Piqray is indicated in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with a PIK3CA mutation after disease progression following endocrine-based therapy.

Treatment with Piqray should be initiated by a physician experienced in the use of anticancer therapies.

Patients with HR-positive, HER2-negative advanced breast cancer should be selected for treatment with Piqray based on the presence of a PIK3CA mutation in tumour or plasma specimens, using a validated test. If a mutation is not detected in a plasma specimen, tumour tissue should be tested if available.

Posology

The recommended dose is 300 mg alpelisib (2x 150 mg film-coated tablets) taken once daily on a continuous basis. Piqray should be taken immediately after food, at approximately the same time each day (see section 5.2). The maximum recommended daily dose of Piqray is 300 mg.

If a dose of Piqray is missed, it can be taken immediately following food and within 9 hours after the time it is usually administered. After more than 9 hours, the dose should be skipped for that day. On the next day, Piqray should be taken at the usual time. If the patient vomits after taking the Piqray dose, the patient should not take an additional dose on that day and should resume the usual dosing schedule the next day at the usual time.

Piqray should be co-administered with fulvestrant. The recommended dose of fulvestrant is 500 mg administered intramuscularly on days 1, 15 and 29, and once monthly thereafter. Please refer to the full prescribing information of fulvestrant.

Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs. Dose modifications may be necessary to improve tolerability.

Dose modifications

Management of severe or intolerable adverse drug reactions (ADRs) may require temporary dose interruption, reduction, and/or discontinuation of Piqray. If dose reduction is required, the dose reduction guidelines for ADRs are listed in Table 1. A maximum of 2 dose reductions are recommended, after which the patient should be permanently discontinued from treatment with Piqray. Dose reduction should be based on the worst preceding toxicity.

Table 1 Recommended dose reduction guidelines for ADRs for Piqray¹

Tables 2-5 summarise the recommendations for dose interruption, reduction or discontinuation of Piqray in the management of specific ADRs. The clinical judgement of the treating physician, including confirmation of laboratory values if deemed necessary, should guide the management plan of each patient based on the individual benefit/risk assessment for treatment with Piqray.

Hyperglycaemia

Consultation with a healthcare professional experienced in the treatment of hyperglycaemia should always be considered and is recommended for patients who are pre-diabetic or those with fasting glucose (FG) >250 mg/dl or 13.9 mmol/l, body mass index (BMI) ≥ 30 or age ≥ 75 years.

Consultation with a diabetologist or a healthcare professional experienced in the treatment of hyperglycaemia should always take place for patients with diabetes.

Table 2 Dose modification and management for hyperglycaemia

Baseline diabetic and pre-diabetic status, baseline BMI ≥ 30 and baseline age ≥ 75 years have been found to be risk factors for hyperglycaemia in patients treated with alpelisib. These risk factors were present in 74.7% of patients with any grade of hyperglycaemia and in 86.2% of patients with grade 3 or 4 hyperglycaemia (see section 4.4).

Rash

Oral antihistamine administration may be considered prophylactically, at the time of initiation of treatment with Piqray. Additionally, antihistamines are recommended to manage symptoms of rash.

Topical corticosteroid treatment should be initiated at the first signs of rash and systemic corticosteroids should be considered for moderate to severe rashes. Based on the severity of rash, Piqray may require dose interruption, reduction or discontinuation as described in Table 3 (see section 4.8).

Table 3 Dose modification and management for rash

Diarrhoea or colitis

Table 4 Dose modification and management for diarrhoea or colitis

Other toxicities

Table 5 Dose modification and management for other toxicities (excluding hyperglycaemia, rash and diarrhoea or colitis)

Special populations

Elderly

No dose regimen adjustment is required in patients aged 65 years or above (see section 5.2). There are limited data in patients aged ≥ 75 years, and especially for those ≥ 85 years.

Renal impairment

Based on population pharmacokinetic analysis, no dose adjustment is necessary in patients with mild or moderate renal impairment (see section 5.2). Caution should be used in patients with severe renal impairment as there is no experience with Piqray in this population.

Hepatic impairment

Based on a hepatic impairment study in non-cancer subjects with impaired hepatic function, no dose adjustment is necessary in patients with mild, moderate or severe hepatic impairment (Child-Pugh class A, B or C, respectively) (see section 5.2).

Paediatric population

The safety and efficacy of Piqray in children aged 0-18 years have not been established. No data are available.

