Inavolisib (Monograph)

Brand name: Itovebi
Drug class: Antineoplastic Agents

Introduction

Antineoplastic agent; a phosphatidylinositol 3-kinase (PI3K) inhibitor.

Uses for Inavolisib

Breast Cancer

Used 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.

ASCO recommends CDK4/6 inhibitor with endocrine therapy as first-line treatment for HR-positive, HER2-negative, metastatic breast cancer. Second and third-line treatment options include targeted therapies (e.g., capivasertib, alpelisib) based on tumor genomics and prior endocrine therapy. Combination therapy with fulvestrant, palbociclib, and inavolisib is recommended as a treatment option for patients with HR-positive, HER2-negative, metastatic breast cancer who have a PIK3CA mutation in ESMO guidelines.

Inavolisib Dosage and Administration

General

Pretreatment Screening

Select patients for treatment based on the presence of one or more PIK3CA mutations in plasma specimens. Information on FDA-approved tests for the detection of PIK3CA mutations in breast cancer is available at [Web].
Evaluate fasting glucose levels and HbA_1C and optimize fasting glucose.
Verify pregnancy status in females of reproductive potential.

Patient Monitoring

After initiating therapy or in patients who experience hyperglycemia during treatment, monitor or self-monitor fasting glucose levels once every 3 days for the first week, then once every week for the next 3 weeks, once every 2 weeks for the next 8 weeks, then once every 4 weeks thereafter, and as clinically indicated. Monitor HbA_1c every 3 months and as clinically indicated.
Monitor patients for signs and symptoms of stomatitis.
Monitor patients for signs and symptoms of diarrhea.

Other General Considerations

Treat premenopausal and perimenopausal women with luteinizing hormone-releasing hormone (LHRH) agonist therapy according to current standards of care. Consider administration of LHRH agonist therapy in male patients according to current standards of care.

Administration

Oral Administration

Administer with or without food at approximately the same time each day.

Commercially available as 3 mg and 9 mg tablets.

Swallow tablets whole; do not chew, crush, or split.

If a dose of inavolisib is missed, take missed dose as soon as possible within 9 hours. If a dose of inavolisib is missed >9 hours, skip the missed dose and take the next dose at the scheduled time.

If a dose of inavolisib is vomited, do not take an extra dose. Take the next dose at the regularly scheduled time.

Dosage

Adults

Breast Cancer

Oral

Recommended dosage is 9 mg once daily.

Continue treatment until disease progression or unacceptable toxicity occurs.

Use in combination with palbociclib and fulvestrant. Recommended dosage of palbociclib is 125 mg taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a cycle of 28 days. Refer to the full prescribing information for palbociclib and fulvestrant for respective dosing information.

Dosage Modification for Adverse Reactions

If adverse reactions occur, dosage interruption and/or reduction, or discontinuance of inavolisib may be necessary (see Table 1).

If dosage reduction from 9 mg once daily is necessary, reduce dosage to 6 mg daily. If toxicity recurs at dosage of 6 mg daily, reduce dosage to 3 mg daily. If patients are unable to tolerate second dosage reduction, permanently discontinue inavolisib.

