Itovebi is the brand name for inavolisib, an oral, selective inhibitor and degrader of the alpha isoform of phosphoinositide 3-kinase (PI3Kα), designed to target tumors harboring PIK3CA mutations. It is approved for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), PIK3CA-mutated locally advanced or metastatic breast cancer in combination with palbociclib and fulvestrant after disease progression following endocrine-based therapy.

Itovebi represents a novel, next-generation approach that not only inhibits PI3Kα enzymatic activity but also induces selective degradation of the mutant enzyme, offering a distinct mechanism over previous PI3K inhibitors.

Efficacy Outcomes from the INAVO120 Trial

Source: INAVO120 Phase III Clinical Trial, 2024

Indications and Use

Itovebi is indicated for use in adult patients with HR-positive, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer whose disease has progressed after at least one line of endocrine therapy. The PIK3CA mutation must be confirmed by an FDA-approved companion diagnostic test, such as the FoundationOne Liquid CDx.

The treatment is administered in combination with:

• Palbociclib (a CDK4/6 inhibitor)
• Fulvestrant (a selective estrogen receptor degrader)

Mechanism of Action

Inavolisib selectively binds to the catalytic subunit of PI3Kα, particularly when mutated (as in the common PIK3CA variants found in breast cancer). Upon binding, it not only inhibits kinase activity but also promotes degradation of the mutant enzyme via the ubiquitin-proteasome system.

The inhibition of PI3Kα disrupts the PI3K/AKT/mTOR signaling pathway, which is involved in cellular proliferation, survival, and metabolism. This dual inhibition and degradation approach helps suppress tumor growth more effectively than traditional PI3K inhibitors, which may be limited by compensatory pathway activation.

Dosage and Administration

The recommended dosage of Itovebi is 9 mg orally once daily, with or without food.

It is given in combination with:

• Palbociclib 125 mg orally once daily for 21 days, followed by 7 days off (28-day cycle)
• Fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, then Day 1 of each subsequent cycle (28-day cycles)

Treatment continues until disease progression or unacceptable toxicity. Dose reductions may be necessary depending on the patient’s tolerance:

• First reduction: 6 mg once daily
• Second reduction: 3 mg once daily
• Discontinue if unable to tolerate 3 mg

Common Adverse Reactions to Itovebi (All Grades)

Supportive care and dose modifications were implemented as needed.

Clinical Efficacy

Efficacy was demonstrated in the pivotal Phase III INAVO120 trial, a randomized, double-blind, placebo-controlled study involving approximately 325 patients with PIK3CA-mutated HR+/HER2− metastatic breast cancer.

Results from the INAVO120 study:

• Median progression-free survival (PFS): 15.0 months with inavolisib versus 7.3 months with placebo
• Overall response rate (ORR): 58% with inavolisib versus 25% with placebo
• Median duration of response: 18.4 months versus 9.6 months
• Hazard ratio for PFS: 0.43 (95% CI: 0.32–0.59), statistically significant (p<0.0001)

These data demonstrate a clinically meaningful benefit in delaying disease progression and achieving tumor response.

Adverse Reactions

The most common adverse reactions (≥20%) observed in clinical trials included:

• Hyperglycemia
• Stomatitis
• Diarrhea
• Nausea
• Fatigue
• Rash
• Decreased appetite
• Anemia
• Thrombocytopenia
• Neutropenia

Hyperglycemia occurred in approximately 85% of patients, with grade 3 or higher events in 12%. Stomatitis and diarrhea often began within the first two to three weeks of treatment. Supportive care, including glucose monitoring, dietary counseling, and use of antihyperglycemic agents or antidiarrheals, may be required.

Serious adverse reactions included febrile neutropenia, infections (including COVID-19), and severe hyperglycemia. Treatment interruptions and dose reductions were common and managed according to severity.

Warnings and Precautions

Patients should be closely monitored for hyperglycemia. Fasting plasma glucose and HbA1c should be evaluated before starting therapy and periodically during treatment. Initiation or adjustment of antidiabetic therapy may be necessary.

Stomatitis and diarrhea should be managed with dose interruptions, reductions, and supportive care as needed.

Itovebi can cause fetal harm. Pregnancy testing is required before initiation in females of reproductive potential. Effective contraception (non-hormonal) should be used during treatment and for at least 2 weeks after the last dose.

Itovebi has not been studied in patients with severe renal or hepatic impairment. Dose reduction is recommended in moderate renal impairment (eGFR 30–59 mL/min/1.73 m²). No dose adjustment is necessary for mild hepatic impairment; use in moderate or severe impairment has not been established.

Contraindications

Itovebi is contraindicated in patients with known hypersensitivity to inavolisib or any of its excipients.

Drug Interactions

No formal clinical drug-drug interaction studies have been conducted. In vitro data suggest that inavolisib may act as both an inducer and an inhibitor of certain cytochrome P450 enzymes (e.g., CYP3A4, CYP2C8, CYP2B6), which may affect the metabolism of other drugs. Clinical monitoring is advised when coadministering with CYP substrates.

Use in Specific Populations

Elderly patients (≥65 years) experienced similar efficacy but may have higher rates of dose interruption due to toxicity.

The safety and efficacy of Itovebi in pediatric patients have not been established.

Pregnant and breastfeeding women should not receive inavolisib due to the risk of embryo-fetal toxicity. It is unknown whether inavolisib is present in human milk.

Storage and Handling

Itovebi is supplied as oral tablets. It should be stored at controlled room temperature, protected from moisture and heat. This product is considered a hazardous drug; healthcare professionals should use appropriate personal protective equipment when handling.

Regulatory Status

Itovebi (inavolisib) received full approval from the U.S. Food and Drug Administration (FDA) in October 2024 following priority review and breakthrough therapy designation. Approval was based on statistically significant improvement in progression-free survival in the INAVO120 trial. It is currently under review in other jurisdictions, including the European Medicines Agency (EMA).

Alternatives and Comparators

Other targeted therapies for HR-positive, HER2-negative advanced breast cancer include:

• Alpelisib (Piqray): a PI3Kα inhibitor approved for PIK3CA-mutant disease, though associated with high rates of hyperglycemia and rash
• CDK4/6 inhibitors: palbociclib, ribociclib, abemaciclib
• Fulvestrant and next-generation oral SERDs (e.g., elacestrant)
• AKT and mTOR inhibitors in clinical development

Compared to alpelisib, inavolisib appears to offer a more favorable toxicity profile with enhanced PIK3CA degradation activity and improved tolerability in combination therapy settings.

Itovebi (inavolisib) offers a significant advancement in the management of PIK3CA-mutant HR+/HER2− metastatic breast cancer. Its dual mechanism of selective inhibition and degradation of PI3Kα leads to meaningful improvements in progression-free survival and tumor response, with manageable side effects under proper clinical monitoring. As a once-daily oral agent in combination with standard-of-care partners, it provides a targeted, personalized approach to overcoming resistance in endocrine-refractory breast cancer.