alpelisib
Sources réglementaires consultées
Indications approuvées
- Avec fulvestrant : cancer du sein localement avancé ou métastatique RH positif, HER2 négatif et muté PIK3CA chez la femme ménopausée et l’homme, après progression sous hormonothérapie seule.
Contre-indications
Absolues
- Hypersensibilité à l’alpélisib ou aux excipients.
Mises en garde cliniques
- Peut provoquer hyperglycémie sévère, syndrome hyperosmolaire ou acidocétose, parfois mortelle. Optimiser la glycémie avant traitement, respecter le calendrier de surveillance et traiter ou modifier rapidement la dose. — CIMA/AEMPS, ficha técnica 1201455002
- Peut provoquer anaphylaxie, angio-œdème et réactions cutanées graves telles que SJS, DRESS ou érythème polymorphe. Suspendre en cas de suspicion et arrêter définitivement si une réaction grave est confirmée ; surveiller aussi pneumopathie et diarrhée/colite. — CIMA/AEMPS, ficha técnica 1201455002
Interactions médicamenteuses
- SévèreInducteurs puissants du CYP3A4
Mécanisme: Ils réduisent fortement l’exposition à l’alpélisib et peuvent diminuer son efficacité.
Recommandation: Éviter l’association, y compris le millepertuis.
CIMA/AEMPS, ficha técnica 1201455002
- SévèreInhibiteurs de la BCRP
Mécanisme: Ils peuvent augmenter l’exposition systémique à l’alpélisib.
Recommandation: Utiliser avec prudence et surveiller la toxicité.
CIMA/AEMPS, ficha técnica 1201455002
Effets indésirables
Communs (≥1%)
hyperglycémie · augmentation de la créatinine · diarrhée · lymphopénie · augmentation de la GGT · éruption cutanée · nausées · anémie · fatigue · augmentation de la lipase
Grossesse et allaitement
Il n’est pas indiqué et ne doit pas être utilisé pendant la grossesse. Vérifier l’absence de grossesse avant traitement. Les femmes doivent utiliser une contraception efficace, par exemple une double barrière, pendant le traitement et pendant au moins 1 semaine après ; les hommes ayant une partenaire susceptible de concevoir doivent utiliser un préservatif pendant la même période. Ne pas allaiter pendant le traitement ni pendant au moins 1 semaine après la dernière dose.
Bibliographie récente (PubMed)
The frequent activation of the PI3K/AKT/mTOR pathway and its crucial role in estrogen receptor-positive (ER+) breast cancer tumorigenesis and drug resistance has made it a highly attractive therapeutic target in this breast cancer subtype. Consequently, the number of new inhibitors in clinical development targeting this pathway has drastically increased. Among these, the PIK3CA isoform-specific inhibitor alpelisib and the pan-AKT inhibitor capivasertib were recently approved in combination with the estrogen receptor degrader fulvestrant for the treatment of ER+ advanced breast cancer after progression on an aromatase inhibitor. Nevertheless, the clinical development of multiple inhibitors of the PI3K/AKT/mTOR pathway, in parallel with the incorporation of CDK4/6 inhibitors into the standard of care treatment in ER+ advanced breast cancer, has led to a multitude of available therapeutic agents and many possible combined strategies which complicate personalizing treatment. Here, we review the role of the PI3K/AKT/mTOR pathway in ER+ advanced breast cancer, highlighting the genomic contexts in which the various inhibitors of this pathway may have superior activity. We also discuss selected trials with agents targeting the PI3K/AKT/mTOR and related pathways as well as the rationale supporting the clinical development of triple combination therapy targeting ER, CDK4/6 and PI3K/AKT/mTOR in ER+ advanced breast cancer.
Dysregulation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway plays a pivotal role in the development and progression of various cancers. In hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer, aberrations in this pathway are increasingly recognized as key drivers of resistance to endocrine therapy and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, the first-line treatments for this disease subtype. Recognizing the urgent need for alternative therapeutic strategies, significant advancements have been made in developing PI3K/AKT/mTOR inhibitors for HR+ advanced/metastatic breast cancer. Among these inhibitors, capivasertib and alpelisib have received approval as targeted therapies for this indication. This review provides a comprehensive summary of the latest developments in PI3K/AKT/mTOR inhibitors for HR+ breast cancer. It also delves into different aspects, including sampling, testing method and timing, of PI3K/AKT/mTOR diagnostic testing. Additionally, the review discusses key considerations for integrating these inhibitors into clinical practice, such as timing and choice of PI3K/AKT/mTOR inhibitors, and management of treatment toxicities. By examining these different aspects, this review aims to provide valuable insights into optimizing the clinical utility of PI3K/AKT/mTOR inhibitors in HR+ advanced breast cancer. No information is available on alpelisib during breastfeeding. Because the drug is 89% protein bound, amounts in milk are likely to be low. Because of possible infant toxicity, the manufacturer recommends that breastfeeding be discontinued during alpelisib therapy and for 1 week after the final dose.
The growing availability of targeted therapies for patients with advanced oestrogen receptor-positive breast cancer has improved survival, but there remains much to learn about the optimal management of these patients. The PI3K-AKT and mTOR pathways are among the most commonly activated pathways in breast cancer, whose crucial role in the pathogenesis of this tumour type has spurred major efforts to target this pathway at specific kinase hubs. Approvals for oestrogen receptor-positive advanced breast cancer include the PI3K inhibitor alpelisib for PIK3CA-mutated tumours, the AKT inhibitor capivasertib for tumours with alterations in PIK3CA, AKT1, or PTEN, and the mTOR inhibitor everolimus, which is used irrespective of mutation status. The availability of different inhibitors leaves physicians with a potentially challenging decision over which of these therapies should be used for individual patients and when. In this Review, we present a comprehensive summary of our current understanding of the pathways and the three inhibitors and discuss strategies for the optimal sequencing of therapies in the clinic, particularly after progression on a CDK4/6 inhibitor.