Method of administration

Piqray is for oral use. The tablets should be swallowed whole. They should not be chewed, crushed or split prior to swallowing. Tablets that are broken, cracked or otherwise not intact should not be ingested.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Fulvestrant

Due to limited data in patients with prior fulvestrant use (n=39, study CBYL719X2101), efficacy is not considered established in this population (see section 5.1).

Hypersensitivity (including anaphylactic reaction)

Serious hypersensitivity reactions (including anaphylactic reaction, anaphylactic shock and angioedema), manifested by symptoms including, but not limited to, dyspnoea, flushing, rash, fever or tachycardia, were reported in patients treated with Piqray (see section 4.8). Piqray should be permanently discontinued and should not be re-introduced in patients with serious hypersensitivity reactions. Appropriate treatment should be promptly initiated.

Severe cutaneous reactions

Severe cutaneous reactions have been reported with alpelisib. In the phase III clinical study, Stevens-Johnson syndrome (SJS) and erythema multiforme (EM) were reported in 1 (0.4%) and 3 (1.1%) patients, respectively. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in the post-marketing setting (see section 4.8).

Piqray treatment should not be initiated in patients with a history of severe cutaneous reactions.

Patients should be advised of the signs and symptoms of severe cutaneous reactions (e.g. a prodrome of fever, flu-like symptoms, mucosal lesions or progressive skin rash). If signs or symptoms of severe cutaneous reactions are present, Piqray should be interrupted until the aetiology of the reaction has been determined. A consultation with a dermatologist is recommended.

If a severe cutaneous reaction is confirmed, Piqray should be permanently discontinued. Piqray should not be re-introduced in patients who have experienced previous severe cutaneous reactions. If a severe cutaneous reaction is not confirmed, Piqray may require treatment interruption, dose reduction or treatment discontinuation as described in Table 3 (see section 4.2).

Hyperglycaemia

Severe hyperglycaemia, in some cases associated with hyperglycaemic hyperosmolar nonketotic syndrome (HHNKS) or ketoacidosis, has been observed in patients treated with Piqray. Some cases of ketoacidosis with fatal outcome have been reported in the post-marketing setting.

In the phase III clinical study, hyperglycaemia occurred more frequently in patients who were diabetic (0 out of 12 patients [0%] with grade 1-2, and 10 out of 12 patients [83.3%] with grade 3-4), pre-diabetic (42 out of 159 patients [26.4%] with grade 1-2, and 77 out of 159 patients [48.4%] with grade 3-4), had BMI ≥ 30 at screening (13 out of 74 patients [17.6%] with grade 1-2, and 38 out of 74 patients [51.4%] with grade 3-4) or ≥ 75 years of age (6 out of 34 patients [17.6%] with grade 1-2, and 19 out of 34 patients [55.9%] with grade 3-4).

As hyperglycaemia may occur with a rapid onset after starting treatment, it is recommended to self-monitor frequently in the first 4 weeks and especially within the first 2 weeks of treatment, as clinically indicated. A specific schedule for fasting glucose monitoring is recommended in Table 6.

In the phase III clinical study, patients with a history of diabetes mellitus intensified use of antidiabetic medicinal products while on treatment with Piqray.

All patients should be instructed on lifestyle changes that may reduce hyperglycaemia (e.g. dietary restrictions and physical activity).

Table 6 Schedule of fasting glucose monitoring

Patients should be advised of the signs and symptoms of hyperglycaemia (e.g. excessive thirst, urinating more often than usual or greater amount of urine than usual, increased appetite with weight loss).

In the 190 patients with hyperglycaemia, 87.4% (166/190) were managed with antidiabetic medication, and 75.8% (144/190) reported use of metformin as single agent or in combination with other antidiabetic medication (e.g. insulin, dipeptidyl peptidase-4 (DPP-4) inhibitors, SGLT2 inhibitors and sulfonylureas).

Oral antidiabetic medication was used in 154 patients. Out of these 154 patients, 17 (11.0%) discontinued study treatment due to hyperglycaemia. Concomitant insulin medication was used in 54 patients; of these 13 (24.1%) discontinued study treatment due to hyperglycaemia.

Out of 162 patients with grade ≥ 2 hyperglycaemia, 155 had at least 1 grade improvement, median time to improvement from the first event was 8 days (95% CI: 8 to 10 days).

Of the patients with elevated FPG who continued fulvestrant treatment after discontinuing Piqray (n=58), 98.3% (n=57) had FPG levels that returned to baseline.

The safety of Piqray in patients with Type 1 and uncontrolled Type 2 diabetes has not been established as these patients were excluded from the phase III clinical study. Patients with a medical history of Type 2 diabetes were included. Patients with a history of diabetes mellitus may require intensified diabetic treatment and should be closely monitored.

