OVERVIEW
Introduction
Inavolisib is a small molecule inhibitor of phosphatidylinositol 3-kinase and is used in combination with other antineoplastic agents to treat selected adults with locally advanced or metastatic breast cancer. Inavolisib is associated with transient elevations in serum aminotransferase levels during therapy but has not been linked to episodes of clinically apparent liver injury with jaundice.
Background
Inavolisib (in a voe’ li sib) is an orally available, specific inhibitor of phosphatidylinositol 3-kinase (PIK3) that is used in the therapy of advanced or metastatic breast cancer that has PIK3 catalytic alpha subunit p110α (CA) mutations and is hormone receptor (HR) positive and human epidermal growth factor receptor 2 (HER2) negative. The mutated, rearranged PIK3-CA is found in 35% to 40% of cases of advanced or metastatic HR-positive breast cancer and is associated with a poor prognosis and resistance to standard PIK3 inhibitors. In cell lines, inavolisib induced apoptosis in PIK3-CA mutated breast cancer cell lines. Inavolisib also demonstrated antitumor activity in animal xenograft models of breast cancer with PIK3-CA mutations. In a large, controlled trial, patients with HR-positive and HER2-negative advanced or metastatic breast cancer harboring PIK3-CA mutations were treated with the combination of palbociclib and fulvestrant with either inavolisib or placebo in 28 day cycles. The median progression-free survival was superior with inavolisib (15 months) compared to placebo (7.3 months). Inavolisib was approved in 2024 in the United States as treatment for patients with locally advanced or metastatic HR-positive, HER2-negative breast cancer with mutations in PIK3-CA. Inavolisib is available in tablets of 3 and 9 mg under the brand name Itovebi. The recommended dose is 9 mg once daily until unacceptable toxicity or disease progression arises. Side effects are common and include mild-to-moderate stomatitis, diarrhea, fatigue, nausea, anorexia, and rash. Laboratory abnormalities can include increases in fasting glucose, creatinine, and serum aminotransferases, as well as decreases in neutrophils, lymphocytes, hemoglobin, platelet counts, calcium, magnesium, potassium, and sodium. Less frequent but potentially severe adverse events include severe hyperglycemia, stomatitis, diarrhea, and embryo-fetal toxicity.
Hepatotoxicity
In the prelicensure trials of inavolisib in combination with palbociclib and fulvestrant as therapy of advanced or metastatic breast cancer, liver test abnormalities were frequent, with elevations in ALT levels in 34% compared to 29% of those on placebo with palbociclib and fulvestrant. The enzyme elevations were usually transient, mild-to-moderate in severity and not associated with symptoms or jaundice. ALT elevations above 5 times the upper limit of normal (ULN) arose in 3% vs 1.2% with placebo. Because inavolisib was always given in combination with other kinase inhibitors and hormonal agents, it was difficult to attribute the liver test abnormalities to inavolisib alone. There were no discontinuations of inavolisib because of liver test abnormalities and no episodes of clinically apparent liver injury or deaths from liver failure. Since approval and clinical availability of inavolisib, there have been no published case reports of clinically apparent liver injury with jaundice, but clinical experience with its use has been limited.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).
Mechanism of Injury
The causes of serum enzyme elevations or liver injury from inavolisib therapy are possibly due to direct toxicity of the kinase inhibition of PIK3. Inavolisib is primarily metabolized by hydrolysis and minimally metabolized by the hepatic microsomal enzyme CYP3A. For these reasons, clinically significant drug-drug interactions are unlikely.
Outcome and Management
The product label for inavolisib does not recommend monitoring of liver tests during therapy. If serum aminotransferase elevations above 5 times the upper limit of normal are identified or if any elevations are accompanied by jaundice or symptoms, therapy should be at least temporary discontinued. There is no evidence to suggest a cross reactivity in risk for adverse events, hypersensitivity, or hepatic injury between inavolisib and other kinase inhibitors used to treat breast cancer, such as palbociclib, alpelisib, ribociclib, and capivaseritib.
Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors
Other Kinase Inhibitors Used for Breast Cancer: Alpelisib, Capivaseritib, Ribociclib, Talazoparib, Tucatinib
ANNOTATED BIBLIOGRAPHY
References updated: 05 April 2025
Abbreviations: HER2, human epidermal growth factor receptor 2; HR, hormone receptor; PIK3, phosphatidylinositol-3-kinase; PIK3-CA, PIK3 catalytic alpha subunit p110α; PTEN, phosphatase and tensin homolog; ULN, upper limit of the normal range.
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https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/219249Orig1s000MultidisciplineR.pdf(FDA review of the data on efficacy and safety of inavolisib in support of its approval for advanced or metastatic breast cancer in the US, mentions that liver test abnormalities were frequent in patients who received palbociclib and fulvestrant both with vs without inavolisib, ALT elevations arising in 19.1% vs 18.5% which were above 5 times the upper limit of normal (ULN) in 3.7% vs 1.9%, but that there were no instances of clinically apparent liver injury with jaundice or life-threatening or fatal liver injury).
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(Review of genetic associations of serum ALT and bilirubin elevations during therapy with tyrosine kinase inhibitors focusing on lapatinib and pazopanib; inavolisib is not discussed).
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(Description of the optimization and characterization of a competitive inhibitor of PIK3-CA mutants [GDC-0077, inavolisib], which induces protein degradation of the mutant protein and relatively spares wild type PIK3-CA as well as other PIK3 isoforms in human breast cancer cells).
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(63 year old woman with metastatic breast cancer and renal disease but normal fasting blood glucose and HbA1c levels developed severe hyperglycemia [glucose 439 mg/dL] within 2 weeks of starting inavolisib [9 mg daily] and fulvestrant that was not controlled until the dose was reduced to 3 mg daily and that resolved completely once the PIK3-CA inhibitor was stopped).
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(Among 325 women with advanced or metastatic HR-positive, HER2-negative breast cancer with PIK3-CA mutations treated with palbociclib and fulvestrant with inavolisib [9 mg daily] vs placebo, the objective response rate was 58% vs 25% and median progression-free survival 15 vs 7.3 months, while adverse events arose in 99% vs 100% that were severe in 58% vs 25%, most frequently neutropenia [89% vs 91%], stomatitis [51% vs 27%], hyperglycemia [59% vs 9%], diarrhea [48% vs 16%], and rash [25% vs 17%], leading to early discontinuation in 7% vs 1%; no mention of ALT elevations or hepatotoxicity).
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(Brief review of the mechanism of action, clinical efficacy, safety, and costs of inavolisib shortly after its approval as therapy of breast cancer in the US, mentions side effects of hyperglycemia, stomatitis, fatigue, nausea, decreased appetite, diarrhea, and hematologic toxicity but does not mention ALT elevations or hepatotoxicity).
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Phase I/Ib trial of inavolisib plus palbociclib and endocrine therapy for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer.
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(Among 53 patients with advanced or metastatic breast cancer harboring PIK3-CA mutations who were treated with inavolisib with palbociclib and either fulvestrant or letrozole, adverse events arose in all patients and were mainly stomatitis, hyperglycemia, neutropenia, diarrhea, thrombocytopenia, leukopenia, asthenia, alopecia, and rash; no mention of ALT elevations or hepatotoxicity).
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(Review of the mechanism of action, history of development, pharmacology, clinical efficacy, and safety of inavolisib shortly after its approval for use in the US, states that inavolisib has “a manageable tolerability profile” and makes no mention of ALT elevations or hepatotoxicity).
