Inavolisib

Inavolisib is an inhibitor of the catalytic subunit alpha isoform of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3Kα), the p110α protein encoded by the PIK3CA gene. The PI3K signalling pathway is often overactive in hormone receptor-positive breast cancer, frequently because of activating PIK3CA mutations. Inavolisib acts in two ways: it inhibits the enzyme, and it promotes the degradation of the mutated p110α protein, which is why it is described as a mutant degrader.

Mechanism of Action

• Pathway inhibition: the PI3K pathway is switched on by receptor tyrosine kinases at the cell membrane and controls cell growth, survival and metabolism. By blocking p110α, inavolisib reduces the activity of downstream targets, including AKT.
• Mutant degradation: inavolisib binds selectively to the mutated p110α protein and triggers its breakdown by the proteasome. Removing the mutant protein is intended to prevent the feedback reactivation of PI3K signalling that can follow inhibition alone, giving a more sustained effect in tumours driven by PIK3CA mutations.
• Cellular effect: in PIK3CA-mutated breast cancer cell lines, this lowers cell proliferation and induces apoptosis.
• Exposure and effects: higher inavolisib exposure was linked to more grade 2 or higher anaemia and hyperglycaemia, and to more dose modifications because of adverse reactions. The relationship between exposure and efficacy has not been characterised.

Pharmacokinetics

• Absorption: absolute oral bioavailability is 76%. At steady state after 9 mg daily (fasted), the median time to peak concentration is 3 hours (range 0.5 to 4 hours). Steady state is reached by about day 5, with roughly 2-fold accumulation; the population-pharmacokinetic steady-state AUC is about 1,019 h·ng/mL and Cmax about 67 ng/mL. Food has no clinically significant effect on exposure.
• Distribution: plasma protein binding is 37% and does not depend on concentration over the range tested. The steady-state oral volume of distribution is about 155 L.
• Metabolism: hydrolysis is the main pathway, and no specific hydrolysing enzymes have been identified. CYP enzymes are not the predominant route, so clinically relevant interactions with CYP inhibitors or inducers are unlikely. Unchanged inavolisib is the most prominent drug-related compound in plasma and urine.
• Elimination: after a single radiolabelled 9 mg dose in healthy volunteers, 48.5% of the dose was recovered in urine (40.4% unchanged) and 48% in faeces (10.8% unchanged). The elimination half-life is about 15 hours, and total clearance about 8.8 L/h.
• Special populations: no dose adjustment is needed from age 65 years onward (population pharmacokinetics; data are limited). The SmPC advises lower starting doses in moderate and severe renal impairment, and safety and efficacy have not been established in moderate to severe hepatic impairment.

• Locally advanced or metastatic breast cancer: in combination with palbociclib and fulvestrant, for adults with PIK3CA-mutated, oestrogen receptor (ER)-positive, HER2-negative disease, following recurrence on or within 12 months of completing adjuvant endocrine treatment.
• Previous CDK4/6 inhibitor: patients treated with a CDK4/6 inhibitor in the (neo)adjuvant setting should have had an interval of at least 12 months between the end of that treatment and the detection of recurrence.
• Endocrine therapy partner: in pre- or perimenopausal women and in men, the endocrine therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist.
• Patient selection: one or more PIK3CA mutations must be shown in a tumour or plasma specimen, using a CE-marked in vitro diagnostic device with the corresponding intended purpose (a validated alternative test if none is available).

• Hypersensitivity to inavolisib or to any of the excipients.

The figures below come from the INAVO120 study (162 patients given inavolisib with palbociclib and fulvestrant) and from post-marketing reports. The most common reactions were hyperglycaemia (59.9%), stomatitis (51.2%), diarrhoea (48.1%), thrombocytopenia (48.1%), fatigue (37.7%), anaemia (37%), nausea (27.8%), decreased appetite (23.5%), rash (22.8%), headache (21%), weight decreased (17.3%), vomiting (14.8%) and urinary tract infection (13%). The most common serious reactions were anaemia (1.9%), diarrhoea (1.2%) and urinary tract infection (1.2%). Treatment was stopped permanently because of a side effect in 3.1% of patients (hyperglycaemia 1.2%; stomatitis, increased alanine aminotransferase and weight decreased 0.6% each).

Very common (≥1/10): urinary tract infection, thrombocytopenia, anaemia, hyperglycaemia, decreased appetite, hypokalaemia, headache, stomatitis, diarrhoea, nausea, abdominal pain, vomiting, rash, alopecia, dry skin, fatigue, increased alanine aminotransferase, weight decreased.

Common (≥1/100 to <1/10): hypocalcaemia, dry eye, dysgeusia, dyspepsia, dermatitis, folliculitis, increased blood insulin.

Uncommon (≥1/1,000 to <1/100): ketoacidosis (reported after marketing; the frequency is an estimate).