Based on the severity of the hyperglycaemia, Piqray may require dose interruption, reduction or discontinuation as described in Table 2 (see section 4.2).

Pneumonitis

Pneumonitis, including serious cases of pneumonitis/acute interstitial lung disease, have been reported in Piqray-treated patients in clinical studies. Patients should be advised to report promptly any new or worsening respiratory symptoms. In patients who have new or worsening respiratory symptoms or are suspected to have developed pneumonitis, Piqray treatment should be interrupted immediately and the patient should be evaluated for pneumonitis. A diagnosis of non-infectious pneumonitis should be considered in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, cough, dyspnoea, or interstitial infiltrates on radiological examination and in whom infectious, neoplastic and other causes have been excluded by means of appropriate investigations. Piqray should be permanently discontinued in all patients with confirmed pneumonitis.

Diarrhoea or colitis

Patients should be monitored for diarrhoea and other symptoms of colitis, such as abdominal pain and mucus or blood in stools.

Severe diarrhoea and clinical consequences, such as dehydration and acute kidney injury, have been reported during treatment with Piqray and resolved with appropriate intervention. 59.5% of patients (n=169) experienced diarrhoea during treatment with Piqray. Grade 3 diarrhoea occurred in 7% (n=20) of patients with no reported cases of grade 4. Among patients with grade 2 or 3 diarrhoea (n=76), the median time to onset was 50 days (range: 1 to 954 days).

Dose reductions of Piqray were required in 5.6% of patients and 2.8% of patients discontinued Piqray due to diarrhoea. In the 169 patients who experienced diarrhoea, antidiarrhoeal medications (e.g. loperamide) were required to manage symptoms in 64.5% (109/169).

Based on the severity of the diarrhoea or colitis, Piqray may require dose interruption, reduction or discontinuation as described in Table 4 (see section 4.2).

Patients should be advised to start antidiarrhoeal treatment, increase oral fluids and notify their physician if diarrhoea or other symptoms of colitis occur while taking Piqray. In case of colitis, additional treatment, such as steroids, may be considered as clinically indicated.

Osteonecrosis of the jaw

Caution should be exercised when Piqray and bisphosphonates or RANK-ligand inhibitors (e.g. denosumab) are used either simultaneously or sequentially. Piqray treatment should not be initiated in patients with ongoing osteonecrosis of the jaw from previous or concurrent treatment with bisphosphonates/denosumab. Patients should be advised to promptly report any new or worsening oral symptoms (such as dental mobility, pain or swelling, non-healing of mouth sores, or discharge) during treatment with Piqray.

In patients who develop osteonecrosis of the jaw, standard medical management should be initiated.

Symptomatic visceral disease

The efficacy and safety of this medicinal product have not been studied in patients with symptomatic visceral disease.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially 'sodium-free'.

Medicinal products that may increase alpelisib plasma concentrations

Breast cancer resistance protein (BCRP) inhibitors

Alpelisib is a substrate for BCRP in vitro. BCRP is involved in the hepatobiliary export and intestinal secretion of alpelisib, therefore inhibition of BCRP in the liver and in the intestine during elimination may lead to an increase in systemic exposure of alpelisib. Therefore, caution and monitoring for toxicity are advised during concomitant treatment with inhibitors of BCRP (e.g. eltrombopag, lapatinib, pantoprazole).

Medicinal products that may decrease alpelisib plasma concentrations

Acid-reducing agents

The co-administration of the H2 receptor antagonist ranitidine in combination with a single 300 mg oral dose of alpelisib slightly reduced the bioavailability of alpelisib and decreased overall exposure of alpelisib. In the presence of a low-fat low-calorie (LFLC) meal, AUC_inf was decreased on average by 21% and C_max by 36% with ranitidine. In the absence of food, the effect was more pronounced with a 30% decrease in AUC_inf and a 51% decrease in C_max with ranitidine compared to the fasted state without co-administration of ranitidine. Population pharmacokinetic analysis showed no significant effect of co-administration of acid-reducing agents, including proton pump inhibitors, H2 receptor antagonists and antacids, on the pharmacokinetics of alpelisib. Therefore, alpelisib can be co-administered with acid-reducing agents, provided alpelisib is taken immediately after food (see section 4.2).

