alpelisib
Regulatory sources consulted
Approved indications
- With fulvestrant: locally advanced or metastatic HR-positive, HER2-negative, PIK3CA-mutated breast cancer in postmenopausal women and men after progression on endocrine monotherapy.
Contraindications
Absolute
- Hypersensitivity to alpelisib or excipients.
Clinical warnings
- It can cause severe hyperglycemia, hyperosmolar syndrome, or ketoacidosis, including fatal cases. Optimize glucose before starting, monitor on schedule, and promptly treat or modify the dose. — CIMA/AEMPS, ficha técnica 1201455002
- It can cause anaphylaxis, angioedema, and severe cutaneous reactions such as SJS, DRESS, or erythema multiforme. Withhold if suspected and permanently discontinue if a severe reaction is confirmed; also monitor pneumonitis and diarrhea/colitis. — CIMA/AEMPS, ficha técnica 1201455002
Drug interactions
- HighStrong CYP3A4 inducers
Mechanism: They markedly reduce alpelisib exposure and may decrease efficacy.
Recommendation: Avoid the combination, including St John’s wort.
CIMA/AEMPS, ficha técnica 1201455002
- HighBCRP inhibitors
Mechanism: They may increase systemic alpelisib exposure.
Recommendation: Use with caution and monitor toxicity.
CIMA/AEMPS, ficha técnica 1201455002
Adverse events
Common (≥1%)
hyperglycemia · increased creatinine · diarrhea · lymphopenia · increased GGT · rash · nausea · anemia · fatigue · increased lipase
Pregnancy and lactation
It is not indicated and must not be used during pregnancy. Verify pregnancy before starting. Women must use effective contraception, such as a double-barrier method, during treatment and for at least 1 week afterward; men with partners who can become pregnant must use condoms for the same period. Do not breastfeed during treatment or for at least 1 week after the last dose.
Recent literature (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.