques ; suspendre, réduire ou arrêter selon la gravité. — DailyMed, ROZLYTREK set_id c7c71b0c-2549-4495-86b6-c2807fa54908
- Mise en garde majeure · Peut provoquer des effets neurologiques centraux et des fractures, plus fréquentes en pédiatrie. Éviter de conduire en cas de troubles cognitifs, de l’humeur, du sommeil ou de vertiges ; évaluer toute douleur ou modification de la mobilité. — DailyMed, ROZLYTREK set_id c7c71b0c-2549-4495-86b6-c2807fa54908
- Mise en garde majeure · Contrôler ALT et AST toutes les 2 semaines pendant le premier mois puis chaque mois. Contrôler l’acide urique avant et pendant le traitement. Évaluer le QT, les électrolytes et les médicaments associés ; éviter si le QTc initial est >450 ms ou en cas de syndrome du QT long. — CIMA/AEMPS, ficha técnica ROZLYTREK 100 mg, registro 1201460001
Interactions médicamenteuses
- SévèreInhibiteurs puissants ou modérés du CYP3A
Mécanisme: Ils augmentent l’exposition à l’entrectinib et sa toxicité.
Recommandation: Éviter l’association. Si elle est indispensable pendant 14 jours au maximum chez les patients de plus de 2 ans, avec un inhibiteur modéré/puissant réduire 600 mg à 200/100 mg ; 400 à 200/50 mg ; 300 à 100/50 mg ; et 200 à 50 mg par jour/50 mg un jour sur deux. Éviter l’association si la dose initiale est <200 mg ou avant 2 ans.
DailyMed, ROZLYTREK set_id c7c71b0c-2549-4495-86b6-c2807fa54908https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c7c71b0c-2549-4495-86b6-c2807fa54908
- SévèreInducteurs puissants ou modérés du CYP3A
Mécanisme: Ils réduisent l’exposition et peuvent compromettre l’efficacité.
Recommandation: Éviter l’association.
CIMA/AEMPS, ficha técnica ROZLYTREK 100 mg, registro 1201460001https://cima.aemps.es/cima/dochtml/ft/1201460001/FT_1201460001.html
- SévèreMédicaments prolongeant le QT
Mécanisme: Ils peuvent augmenter le risque de prolongation du QT et d’arythmie.
Recommandation: Éviter si possible ; si nécessaire, surveiller l’ECG et les électrolytes.
CIMA/AEMPS, ficha técnica ROZLYTREK 100 mg, registro 1201460001https://cima.aemps.es/cima/dochtml/ft/1201460001/FT_1201460001.html
Effets indésirables
Communs (≥1%)
fatigue · constipation · diarrhée · vertiges · dysgueusie · œdème · prise de poids · anémie · élévation de la créatinine · nausées · vomissements · fièvre · arthralgie · dyspnée · toux
Grossesse et allaitement
Peut provoquer une toxicité embryofœtale. Vérifier la grossesse avant de commencer. Les femmes doivent utiliser une contraception très efficace pendant le traitement et pendant 5 semaines après ; ajouter une méthode barrière avec une contraception hormonale. Les hommes doivent utiliser une contraception pendant le traitement et pendant 3 mois après. Ne pas allaiter pendant le traitement ni pendant 7 jours après.
Bibliographie récente (PubMed)
ROS1 gene fusions are an established oncogenic driver comprising 1%-2% of non-small cell lung cancer (NSCLC). Successful targeting of ROS1 fusion oncoprotein with oral small-molecule tyrosine kinase inhibitors (TKIs) has revolutionized the treatment landscape of metastatic ROS1 fusion-positive (ROS1+) NSCLC and transformed outcomes for patients. The preferred Food and Drug Administration-approved first-line therapies include crizotinib, entrectinib, and repotrectinib, and currently, selection amongst these options requires consideration of the systemic and CNS efficacy, tolerability, and access to therapy. Of note, resistance to ROS1 TKIs invariably develops, limiting the clinical benefit of these agents and leading to disease relapse. Progress in understanding the molecular mechanisms of resistance has enabled the development of numerous next-generation ROS1 TKIs, which achieve broader coverage of ROS1 resistance mutations and superior CNS penetration than first-generation TKIs, as well as other therapeutic strategies to address TKI resistance. The approach to subsequent therapy depends on the pace and pattern of progressive disease on the initial ROS1 TKI and, if known, the mechanisms of TKI resistance. Herein, we describe a practical approach for the selection of initial and subsequent therapies for metastatic ROS1+ NSCLC based on these clinical considerations. Additionally, we explore the evolving evidence for the optimal treatment of earlier-stage, non-metastatic ROS1+ NSCLC, while, in parallel, highlighting future research directions with the goal of continuing to build on the tremendous progress in the management of ROS1+ NSCLC and ultimately improving the longevity and well-being of people living with this disease.
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
- Targeting ROS1 rearrangements in non-small cell lung cancer: Current insights and future directions.
ROS1 rearrangements define a molecular subset of non-small cell lung cancer (NSCLC) by accounting for 1%-2% of cases. Targeted therapy with ROS1 tyrosine kinase inhibitors (TKIs) has significantly improved the outcomes for these patients. First-generation inhibitors, such as crizotinib and entrectinib, have demonstrated impressive efficacy, with objective response rates exceeding 60%-70%. However, the emergence of resistance mechanisms, including solvent-front mutations such as ROS1 G2032R, and limited blood-brain barrier penetration have limited the long-term efficacy of early-generation agents. Next-generation TKIs, including lorlatinib, taletrectinib, and repotrectinib, have been developed to overcome these challenges. These agents show enhanced central nervous system (CNS) penetration and activity against on-target ROS1 resistance mutations. Repotrectinib, a potent, CNS-penetrant ROS1 inhibitor, has demonstrated superior activity in both TKI-naive and -resistant tumors, including those harboring the G2032R mutation. Zidesamtinib, a highly selective next-generation ROS1 inhibitor, further addresses TRK-mediated off-target neurological toxicities seen with prior agents, and is poised to offer improved tolerability. Ongoing research is focused on optimizing sequencing strategies for ROS1 inhibitors and exploring combination approaches to prevent or overcome resistance. In addition, the development of novel diagnostic tools, including RNA-based next-generation sequencing, has enhanced the detection of functional ROS1 fusions by ensuring that patients with actionable mutations receive appropriate targeted therapies. These advances highlight the evolving landscape of treatment for ROS1-positive NSCLC, with the aim of maximizing long-term survival and quality of life. No information is available on the clinical use of entrectinib during breastfeeding. Because entrectinib and its active metabolite are >99% bound to plasma proteins, the amount in milk is likely to be low