Hyperglycaemia is the reaction to watch most closely. Severe cases, including ketoacidosis with fatal outcome, have occurred. In INAVO120, hyperglycaemia of grade 2 occurred in 38.3% of patients and of grade 3 in 5.6%; the median time to the first event was 7 days (range 2 to 955 days), with most new cases in the first two months. It led to dose interruption in 27.8% of patients, dose reduction in 2.5% and permanent discontinuation in 1.2%. Stomatitis (grade 1 in 32.1%, grade 2 in 13.6%, grade 3 in 5.6%) began after a median of 13 days (range 1 to 610 days) and led to interruption in 9.9%, dose reduction in 3.7% and discontinuation in 0.6%.

No interaction studies have been performed. The SmPC advises the following.

• CYP inhibitors and inducers: clinically relevant interactions are unlikely, because hydrolysis rather than CYP metabolism is the main route of elimination.
• Sensitive CYP3A4 substrates with a narrow therapeutic index (alfentanil, an opioid; astemizole; cisapride; ciclosporin; quinidine; sirolimus; tacrolimus): inavolisib induces CYP3A and is a time-dependent inhibitor of CYP3A in vitro, so it may raise or lower their exposure. Use with caution.
• Sensitive substrates of CYP2B6, CYP2C8, CYP2C9 and CYP2C19 with a narrow therapeutic index (paclitaxel, warfarin, phenytoin, S-mephenytoin): inavolisib induces these enzymes in vitro and may lower the exposure and efficacy of such medicines. Use with caution.
• Glucose-lowering medicines: when insulin or sulfonylureas are used to treat hyperglycaemia, the risk of hypoglycaemia must be kept in mind before inavolisib is interrupted or stopped. Metformin was the preferred first agent in the INAVO120 study.
• Corticosteroids: fasting glucose needs more frequent testing in patients who take corticosteroids.
• Food: inavolisib can be taken with or without food; a high-fat meal had no clinically significant effect.
• Combination partners: inavolisib is always given with palbociclib and fulvestrant, whose own SmPCs apply.

Treatment must be started by a physician experienced in anticancer therapy, after a PIK3CA mutation has been confirmed. The tablets are swallowed whole, with or without food, at about the same time each day. They must not be chewed, crushed, dissolved or divided.

Recommended Dose

• Inavolisib: 9 mg once daily.
• Palbociclib: 125 mg once daily for 21 consecutive days followed by 7 days off treatment, making a 28-day cycle.
• Fulvestrant: 500 mg intramuscularly on days 1, 15 and 29, then once monthly. Refer to the SmPCs of palbociclib and fulvestrant for details.
• LHRH agonist: pre- or perimenopausal women and men also receive an LHRH agonist, in line with local clinical practice.
• Duration: until disease progression or unacceptable toxicity.

Dose Adjustments for Side Effects

• Dose levels: starting dose 9 mg daily; first reduction 6 mg daily; second reduction 3 mg daily. Treatment is stopped permanently if 3 mg daily is not tolerated. The dose may be raised again, up to 9 mg daily, on the treating physician’s clinical evaluation.
• Fasting glucose above the upper limit of normal up to 160 mg/dL (8.9 mmol/L): no adjustment; consider dietary changes and hydration, and consider starting or intensifying oral glucose-lowering treatment in patients with risk factors.
• Above 160 to 250 mg/dL (8.9 to 13.9 mmol/L): interrupt until the level is 160 mg/dL or below, start or intensify glucose-lowering treatment, then resume at the same dose. If the level stays above 200 to 250 mg/dL for 7 days despite treatment, consult a professional experienced in treating hyperglycaemia.
• Above 250 to 500 mg/dL (13.9 to 27.8 mmol/L): interrupt, start or intensify treatment and hydrate as needed. If the level falls to 160 mg/dL or below within 7 days, resume at the same dose; if it takes 8 days or more, resume one dose level lower. If it recurs within 30 days, interrupt again until the level is 160 mg/dL or below and resume one dose level lower.
• Above 500 mg/dL (27.8 mmol/L): interrupt, start or intensify treatment, assess for volume depletion and ketosis, and hydrate. Once the level is 160 mg/dL or below, resume one dose level lower. If it recurs within 30 days, stop permanently.
• Stomatitis: grade 1, no adjustment, and start or intensify treatment such as a corticosteroid mouthwash. Grade 2, withhold until grade 1 or lower and resume at the same dose; for recurrent grade 2, resume one dose level lower. Grade 3, withhold until grade 1 or lower and resume one dose level lower. Grade 4, stop permanently.
• Other adverse reactions: supportive therapy and monitoring at every grade. Grade 1, no adjustment. Grade 2, consider interruption until grade 1 or lower, then resume at the same dose. First grade 3 event, interrupt until grade 1 or lower and resume at the same dose or one level lower. Recurrent grade 3 or non-life-threatening grade 4, interrupt until grade 1 or lower and resume one level lower. Life-threatening grade 4, stop permanently.

