Background: The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway is frequently activated in breast cancer and can promote tumor growth, progression, and resistance to anticancer therapies such as endocrine therapy (ET). Mutation or amplification of the PIK3CA gene, which encodes the catalytic subunit of the α-isoform of class I PI3K (PI3Kα), is a common mechanism of PI3K/AKT/mTOR pathway activation. Alpelisib (BYL719) is an oral inhibitor that specifically targets PI3Kα and is under investigation in combination with letrozole or fulvestrant for hormone receptor–positive, human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC).
Objective: To provide information on common adverse events (AEs) observed with alpelisib to help optimize management and improve patient outcomes.
Methods: Incidence of AEs observed with alpelisib during clinical trials of patients with breast cancer was collated from PubMed (search string: [alpelisib OR BYL719] AND breast AND [“clinical trial” OR study]) and presentations at oncology congresses. A literature search was also conducted for management strategies of AEs that were commonly identified.
Results: Three phase 1 trials of alpelisib alone or in combination with ET were identified. In advanced solid tumors (N = 134 [NCT01219699]1), the most common all-grade AEs (≥15%) suspected to be related to single-agent alpelisib were hyperglycemia (52%), nausea (50%), decreased appetite (42%), diarrhea (40%), vomiting (31%), fatigue (30%), and stomatitis (20%). The only grade 3/4 AE occurring in >3% of patients was hyperglycemia (24%), which was effectively managed by dose interruptions and concomitant antidiabetic medications; dose-limiting toxicities comprised grade 3/4 hyperglycemia (n = 6), grade 3 nausea (n = 2), and grade 3 hypophosphatemia with grade 3 hyperglycemia (n = 1). When alpelisib was used in combination with fulvestrant (N = 87 [NCT01219699]2) or letrozole (N = 17 [NCT01872260]3; N = 26 [NCT01791478]4) in patients with estrogen receptor–positive, HER2– ABC, the most common grade 3/4 AEs included hyperglycemia, rash, and gastrointestinal events; these AEs are all on-target effects of PI3K inhibition. Management of cancer treatment–related hyperglycemia can include monitoring of blood glucose and hemoglobin A1c, patient self-monitoring of blood glucose, treatment per American Diabetes Association guidelines, and anticancer therapy dose adjustments, depending on the AE severity. Additionally, educating patients on the symptoms of on-target AEs can aid in early identification and intervention, which can help reduce AE severity. Additional management and screening guidelines will be discussed in the presentation.
Conclusions: The most common grade 3/4 AEs of alpelisib alone or in combination with letrozole or fulvestrant are on-target effects of PI3K inhibition, including hyperglycemia and rash. Physician and patient awareness of possible symptoms along with monitoring to enable early intervention are critical for successful management.
Disclosures: Editorial assistance with this abstract was funded by Novartis Pharmaceuticals Corporation.
Previous submission: This abstract is an updated version of an earlier presentation at ONS 2018.
Sources
- Juric D, Rodon J, Tabernero J, et al. Phosphatidylinositol 3-kinase α-selective inhibition with alpelisib (BYL719) in PIK3CA-altered solid tumors: results from the first-in-human study. J Clin Oncol. 2018;36:1291-1299.
- Juric D, et al. 33rd Annual Miami Breast Cancer Conference 2016. Poster 334.
- Juric D, Hamilton E, Garcia Estévez L, et al. Phase Ib/II study of LEE011 and BYL719 and letrozole in ER+, HER2– breast cancer: safety, preliminary efficacy and molecular analysis. Cancer Res. 2015;75(9 suppl). Abstract P5-19-24.
- Mayer IA, Abramson VG, Formisano L, et al. A phase Ib study of alpelisib (BYL719), a PI3Kα-specific inhibitor, with letrozole in ER+/HER2- metastatic breast cancer. Clin Cancer Res. 2017;23:26-34.
