Inavolisib

Inavolisib induces CYP3A and is a time-dependent inhibitor of CYP3A in vitro. Therefore, inavolisib should be used with caution in combination with sensitive CYP3A4 substrates with a narrow therapeutic index (e.g., alfentanil, astemizole, cisapride, cyclosporine, quinidine, sirolimus, tacrolimus) as inavolisib may increase or decrease the systemic exposure of these substrates.

In addition, inavolisib induces CYP2B6, CYP2C8, CYP2C9, and CYP2C19 in vitro. Therefore, inavolisib should be used with caution in combination with sensitive substrates of these enzymes with a narrow therapeutic index (e.g., paclitaxel, warfarin, phenytoin, S-mephenytoin) as inavolisib may decrease their systemic exposure and consequently lead to decreased efficacy.

The recommended starting dose of inavolisib for patients with moderate renal impairment (eGFR 30 to <60 mL/min based on CKD-EPI) is 6 mg orally once daily. The safety and efficacy of inavolisib have not been established in patients with severe renal impairment.

The safety and efficacy of inavolisib have not been established in patients with moderate to severe hepatic impairment.

Information on the efficacy of the combination of Itovebi, palbociclib, and fulvestrant is very limited in patients who previously received a CDK4/6 inhibitor as part of neoadjuvant or adjuvant treatment. Efficacy may be lower in such patients.

No human data on the effect of inavolisib on fertility are available. Based on animal studies, inavolisib may impact fertility in females and males of reproductive potential.

The safety and efficacy of inavolisib in patients with Type 1 diabetes mellitus or Type 2 diabetes mellitus requiring ongoing anti-hyperglycaemic therapy have not been studied as these patients were excluded from the INAVO120 study. Only 1 patient with Type 2 diabetes was included in the inavolisib arm of the INAVO120 study, which should be considered when inavolisib is prescribed to patients with diabetes mellitus. Patients with a history of diabetes mellitus may require intensified anti-hyperglycaemic treatment and more frequent fasting glucose testing during inavolisib treatment. Treatment with inavolisib should not be initiated until fasting glucose levels are optimised. Consultation with a healthcare professional experienced in the treatment of hyperglycaemia should be considered before initiating inavolisib.

The pregnancy status of females of reproductive potential should be verified prior to initiating inavolisib therapy. Pregnant women should be clearly advised of the potential risk to the foetus.

There are no or limited amount of data from the use of inavolisib in pregnant women. Studies in animals have shown reproductive toxicity. Inavolisib is not recommended during pregnancy and in women of childbearing potential not using contraception.

It is unknown whether inavolisib/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with inavolisib and for 1 week after the last dose of inavolisib.

Women of childbearing potential/Contraception in males and females

Females

Patients should be advised to use effective non-hormonal contraception during treatment with inavolisib and for 1 week after the last dose of inavolisib.

Males

It is not known if inavolisib is present in semen. To avoid potential foetal exposure during pregnancy, male patients with female partners of childbearing potential or pregnant female partners should use a condom during treatment with inavolisib and for 1 week after the last dose of inavolisib.

Fertility

No human data on the effect of inavolisib on fertility are available. Based on animal studies, inavolisib may impact fertility in females and males of reproductive potential.

Inavolisib has minor influence on the ability to drive or use machines because fatigue has been reported during treatment with inavolisib.

Summary of the safety profile

The most common adverse reactions in patients who received inavolisib 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 adverse reactions reported in patients who received inavolisib were anaemia (1.9%), diarrhoea (1.2%), and urinary tract infection (1.2%).

Permanent discontinuation of inavolisib due to an adverse reaction occurred in 3.1% of patients. The adverse reactions leading to permanent discontinuation of inavolisib were hyperglycaemia (1.2%), stomatitis (0.6%), alanine transaminase (ALT) increased (0.6%), and weight decreased (0.6%).

Tabulated list of adverse drug reactions

Adverse drug reactions, based on data from 162 patients with locally advanced or metastatic breast cancer who received inavolisib in combination with palbociclib and fulvestrant in the INAVO120 Phase 3, randomised study, and from post-marketing surveillance are listed by MedDRA system organ class in the table below. The median duration of inavolisib treatment at the time of the analysis was 9.2 months (range: 0 to 38.8 months).

Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. The corresponding frequency category for each adverse drug reaction is based on the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000), not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse drug reactions observed in patients treated with inavolisib:

Grading according to CTCAE version 5.0.
^* No Grade 4 events were observed.
^a Includes hyperglycaemia, blood glucose increased, hyperglycaemic crisis, glycated serum protein increased, glucose tolerance impaired, diabetes mellitus, Type 2 diabetes mellitus, and glycosylated haemoglobin increased.
^b Adverse reaction reported during post-marketing experience. The frequency category was estimated as the upper limit of the 95% confidence interval calculated on the basis of the total number of patients exposed to inavolisib in clinical trials.
^c Includes aphthous ulcer, glossitis, glossodynia, lip ulceration, mouth ulceration, mucosal inflammation, and stomatitis.
^d Includes rash, rash erythematous, rash maculo-papular, rash papular, rash pruritic, and rash pustular.
^e Includes dry skin, skin fissures, xerosis, and xeroderma.
^f Includes dermatitis, dermatitis acneiform, and dermatitis bullous.

Description of selected adverse drug reactions

Hyperglycaemia

In the INAVO120 study, hyperglycaemia of any grade was reported in 59.9% of patients treated with inavolisib in combination with palbociclib and fulvestrant; Grade 2 and Grade 3 events were reported in 38.3% and 5.6% of patients, respectively (based on CTCAE version 5.0). Among the patients who experienced hyperglycaemia, the rate of new onset of hyperglycaemia events was highest during the first two months of treatment with a median time to first onset of 7 days (range: 2 to 955 days).

In the 97 patients who received inavolisib in combination with palbociclib and fulvestrant and experienced hyperglycaemia, 74.2% (72/97) received anti-hyperglycaemic medicines including SGLT2 inhibitors, thiazolidinediones, and DPP-4 inhibitors for prophylaxis or treatment of hyperglycaemia. All patients who received anti-hyperglycaemic medicines received metformin as a single agent or in combination with other anti-hyperglycaemic medicines (i.e., insulin, DPP-4 inhibitors, and sulfonylureas); and 11.3% (11/97) received insulin.

In patients with fasting glucose levels >160 mg/dL (>8.9 mmol/L) with at least one level improvement in fasting blood glucose levels (n=52), the median time to improvement was 8 days (range: 2 to 43 days).

Hyperglycaemia led to interruption of inavolisib in 27.8%, to dose reduction of inavolisib in 2.5%, and to discontinuation of inavolisib in 1.2% of patients.

Stomatitis

Stomatitis was reported in 51.2% of patients treated with inavolisib in combination with palbociclib and fulvestrant; Grade 1 events were reported in 32.1% of patients, Grade 2 events in 13.6% of patients, and Grade 3 events in 5.6% of patients. Among patients who experienced stomatitis, the median time to first onset was 13 days (range: 1 to 610 days).

Stomatitis led to interruption of inavolisib in 9.9%, to dose reduction of inavolisib in 3.7%, and to discontinuation of inavolisib in 0.6% of patients.

In patients who received inavolisib in combination with palbociclib and fulvestrant, 24.1% used a mouthwash containing dexamethasone for management of stomatitis.

Diarrhoea

Diarrhoea was reported in 48.1% of patients treated with inavolisib in combination with palbociclib and fulvestrant; Grade 1 events were reported in 27.8% of patients, Grade 2 events in 16.7% of patients, and Grade 3 events in 3.7% of patients. Among patients who experienced diarrhoea, the median time to first onset was 15 days (range: 2 to 602 days).

Diarrhoea led to interruption of inavolisib in 6.8%, to dose reduction of inavolisib in 1.2%, and did not lead to discontinuation of inavolisib in any patients.

Anti-diarrhoeal medicines (e.g., loperamide) were used in 28.4% of patients who received inavolisib in combination with palbociclib and fulvestrant to manage symptoms.

Elderly

Analysis of the safety of inavolisib comparing patients ≥65 years of age (14.8%) to younger patients (85.2%) suggests a higher incidence of inavolisib dose modification/interruptions (79.2% versus 68.1%).