Special Populations

• Elderly: no dose adjustment from age 65 years onward; data in this group are limited.
• Renal impairment: starting dose 6 mg once daily in moderate impairment (eGFR 30 to below 60 mL/min, CKD-EPI) and 3 mg once daily in severe impairment (eGFR below 30 mL/min). No adjustment in mild impairment (eGFR 60 to below 90 mL/min).
• Hepatic impairment: no adjustment in mild impairment (total bilirubin above the upper limit of normal up to 1.5 times it, or AST above the upper limit with normal bilirubin). Safety and efficacy have not been established in moderate to severe impairment.
• Children and adolescents: safety and efficacy at ages 0 to 17 years have not been established; no data are available.

Missed or Vomited Dose

A missed dose can be taken within 9 hours of the usual time. After more than 9 hours, skip it and take the next dose at the usual time the following day. If the patient vomits after a dose, no extra dose is taken that day; dosing resumes the next day at the usual time.

Hyperglycaemia

• Diabetes: patients with type 1 diabetes, or type 2 diabetes needing ongoing glucose-lowering treatment, were excluded from INAVO120 (only one patient with type 2 diabetes received inavolisib), so safety and efficacy in them are not known. Patients with a history of diabetes may need intensified treatment and more frequent testing. Treatment should not start until fasting glucose has been optimised, and consultation with a professional experienced in treating hyperglycaemia should be considered beforehand.
• Patient advice: before treatment, patients are told the signs of hyperglycaemia (excessive thirst, passing urine more often, blurred vision, mental confusion, difficulty breathing, or increased appetite with weight loss) and to contact a healthcare professional immediately if they occur. Good hydration is maintained before and during treatment.
• Monitoring: fasting glucose and HbA1c are tested before treatment. Afterwards fasting glucose is measured (or self-measured) every 3 days in the first week, weekly for the next 3 weeks (days 8 to 28), every 2 weeks for the next 8 weeks, and then every 4 weeks, and as clinically indicated. HbA1c is checked every 3 months. If hyperglycaemia develops, monitoring is closer, and during glucose-lowering treatment fasting glucose is checked at least weekly for 8 weeks and then every 2 weeks.
• Higher-risk patients: more frequent testing is considered with risk factors ((pre)diabetes, HbA1c of 5.7% or more, BMI of 30 kg/m² or more, age 45 years or more, previous gestational diabetes, family history of diabetes). It is required with corticosteroids, intercurrent infections or other conditions that can worsen glucose control, and HbA1c and ketones (preferably in blood) are then also monitored. Home glucose monitoring and metformin premedication can be considered.
• Rescue treatment: short-term insulin may be used, although experience with insulin during inavolisib treatment is limited.

Stomatitis

Corticosteroid mouthwash was recommended for prevention in INAVO120 (dexamethasone in 19.1% of patients and triamcinolone in 1.2%). Patients should start an alcohol-free corticosteroid mouthwash at the first sign of stomatitis and avoid mouthwashes that contain alcohol or peroxide, which can make it worse. Dietary changes such as avoiding spicy food should be considered.

Previous CDK4/6 Inhibitor

Information on the combination in patients who received a CDK4/6 inhibitor in the neoadjuvant or adjuvant setting is very limited, and efficacy may be lower in them.

Pregnancy, Breastfeeding and Fertility

• Pregnancy test: the pregnancy status of females of reproductive potential is verified before treatment starts. Inavolisib is not recommended during pregnancy or in women of childbearing potential who are not using contraception. Animal studies showed reproductive toxicity, and pregnant women should be told of the potential risk to the foetus.
• Contraception: women use effective non-hormonal contraception during treatment and for 1 week after the last dose. Male patients with a partner who is pregnant or of childbearing potential use a condom during treatment and for 1 week after the last dose.
• Breastfeeding: it is unknown whether inavolisib or its metabolites pass into breast milk, and a risk to the infant cannot be excluded. Breastfeeding should stop during treatment and for 1 week after the last dose.
• Fertility: there are no human data. Animal studies indicate that inavolisib may affect fertility in females and males.

Lactose and Sodium

The tablets contain lactose (22 mg in the 3 mg tablet, 66 mg in the 9 mg tablet). Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them. Each tablet contains less than 1 mmol (23 mg) of sodium, so it is essentially sodium-free.

Effect on Driving

Itovebi has a minor influence on the ability to drive and use machines, because fatigue has been reported.

Itovebi needs no special temperature storage conditions. Keep the tablets in the original package, aluminium/aluminium perforated unit-dose blisters in cartons of 28 × 1 tablets, to protect them from moisture. No cold chain is required. Keep out of the sight and reach of children.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), under restricted medical prescription (Annex II B). Treatment is started and supervised by a physician experienced in anticancer therapy, after PIK3CA mutation testing. Itovebi is a tablet taken at home, so it is supplied to the patient or to the treating clinic on prescription. No cold-chain delivery is needed.