Inavolisib

{{DrugProjectFormSinglePage |authorTag=Parth Vikram Singh |genericName=Inavolisib |aOrAn=a |drugClass=phosphoinositide 3-kinase inhibitors |indicationType=treatment |indication=Inavolisib is a phosphoinositide 3-kinase inhibitor that is FDA approved 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 breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy. |adverseReactions=Common adverse reactions include 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, and headache. |blackBoxWarningTitle=TITLE |blackBoxWarningBody=Condition Name: (Content) |fdaLIADAdult=HR-positive, HER2-negative, locally advanced or metastatic breast cancer with the presence of one or more PIK3CA mutations in plasma specimens Recommended dosage of Inavolisib is 9 mg taken orally once daily, with or without food, until disease progression or unacceptable toxicity. |offLabelAdultGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Inavolisib in adult patients. |offLabelAdultNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Inavolisib in adult patients. |offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Inavolisib in pediatric patients. |offLabelPedNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Inavolisib in pediatric patients. |contraindications=None. |warnings=•Hyperglycemia

  •Severe hyperglycemia can occur in patients treated with Inavolisib. Increased fasting glucose occurred in 85% of patients treated with Inavolisib, including 22% of patients with Grade 2 (FPG > 160 to 250 mg/dL), 12% with Grade 3 (FPG > 250 to 500 mg/dL), and 0.6% with Grade 4 (FPG > 500 mg/dL) events. Among patients with hyperglycemia, the median time to first onset was 7 days (range: 2 to 955 days). Hyperglycemia led to dose interruption in 28%, to dose reduction in 2.5%, and to discontinuation of Inavolisib in 1.2% of patients. The safety of ITOVEBI in patients with Type 1 diabetes mellitus, or Type 2 diabetes mellitus requiring ongoing anti-hyperglycemic treatment have not been studied. Before initiating treatment with Inavolisib, test fasting glucose levels (FPG or FBG), HbA1C levels, and optimize fasting glucose. After initiating treatment with Inavolisib, or in patients who experience hyperglycemia after initiating treatment with Inavolisib, monitor or self-monitor fasting glucose levels once every 3 days for the first week (Day 1 to 7), then once every week for the next 3 weeks (Day 8 to 28), then once every 2 weeks for the next 8 weeks, then once every 4 weeks thereafter, and as clinically indicated. Monitor HbA1C every 3 months and as clinically indicated. Manage hyperglycemia with anti-hyperglycemic medications as clinically indicated. During treatment with anti-hyperglycemic medication, continue monitoring fasting glucose levels. Patients with a history of well-controlled Type 2 diabetes mellitus may require intensified anti-hyperglycemic treatment and close monitoring of fasting glucose levels. Based on the severity of the hyperglycemia, ITOVEBI may require dose interruption, reduction, or discontinuation.

•Stomatitis

  •Severe stomatitis can occur in patients treated with INAVOLISIB. Stomatitis occurred in 51% of patients treated with INAVOLISIB in combination with palbociclib and fulvestrant, including Grade 3 events in 6% of patients. The median time to first onset was 13 days (range: 1 to 610 days). Stomatitis led to interruption of INAVOLISIB in 10%, to dose reduction in 3.7%, and to discontinuation of INAVOLISIB in 0.6% of patients. Monitor patients for signs and symptoms of stomatitis. Withhold, reduce dose, or permanently discontinue INAVOLISIB based on severity.

•Diarrhea

  •Severe diarrhea, including dehydration and acute kidney injury, can occur in patients treated with Inavolisib. Diarrhea occurred in 48% of patients treated with Inavolisib in combination with palbociclib and fulvestrant, including Grade 3 events in 3.7% of patients. The median time to first onset was 15 days (range: 2 to 602 days). Anti-diarrheal medicines were used in 28% (46/162) of patients who received ITOVEBI in combination with palbociclib and fulvestrant to manage symptoms. Dose interruptions were required in 7% of patients, and dose reductions occurred in 1.2% of patients. Monitor patients for signs and symptoms of diarrhea. Advise patients to increase oral fluids and start anti-diarrheal treatment at the first sign of diarrhea while taking ITOVEBI. Withhold, reduce dose, or permanently discontinue ITOVEBI based on severity 

