Inavolisib Advanced Drug Monograph

Inavolisib Report

Name: Inavolisib Name (English): Inavolisib DrugBank ID: DB15275 Type: Small Molecule CAS Number: 2060571-02-8

Mechanism of Action: Inavolisib is a selective inhibitor of the Class I PI3Kα isoform (p110α). It binds to the ATP-binding site of PI3Kα, inhibiting the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3). This reduces downstream activation of AKT and ribosomal protein S6, leading to decreased cell proliferation, metabolism, and angiogenesis. Inavolisib also specifically triggers the degradation of the mutant p110α protein.

Indication: Inavolisib is indicated in combination with palbociclib and fulvestrant for the treatment of adults with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy.

Contraindications: There are no specific contraindications listed beyond potential hypersensitivity to the drug or any of its components. Caution should be exercised in patients with a history of diabetes or kidney disease.

Pharmacokinetics:

• Absorption: The absolute oral bioavailability of inavolisib is 76%. Steady-state is reached by approximately day 5, with a Tmax of 3 hours. Food does not significantly affect pharmacokinetics.
• Distribution: Not specified in detail but it crosses cell membranes.
• Metabolism: Inavolisib appears metabolically stable in hepatocytes.
• Elimination: The total clearance of inavolisib is 8.8 L/h. It is a substrate of P-gp and BCRP/ABCG2 transporters.

Side Effects: Common side effects include:

• Neutropenia
• Thrombocytopenia
• Anemia
• Hyperglycemia
• Stomatitis
• Diarrhea
• Nausea
• Rash
• Decreased appetite
• Fatigue
• Headache
• COVID-19 infection

Serious side effects may include severe hyperglycemia, severe stomatitis, and potential fetal harm if administered during pregnancy.

Drug Interactions: No severe, serious, moderate, or minor drug interactions are currently noted. However, it is a CYP2B6 inducer.

Clinical Trials: Inavolisib is being evaluated in several Phase III clinical trials (INAVO120, INAVO121, INAVO122) in PIK3CA-mutated locally advanced or metastatic breast cancer in various combinations. The INAVO120 trial demonstrated significantly longer progression-free survival when inavolisib was added to palbociclib and fulvestrant.

Regulatory Status: Inavolisib (Itovebi) was approved by the FDA on October 10, 2024, for the treatment of PIK3CA-mutated, HR-positive, HER2-negative advanced or metastatic breast cancer in combination with palbociclib and fulvestrant. The application for EMA approval has been under review since March 2024.

Warnings and Precautions:

• Hyperglycemia: Severe hyperglycemia can occur; monitor glucose levels frequently.
• Stomatitis: Monitor for signs and symptoms; corticosteroid mouthwash may be used for management or prophylaxis.
• Hematologic Toxicities: Monitor blood counts.
• Embryo-Fetal Toxicity: Can cause fetal harm; advise females and males of reproductive potential about contraception.
• Lactation: Advise women not to breastfeed during and for 1 week after the last dose.
• Potential for Infertility: May impair fertility in females and males.