Role of Alpelisib in the Treatment of PIK3CA-Mutated Breast Cancer: Patient Selection and Clinical Perspectives

Abstract

The PI3K/AKT/mTOR pathway has long been known to play a major role in the growth and survival of cancer cells. Breast tumors often harbor PIK3CA gene alterations, which therefore constitute a rational drug target. However, it has taken many years to demonstrate clinically-relevant efficacy of PI3K inhibition and eventually attain regulatory approvals. As data on PI3K inhibitors continue to mature, this review updates and summarizes the current state of the science, including the prognostic role of PIK3CA alterations in breast cancer; the evolution of PI3K inhibitors; the clinical utility of the first-in-class oral selective PI3Kα inhibitor, alpelisib; PIK3CA mutation detection techniques; and adverse effect management. PIK3CA -mutated breast carcinomas predict survival benefit from PI3K inhibitor therapy. The pan-PI3K inhibitor, buparlisib and the beta-isoform-sparing PI3K inhibitor, taselisib, met efficacy endpoints in clinical trials, but pictilisib did not; moreover, poor tolerability of these three drugs abrogated further clinical trials. Alpelisib is better tolerated, with a more manageable toxicity profile; the principal adverse events, hyperglycemia, rash and diarrhea, can be mitigated by intensive monitoring and timely intervention, thereby enabling patients to remain adherent to clinically beneficial treatment. Alpelisib plus endocrine therapy shows promising efficacy for treating postmenopausal women with HR+/HER2– advanced breast cancer. Available evidence supporting using alpelisib after disease progression on first-line endocrine therapy with or without CDK4/6 inhibitors justifies PIK3CA mutation testing upon diagnosing HR+/HER2– advanced breast cancer, which can be done using either tumor tissue or circulating tumor DNA. With appropriate toxicity management and patient selection using validated testing methods, all eligible patients can potentially benefit from this new treatment. Further clinical trials to assess combinations of hormone therapy with PI3K, AKT, mTOR, or CDK 4/6 inhibitors, or studies in men and women with other breast subtypes are ongoing.

Oncomine™ Comprehensive Assay v3 vs. Oncomine™ Comprehensive Assay Plus

“…PIK3CA encodes the catalytic subunit of PI3K performing phosphorylation, triggering the downstream signaling of cell growth/proliferation and cell survival inter alia, facilitating uncontrolled cell growth when the genome is harboring pathogenic PIK3CA mutations [29]. The biological drug, Alpelisib, is specifically inhibiting PI3K-signaling in the PI3K/AKT signaling pathway [30]. The phosphatase PTEN is contributing the regulation of PI3K phosphorylation, hence controlling PI3K/AKT downstream signaling [31,32].…”

Characterization of Alpelisib in Rat Plasma by a Newly Developed UPLC-MS/MS Method: Application to a Drug-Drug Interaction Study

“…Thus, drugs against different-level PI3K networks have been evaluated in clinical trials ( Engelman, 2009 ; Thorpe et al, 2015 ). Alpelisib (BYL719, Figure 1A ), an oral selective, small-molecule, and α-specific class I PI3K inhibitor, can selectively inhibit wild-type and mutant p110α approximately 50 times more effective than other subtypes ( Brana and Siu, 2012 ; Furet et al, 2013 ; Chang et al, 2021 ). Several studies have demonstrated the efficacy of treating breast cancer as a single agent and combination therapy ( Miller et al, 2010 ; Juric et al, 2018 ; Juric et al, 2019 ; Sharma et al, 2021 ).…”

The PIK3CA H1047R Mutation Confers Resistance to BRAF and MEK Inhibitors in A375 Melanoma Cells through the Cross-Activation of MAPK and PI3K–Akt Pathways

“…These drugs were selected as they are most widely used in clinical practice [ 32 ]. Similarly, BYL719 was selected as the PI3K inhibitor as it is widely used for the treatment of PI3K-mutated tumours [ 33 ].…”