Table 1: Recommended Dosage Modifications for Inavolisib Adverse Reactions1
Adverse Reaction	Dosage Modification Based on Severity
Hyperglycemia	Fasting glucose levels (FPG or FBG) >ULN to 160 mg/dL: No adjustment required. Consider dietary modifications and ensure adequate hydration; initiate or intensify oral anti-hyperglycemic medications for patients with risk factors for hyperglycemia. Fasting glucose levels >160 to 250 mg/dL: Withhold until FPG or FBG ≤160 mg/dL; initiate or intensify anti-hyperglycemic medications. Resume at the same dose level. If FPG or FBG persists >200-250 mg/dL for 7 days under the appropriate anti-hyperglycemic treatment, consider consultation with a healthcare professional experienced in hyperglycemia management. Fasting blood glucose levels >250 to 500 mg/dL: Withhold. Initiate or intensify anti-hyperglycemic medications. Administer appropriate hydration if required. If FPG or FBG decreases to ≤160 mg/dL within 7 days, resume at the same dose. If FPG or FBG decreases to ≤160 mg/dL in ≥8 days, resume at 1 lower dose level. If FPG or FBG >250 to 500 mg/dL recurs within 30 days, withhold until FPG or FBG decreases to ≤160, then resume at 1 lower dose level. Fasting blood glucose levels >500 mg/dL: Withhold. Initiate or intensify anti-hyperglycemic medications. Assess for volume depletion and ketosis and administer appropriate hydration. If FPG or FBG decreases to ≤160 mg/dL, resume at 1 lower dose level. If FPG or FBG >500 mg/dL recurs within 30 days, permanently discontinue.
Stomatitis	Grade 1: No adjustment necessary. Initiate or intensify appropriate medical therapy (e.g., corticosteroid-containing mouthwash) as clinically indicated. Grade 2: Withhold until improvement to grade 1 or lower. Initiate or intensify appropriate medical therapy. Resume at the same dose level. For recurrent grade 2 stomatitis, withhold until recovery to grade 1 or lower, then resume at one lower dose level. Grade 3: Withhold until recovery to grade 1 or lower. Initiate or intensify appropriate medical therapy. Resume at 1 lower dose level. Grade 4: Permanently discontinue.
Diarrhea	Grade 1: No adjustment required. Initiate appropriate medical therapy and monitor as clinically indicated. Grade 2: Withhold until recovery to grade 1 or lower, then resume at same dose level. Initiate or intensify appropriate medical therapy and monitor as clinically indicated. For recurrent grade 2 diarrhea, withhold until recovery to grade 1 or lower, then resume at one lower dose level. Grade 3: Withhold until recovery to grade 1 or lower, then resume at one lower dose level. Initiate or intensify appropriate medical therapy and monitor as clinically indicated. Grade 4: Permanently discontinue.
Hematologic toxicities	Grade 1, 2, or 3: No adjustment required. Monitor CBC and for signs or symptoms of hematologic toxicities as clinically indicated. Grade 4: Withhold until recovery to grade 2 or lower. Resume at the same dose level or reduce to one lower dose level as clinically indicated.
Other adverse reactions	Grade 1: No adjustment required. Grade 2: Consider withholding, if clinically indicated, until recovery to grade 1 or lower. Resume at the same dose level. Grade 3 (first event): Withhold until recovery to grade 1 or lower. Resume at the same dose level or one lower dose level based on clinical evaluation. Grade 3 (recurrent): Withhold until recovery to grade 1 or lower. Resume at one lower dose level. Grade 4: Permanently discontinue.

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

In patients with moderate renal impairment (eGFR 30 to <60 mL/min), recommended starting dosage of inavolisib is 6 mg orally once daily.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Inavolisib

Contraindications

None.

Warnings/Precautions

Hyperglycemia

May cause severe hyperglycemia.

Safety in patients with Type 1 diabetes mellitus, or Type 2 diabetes mellitus requiring ongoing antihyperglycemic treatment, not studied.

Prior to initiating treatment, evaluate fasting glucose levels and HbA_1C, and optimize fasting glucose. After initiating therapy, or in patients who experience hyperglycemia during treatment, monitor or self-monitor fasting glucose levels once every 3 days for first week, then once every week for next 3 weeks, once every 2 weeks for next 8 weeks, then once every 4 weeks thereafter, and as clinically indicated. Monitor HbA_1c every 3 months and as clinically indicated.

Manage hyperglycemia with anti-hyperglycemic medications as clinically indicated. Monitor fasting blood glucose levels while on anti-hyperglycemic medications.

Consider consultation with healthcare professional experienced with hyperglycemia and monitoring patient’s blood glucose levels at home for patients with risk factors for hyperglycemia or those who experience hyperglycemia. Advise patients of signs and symptoms of hyperglycemia; counsel on lifestyle changes. Interrupt, reduce dosage, or discontinue therapy based on severity.

Stomatitis

May cause severe stomatitis. May consider use of a mouthwash containing a corticosteroid for management or prophylaxis of stomatitis.

Monitor patients for signs and symptoms of stomatitis. Interrupt, reduce dosage, or discontinue therapy based on severity.

Diarrhea

May cause severe diarrhea, including dehydration and acute kidney injury.

Monitor patients for signs and symptoms of diarrhea. If diarrhea occurs while on treatment, advise patients to increase oral fluids and start antidiarrheal treatment. Interrupt, reduce dose, or discontinue therapy based on severity.

Fetal/Neonatal Morbidity and Mortality

May cause embryo-fetal harm based on animal reproductive studies and its mechanism of action.

Advise pregnant women and females of reproductive potential of potential risk to fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment and for 1 week after last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 1 week after last dose.

Specific Populations

Pregnancy

No available human data. May cause fetal harm based on animal reproductive studies and its mechanism of action.

