The PI3K inhibitor member Buparlisib code-named BKM120, is not yet available, but has been clinically studied in a variety of tumors and has been shown in advanced breast cancer that is resistant to endocrine therapy as well as anti HER2 (i.e., human epidermal growth factor receptor 2)-targeted therapy. This article will take you through the clinical studies of this drug. This article takes a look at this drug.
Theoretical basis for the PI3K inhibitor mechanism
Buparlisib is a PI3K inhibitor that works through the “PI3K/Akt/mTOR signaling pathway.
The activation of many malignancies is associated with the PI3K/Akt/mTOR signaling pathway. Under normal circumstances, PI3K can be controlled by the “oncogene PTEN”, which prevents these signaling pathways from acting. However, when the PTEN gene is inactivated for various reasons, its inhibitory effect on PI3K is disabled, and the signaling pathway is activated, thus altering the cell cycle and apoptosis, leading to a much higher likelihood of tumor development.
In breast cancer, activation of the PI3K/Akt/mTOR signaling pathway is up to 70%. Therefore, theoretically, it may be possible to control breast cancer by blocking PI3K/Akt/mTOR signaling pathway activation through PI3K inhibitors.
Buparlisib: An option for tackling drug resistance
In phase I clinical studies, Buparlisib demonstrated some control of advanced solid tumors, including breast cancer. In subsequent studies, Buparlisib in combination with other agents may play a role in the treatment of multiple subtypes of breast cancer.
Hormone receptor-positive advanced breast cancer: dealing with endocrine therapy resistance while being alert for adverse effects
For hormone-receptor-positive breast cancer, endocrine therapy is an important treatment option, yet resistance issues often lead to treatment failure. buparlisib has the potential to address this issue of endocrine therapy resistance.
BELLE-2 is a phase III clinical study enrolling 1147 hormone receptor-positive, HER2-negative breast cancer patients with inoperable, locally advanced or metastatic breast cancer that is postmenopausal and progressed during or after treatment with an aromatase inhibitor. and may have been treated with a previous chemotherapy regimen for advanced breast cancer.
The results were that the combination of Buparlisib on top of fulvestrant treatment prolonged median progression-free survival by 1.9 months (from 5.0 months to 6.9 months) and increased the risk of disease progression by risk of disease progression by 22%. In PI3K pathway activation in 372 patients, the combination of Buparlisib prolonged median progression-free survival by 2.8 months (from 4.0 months to 6.8  nbsp;months), and the risk of disease progression was reduced by 24%.
For safety, patients who were added to Buparlisib had an increased incidence of grade 3 to 4 adverse reactions, including elevated alanine aminotransferase (ALT) (25%, 1%, respectively), elevated aspartate aminotransferase (AST) (18%, 3%), hyperglycemia (15%, <1%) , rash (8%, 0), and slightly higher rates of serious adverse reactions ALT elevation (3%, <1%), AST elevation (2%, <1%).
In the BELLE-3 study, the enrolled 432 patients progressed during or after treatment with endocrine therapy and mTOR inhibitors. The addition of Buparlisib to fulvestrant similarly prolonged median progression-free survival by 2.1 months (from 1.8 months to 3.9 months), and the risk of tumor progression was reduced by 33%. But the same adverse effects occurred.
It is clear that in endocrine therapy-resistant hormone receptor-positive, HER2 -negative advanced breast cancer, the combination of Buparlisib on top of fulvestrant therapy may further improve patient survival and control disease progression, but safety is also an issue that needs attention.
In another phase Ib clinical study enrolling 51 estrogen receptor-positive, HER2 -negative metastatic breast cancer, all patients enrolled were endocrine therapy resistant. After treatment with Buparlisib in combination with letrozole (Letrozole), the clinical benefit rate (i.e., time to tumor progression ≥6 months) for patients was 31%. Adverse events during the study period included ≤ grade 2 hyperglycemia, nausea, fatigue, elevated transaminases, and mood abnormalities.
From the results of this study, the treatment regimen of letrozole combined with Buparlisib was accompanied by adverse events, but they were all reversible, suggesting that the regimen is safe and demonstrated efficacy.
HER2 positive advanced breast cancer: combination with Buparlisib after targeted therapy resistance
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The PI3K inhibitor Buparlisib combined with targeted anti-HER2 therapy also has a role in HER2-positive breast cancer.
17 patients with HER2 positive locally advanced or metastatic breast cancer were treated with Buparlisib after progression on trastuzumab (Trastuzumab). results showed a disease control rate of 75%, meaning that 17% of patients achieved partial remission. nbsp;of patients achieved partial remission and 58% of patients had stable disease for ≥6 weeks. Patients in the study were well tolerated, with major adverse effects including rash (39%), hyperglycemia (33%), and diarrhea (28%).
24 trastuzumab treatment-resistant HER2 positive locally advanced or metastatic breast cancer patients treated with lapatinib in combination with buparlisib had a disease control rate of 79%, with 1 patient in complete remission and 6  nbsp;one patient had complete remission and 6 patients had stable disease for ≥24 weeks. The major adverse reactions during this period were diarrhea, nausea, rash, malaise, depression, anxiety, and elevated transaminases.
As seen, in HER2 positive locally advanced or metastatic breast cancer, the combination of Buparlisib in anti HER2 therapy may continue to work after resistance to targeted therapy against HER2 but still needs to be validated in large randomized controlled Phase III clinical studies are needed for validation.
More to explore
More studies of Buparlisib in breast cancer are ongoing, in addition to continuing to explore its use in endocrine therapy-resistant hormone receptor-positive advanced breast cancer (NCT01610284) and in combination with chemotherapy agents in metastatic breast cancer (NCT01300962, NCT0200088). nbsp;NCT02000882), triple-negative breast cancer is also a direction of interest for investigators (NCT01790932).
Desirably, studies on Buparlisib have also been conducted in our population.The study of Buparlisib in advanced solid tumors such as breast cancer has been concluded, but the results are not yet available (CTR20130853). The study in endocrine therapy-resistant estrogen receptor-positive, HER2 -negative advanced breast cancer is up to phase III clinical study (CTR20130871), and patient recruitment has been completed, so let’s see how Buparlisib in combination with fulvestrant works in these patients.
Summary
For advanced breast cancer that is resistant to anti HER2 targeted therapy or resistant to endocrine therapy, the combination of Buparlisib can help address drug resistance and control tumor progression:
- Hormone receptor-positive, HER2 -negative breast cancer, the combination of Buparlisib prolongs median progression-free survival by nearly 2 months and reduces the risk of disease progression by 30% or so;
- HER2 positive, hormone receptor-negative breast cancer with disease control rates approaching 80% after combination Buparlisib .
Adverse effects such as elevated transaminases, hyperglycemia, nausea, fatigue, diarrhea, rash, and mood abnormalities can accompany the use of Buparlisib during Buparlisib and although largely tolerated, this is something to consider when choosing to apply the drug in the future.
More studies of Buparlisib in breast cancer are ongoing, and expect more data to surprise for Buparlisib to address drug resistance issues.