•Embryo-Fetal Toxicity

  •Based on findings in animals and its mechanism of action, INAVOLISIB can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, oral administration of inavolisib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, structural abnormalities, and alterations to growth at maternal exposures approximately equivalent to the human exposure at the recommended dose of 9 mg/day based on area under the curve (AUC). Advise 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.

|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of INAVOLISIB was evaluated in a randomized, double-blind, placebo-controlled study (INAVO120) in 324 patients with PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer. Patients received either INAVOLISIB 9 mg (n=162) or placebo (n=162) with palbociclib and fulvestrant. The median duration of treatment with INAVOLISIB was 9 months (range: 0 to 39 months) in the INAVOLISIB with palbociclib and fulvestrant arm. Serious adverse reactions occurred in 24% of patients who received INAVOLISIB with palbociclib and fulvestrant. Serious adverse reactions in ≥ 1% of patients included anemia (1.9%), diarrhea (1.2%), and urinary tract infection (1.2%). Fatal adverse reactions occurred in 3.7% of patients who received INAVOLISIB with palbociclib and fulvestrant, including (0.6% each) acute coronary syndrome, cerebral hemorrhage, cerebrovascular accident, COVID-19 infection, and gastrointestinal hemorrhage. Permanent discontinuation of INAVOLISIB due to an adverse reaction occurred in 6% of patients. Adverse reactions which resulted in permanent discontinuation of INAVOLISIB included hyperglycemia (1.2%), and (0.6% each) stomatitis, gastric ulcer, intestinal perforation, anal abscess, increased ALT, decreased weight, bone pain, musculoskeletal pain, transitional cell carcinoma, and acute kidney injury. Dosage interruptions of INAVOLISIB due to an adverse reaction occurred in 69% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients included hyperglycemia (28%), neutropenia (23%), COVID-19 infection (16%), stomatitis (10%), diarrhea (7%), thrombocytopenia (4.9%), anemia (4.3%), upper respiratory tract infection (4.3%), decreased white blood cell count (3.7%), pyrexia (3.1%), nausea (2.5%), and fatigue (2.5%). Dose reductions of INAVOLISIB due to adverse reactions occurred in 14% of patients. Adverse reactions which required dose reduction of INAVOLISIB in ≥ 2% of patients were stomatitis (3.7%) and hyperglycemia (2.5%). The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were 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, and headache.

•Gastrointestinal Disorders

  •Stomatitis
  •Diarrhea
  •Nausea
  •Vomiting

•General Disorders and Administration Site Conditions

  •Fatigue

•Skin and Subcutaneous Tissue Disorders

  •Rash
  •Alopecia
  •Dry skin

•Metabolism and Nutrition Disorders

  •Decreased appetite	

•Infections and Infestations

  •COVID-19 infection
  •Urinary tract infection
  

•Nervous System Disorders

  •Headache

•Investigations

  •Decreased weight

|drugInteractions=•Clinical Studies and Model-Informed Approaches

  •Proton Pump Inhibitors: No clinically significant difference in steady-state inavolisib pharmacokinetics were observed based upon concomitant use of a proton pump inhibitor (lansoprazole, omeprazole, esomeprazole, pantoprazole, or rabeprazole).

•In Vitro Studies

  •CYP450 Enzymes: Inavolisib induces CYP3A and CYP2B6. Inavolisib is a time-dependent inhibitor of CYP3A. Inavolisib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.
  •Transporter Systems: Inavolisib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2K, OAT1, OAT2. Inavolisib does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2K.

|FDAPregCat=C |useInPregnancyFDA=•Risk Summary

  •Based on animal data and its mechanism of action, ITOVEBI can cause fetal harm when administered to a pregnant woman. There are no available data on the use of ITOVEBI in pregnant women to inform a drug-associated risk. In an animal reproduction study, oral administration of inavolisib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, structural abnormalities, and alterations to growth at maternal exposures approximately equivalent to the human exposure at the recommended dose of 9 mg/day based on AUC. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

