Alpelisib — Drug Monograph

Brand names: Piqray, Vijoice

Drug class: Tyrosine Kinase Inhibitor

Mechanism of Action

Alpelisib is a class I PI3K alpha-specific inhibitor that selectively and potently blocks the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), encoded by PIK3CA. Inhibition of PI3Kα prevents phosphorylation of PIP2 to PIP3, thereby suppressing downstream AKT/mTOR signaling that drives tumor cell proliferation and survival. PIK3CA-activating mutations (helical domain: E542K, E545K; kinase domain: H1047R) render cancer cells heavily dependent on this pathway, conferring sensitivity to alpelisib. In PIK3CA-related overgrowth spectrum (PROS), somatic gain-of-function PIK3CA…

FDA Indications

• PIK3CA-mutated, hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer (postmenopausal women and men), in combination with fulvestrant, following progression on or after an endocrine-based regimen — detected by an FDA-approved companion diagnostic (Piqray)
• PIK3CA-Related Overgrowth Spectrum (PROS) in adult and pediatric patients ≥2 years of age requiring systemic therapy (Vijoice)

Common Side Effects

• Hyperglycemia (≥50%; fasting plasma glucose elevation — most common and clinically critical adverse effect)
• Diarrhea (≥58%)
• Nausea (≥45%)
• Rash / acneiform dermatitis (≥36%; distinct from SCAR)
• Decreased appetite (≥36%)
• Stomatitis / oral mucositis (≥30%)
• Fatigue (≥28%)
• Weight loss (≥27%)
• Alopecia (≥20%)
• Vomiting (≥24%)
• Peripheral edema (≥18%)
• Dysgeusia (≥16%)
• Elevated creatinine (≥40%)
• Lymphopenia (≥52%)
• Decreased hemoglobin (≥29%)
• Elevated gamma-glutamyltransferase (≥32%)
• Elevated lipase (≥18%)
• Prolonged prothrombin time (≥18%)

Clinical Pearl

The pivotal SOLAR-1 trial (N=572) demonstrated that alpelisib + fulvestrant significantly improved PFS versus placebo + fulvestrant in PIK3CA-mutated HR+/HER2- advanced breast cancer (11.0 vs 5.7 months; HR 0.65; p<0.001). Hyperglycemia is the most clinically impactful toxicity — prophylactic metformin (initiated at or before cycle 1) substantially reduced the incidence and severity of Grade ≥3 hyperglycemia in a SOLAR-1 subgroup analysis and is now standard practice at most centers. Rash can…

Related Therapies & Mechanisms

• Tucatinib (Tukysa) — Tyrosine Kinase Inhibitor · Breast
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• Asciminib (Scemblix) — Tyrosine Kinase Inhibitor