Lactation

Unknown whether inavolisib is distributed into human milk, or if drug has any effects on breastfed infant or milk production. Because of potential for serious adverse reactions in nursing infants, advise patients to discontinue breastfeeding during and for 1 week after final dose.

Females and Males of Reproductive Potential

Animal studies suggest inavolisib may impair female and male fertility.

Verify pregnancy status in females of reproductive potential prior to initiating treatment. Advise females of reproductive potential to use effective non-hormonal contraception during treatment and for 1 week after last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 1 week after last dose.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Insufficient number of patients ≥65 years of age included in clinical studies to determine whether they respond differently from younger patients.

Hepatic Impairment

No clinically significant differences in pharmacokinetics in patients with mild hepatic impairment; not studied in patients with moderate and severe hepatic impairment.

Renal Impairment

No clinically significant differences in pharmacokinetics in patients with mild renal impairment. Dosage reduction is recommended in patients with moderate renal impairment. Safety and efficacy not established in patients with severe renal impairment.

Common Adverse Effects

Most common adverse reactions (≥20%), including laboratory abnormalities: decreased neutrophils, decreased hemoglobin, increased fasting glucose, decreased platelets, decreased lymphocytes, stomatitis, diarrhea, decreased calcium, fatigue, decreased potassium, increased creatinine, increased ALT, nausea, decreased sodium, decreased magnesium, rash, decreased appetite, COVID-19 infection, headache.

Drug Interactions

Induces CYP3A and CYP2B6.

Time-dependent inhibitor of CYP3A. Not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.

Substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but not a substrate of organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic cation transporter (OCT)1, OCT2, multidrug and toxin extrusion transporter (MATE)1, MATE2K, or organic anion transporter (OAT)1, OAT2.

Not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2K.

Proton Pump Inhibitors

No clinically meaningful effect on inavolisib exposure.

Inavolisib Pharmacokinetics

Absorption

Bioavailability

76%.

Food

No clinically significant effects on pharmacokinetics following high fat meal.

Plasma Concentrations

Median time to maximum plasma concentration is 3 hours.

Distribution

Plasma Protein Binding

37%.

Elimination

Metabolism

Primarily metabolized by hydrolysis. Minimally metabolized by CYP3A.

Elimination Route

49% urine and 48% feces.

Half-life

15 hours.

Stability

Storage

Oral

Tablets

Store at 20–25ºC, excursions permitted 15–30ºC.

Actions

Highly selective small molecule inhibitor of p110 catalytic subunit alpha isoform protein of phosphatidylinositol 3-kinase (PI3K).
Activation of PI3K pathway activity frequently observed in breast cancer, leading to uncontrolled tumor cell growth and drug resistance.
In vitro, inavolisib induced degradation of mutated PI3K catalytic alpha subunits p110α, inhibited phosphorylation of the downstream target protein kinase B (AKT), reduced cellular proliferation, and induced apoptosis in PIK3CA-mutated breast cancer cell lines.
In vivo, inavolisib reduced tumor growth in PIK3CA-mutated, estrogen receptor-positive, breast cancer xenograft models. Anti-tumor activity more pronounced when used in combination with fulvestrant and palbociclib.

Advice to Patients

Advise patients to read the FDA-approved patient labeling (Patient Information).
Advise patients that inavolisib may cause hyperglycemia and the need to monitor fasting glucose levels periodically during therapy. Advise patients to contact their healthcare provider immediately for signs and symptoms of hyperglycemia (e.g., excessive thirst, urinating more often, blurred vision, mental confusion, difficulty breathing, or increased appetite with weight loss).
Advise patients that inavolisib may cause stomatitis, which may be severe, and to notify their healthcare provider if they develop symptoms of stomatitis (e.g., painful redness, swelling, or sores in the mouth).
Advise patients that inavolisib may cause diarrhea, which may be severe, and to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking inavolisib.
Advise patients to inform their healthcare provider of a known or suspected pregnancy. Inform pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with inavolisib and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with inavolisib and for 1 week after the last dose.
Advise patients not to breastfeed during treatment with inavolisib and for 1 week after the last dose.
Advise females and males of reproductive potential that inavolisib may impair fertility.
Instruct patients to take inavolisib at approximately the same time each day. Instruct patients that if vomiting occurs after taking the inavolisib dose, do not take an additional dose on that day. Resume the usual dosing schedule the next day.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Inavolisib is available through designated specialty pharmacies. Contact the manufacturer, Genentech, for more information.