•Animal Data

  •In an embryo-fetal development study, pregnant rats received oral doses of inavolisib up to 6 mg/kg/day during the period of organogenesis. Administration of doses ≥ 2 mg/kg/day resulted in decreases in fetal body weight and placental weight, post-implantation loss, lower fetal viability, fetal malformations (including kyphosis of vertebral column, fused thoracic arch, microphthalmia) and variations (including dilated renal pelvis, short supernumerary rib, wavy rib). At a dose of 2 mg/kg/day, maternal exposures were 0.9 times the human exposure at the recommended dose of 9 mg/day based on AUC.

|useInNursing=There are no data on the presence of inavolisib or its metabolites in human milk, its effects on milk production or a breastfed child. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women to not breastfeed during treatment with INAVOLISIB and for 1 week after the last dose. |useInPed=The safety and efficacy of inavolisib in pediatric patients have not been established. |useInGeri=Of the 162 patients who received inavolisib in INAVO120, 15% were ≥ 65 years of age, and 3% were ≥ 75 years of age. Dosage modifications or interruptions of inavolisib due to adverse reactions occurred at a higher incidence for patients ≥ 65 years of age compared to younger patients (79% versus 68%, respectively). Clinical studies of inavolisib did not include sufficient numbers of patients ≥ 65 years of age to determine whether they respond differently from younger patients. |useInRenalImpair=Reduce the dosage in patients with moderate renal impairment (eGFR 30 to < 60 mL/min based on CKD-EPI). No dosage modification is recommended in patients with mild renal impairment (eGFR 60 to < 90 mL/min). Inavolisib has not been evaluated in patients with severe renal impairment (eGFR < 30 mL/min). |useInReproPotential=INAVOLISIB can cause fetal harm when administered to a pregnant woman.

•Pregnancy Testing

  •Verify pregnancy status in females of reproductive potential prior to initiating treatment with INAVOLISIB.

•Contraception

  •Advise females of reproductive potential to use effective non-hormonal contraception during treatment with INAVOLISIB and for 1 week after the last dose.

•Infertility

  •Based on animal studies, INAVOLISIB may impair fertility in females and males of reproductive potential.

|administration=Oral |monitoring=•Hyperglycemia:

  •ITOVEBI can cause hyperglycemia. Initiate or optimize anti-hyperglycemic medications as clinically indicated. Interrupt, reduce dose, or discontinue ITOVEBI if severe hyperglycemia occurs. 

•Stomatitis:

  •ITOVEBI can cause severe stomatitis. Consider treating with a corticosteroid-containing mouthwash if stomatitis occurs. Monitor patients for signs and symptoms of stomatitis. Withhold, reduce dose, or permanently discontinue ITOVEBI based on severity. 

•Diarrhea:

  •ITOVEBI can cause diarrhea, which may be severe, and result in dehydration and acute kidney injury. Advise patients to start anti-diarrheal treatment, increase oral fluids, and notify their healthcare provider if severe diarrhea occurs. Interrupt, reduce dose, or discontinue ITOVEBI if severe diarrhea occurs. 

•Embryo-Fetal Toxicity:

  •ITOVEBI can cause fetal harm.  Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ITOVEBI and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ITOVEBI and for 1 week after the last dose.

|mechAction=Inavolisib is an inhibitor of phosphatidylinositol 3-kinase (PI3K) with inhibitory activity predominantly against PI3Kα. In vitro, inavolisib induced the degradation of mutated PI3K catalytic alpha subunit p110α (encoded by the PIK3CA gene), inhibited phosphorylation of the downstream target 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. The combination of inavolisib with palbociclib and fulvestrant increased tumor growth inhibition compared to each treatment alone or the doublet combinations. |structure=The chemical name of inavolisib is (2S)-2-[[2-[(4S)-4-(difluoromethyl)-2-oxo-oxazolidin-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]amino]propanamide. Inavolisib is a white to off-white, greyish pink, greyish orange, or greyish yellow powder or powder with lumps. Inavolisib demonstrates pH-dependent aqueous solubility; the greatest solubility is at low pH, and solubility decreases with increasing pH. The molecular formula for inavolisib is C18H19F2N5O4 and the molecular weight is 407.37 g/mol. Inavolisib film-coated tablets are supplied for oral administration with two strengths that contain 3 mg and 9 mg of inavolisib. The tablets also contain lactose, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The film-coating contains the following inactive ingredients: polyvinyl alcohol (partially hydrolyzed), titanium dioxide, macrogol/polyethylene glycol, talc, iron oxide red, and iron oxide yellow (in the 9 mg tablet only). |PD=•Exposure-Response Relationships

  •The exposure-response relationship for the efficacy of inavolisib has not been fully characterized. Inavolisib time course of pharmacodynamic response is unknown. Higher systemic exposure of inavolisib was associated with higher incidence of Grade ≥ 2 anemia, Grade ≥ 2 hyperglycemia, and inavolisib dosage modifications due to adverse reactions.

•Cardiac Electrophysiology

  •At the recommended approved dosage, a mean increase in the QTc interval of > 20 ms is unlikely.

|PK=Inavolisib pharmacokinetics are presented as geometric mean (geometric coefficient of variation [geo CV]%) following administration of the approved recommended dosage unless otherwise specified. The inavolisib steady-state AUC is 1,010 h*ng/mL (25%) and Cmax is 69 ng/mL (27%). Steady-state concentrations are predicted to be attained by day 5. Inavolisib accumulation is approximately 2-fold. Inavolisib steady-state AUC is proportional with dose from 6 to 12 mg (0.7 to 1.3 times the approved recommended dosage). •Absorption

•Inavolisib absolute oral bioavailability is 76%. Inavolisib steady-state median (min, max) time to maximum plasma concentration (Tmax) is 3 hours (0.5, 4 hours).

•Effect of Food

 •No clinically significant differences in inavolisib pharmacokinetics were observed following administration of inavolisib with a high-fat meal (approximately 1,000 calories, 50% fat).

•Distribution

 •Inavolisib apparent (oral) volume of distribution is 155 L (26%). Inavolisib plasma protein binding is 37% and is not concentration-dependent in vitro. Inavolisib blood-to-plasma ratio is 0.8.

•Elimination

 •Inavolisib elimination half-life is 15 hours (24%) with a total clearance of 8.8 L/hr (29%).

•Metabolism

  •Inavolisib is primarily metabolized by hydrolysis. In vitro, inavolisib was minimally metabolized by CYP3A.

•Excretion

 •Following oral administration of a single radiolabeled dose, 49% of the administered dose was recovered in urine (40% unchanged) and 48% in feces (11% unchanged).

•Specific Populations

  •No clinically significant differences in the pharmacokinetics of inavolisib were observed based on age (27 to 85 years), sex, race (Asian or White), body weight (39 to 159 kg), or mild hepatic impairment (total bilirubin > ULN to ≤ 1.5 × ULN or AST > ULN and total bilirubin ≤ ULN). The effect of moderate to severe hepatic impairment on inavolisib pharmacokinetics is unknown.

•Patients with Renal Impairment

  •Inavolisib AUC was 73% higher in patients with moderate renal impairment compared to patients with normal renal function (eGFR ≥ 90 mL/min). No clinically significant differences in the pharmacokinetics of inavolisib were observed in patients with mild renal impairment compared to patients with normal renal function. The effect of severe renal impairment (eGFR < 30 mL/min) on the pharmacokinetics of inavolisib is unknown.

•Drug Interaction Studies

  •Clinical Studies and Model-Informed Approaches
     •Proton Pump Inhibitors: No clinically significant difference in steady-state inavolisib pharmacokinetics were observed based upon concomitant use of a proton pump inhibitor (lansoprazole, omeprazole, esomeprazole, pantoprazole, or rabeprazole).
  •In Vitro Studies
     •CYP450 Enzymes: Inavolisib induces CYP3A and CYP2B6. Inavolisib is a time-dependent inhibitor of CYP3A. Inavolisib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.
     •Transporter Systems: Inavolisib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2K, OAT1, OAT2. Inavolisib does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2K.

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