CYP3A4 inducers

Once-daily administration of 600 mg rifampin (a strong CYP3A4 inducer) for 7 days followed by co-administration with a single 300 mg oral dose of alpelisib on day 8, decreased alpelisib C_max by 38% and AUC by 57% in healthy adults (N=25). Co-administration of rifampin 600 mg once daily for 15 days with alpelisib 300 mg once daily starting from day 8 to day 15 decreased the steady-state alpelisib C_max by 59% and AUC by 74%.

Co-administration with a strong CYP3A4 inducer decreases alpelisib AUC, which may reduce alpelisib efficacy. Co-administration of alpelisib with strong CYP3A4 inducers (e.g. apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's wort) should be avoided and selection of an alternative concomitant medicinal product, with no or minimal potential to induce CYP3A4, should be considered.

Medicinal products whose plasma concentrations may be altered by alpelisib

CYP3A4, CYP2C8, CYP2C9, CYP2C19 and CYP2B6 substrates

No dose adjustment is required when co-administering Piqray with CYP3A4 substrates (e.g. everolimus, midazolam), CYP2C8 substrates (e.g. repaglinide), CYP2C9 substrates (e.g. warfarin), CYP2C19 substrates (e.g. omeprazole). For CYP2B6 substrate, no relevant changes in the exposure were observed when co-administered with Piqray however the results should be considered with caution due to limited data (see section 5.2).

In a drug-drug interaction study, co-administration of alpelisib with everolimus, a sensitive CYP3A4 substrate, confirmed that there are no clinically significant pharmacokinetic interactions (increase in AUC by 11.2%) between alpelisib and CYP3A4 substrates. No change in everolimus exposure was observed at alpelisib doses ranging from 250 to 300 mg.

In healthy subjects, co-administration of a CYP2C9 substrate (S-warfarin) with alpelisib increased S-warfarin exposure on average by 34% and 19% for AUCinf and Cmax respectively, compared to administration with S-warfarin alone, which indicates that alpesilib is a mild inhibitor of CYP2C9.

Substances that are substrates of transporters

In vitro evaluations indicated that alpelisib (and/or its metabolite BZG791) has a potential to inhibit the activities of OAT3 drug transporters and intestinal BCRP and P-gp. Piqray should be used with caution in combination with sensitive substrates of these transporters which exhibit a narrow therapeutic index because Piqray may increase the systemic exposure of these substrates.

Hormonal contraceptives

No clinical studies were conducted assessing the drug-drug interaction potential between alpelisib and hormonal contraceptives.

Piqray is indicated in men and postmenopausal women. It is not to be used in women who are, or may be, pregnant or breast-feeding (see section 4.1).

Women of childbearing potential/Contraception in males and females

Females of reproductive potential should be advised that animal studies and the mechanism of action have shown that alpelisib can be harmful to the developing foetus. Embryo-foetal development studies in rats and rabbits have demonstrated that oral administration of alpelisib during organogenesis induced embryotoxicity, foetotoxicity and teratogenicity (see section 5.3).

In case females of reproductive potential take Piqray, they should use effective contraception (e.g. double-barrier method) when taking Piqray and for at least 1 week after stopping treatment with Piqray.

Male patients with sexual partners who are pregnant, possibly pregnant or who could become pregnant should use condoms during sexual intercourse while taking Piqray and for at least 1 week after stopping treatment with Piqray.

Please refer to section 4.6 of the prescribing information for fulvestrant.

Pregnancy

Piqray is not indicated and is not to be used in women who are, or may be, pregnant (see section 4.1).

There are no data from the use of alpelisib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Piqray is not recommended during pregnancy and in women of childbearing potential not using contraception.

The pregnancy status of females of reproductive potential should be verified prior to starting treatment with Piqray.

Breast-feeding

It is not known if alpelisib is excreted in human or animal milk.

Because of the potential for serious adverse reactions in the breast-fed infant, it is recommended that women should not breast-feed during treatment and for at least 1 week after the last dose of Piqray.

Fertility

There are no clinical data available on the effects of alpelisib on fertility. Based on repeated dose toxicity and fertility studies in animals, alpelisib may impair fertility in males and females of reproductive potential (see section 5.3).

Piqray has minor influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines in case they experience fatigue or blurred vision during treatment (see section 4.8).

Summary of the safety profile

Study CBYL719C2301 (SOLAR-1)

The safety profile is based on data from 284 patients in the Piqray plus fulvestrant arm of the double-blind, placebo-controlled phase III study.

The most common ADRs (reported at a frequency >20% in the combined mutant and non-mutant study population) were plasma glucose increased (79.2%), creatinine increased (67.6%), diarrhoea (59.5%), gamma-glutamyltransferase increased (53.2%), rash (51.8%), lymphocyte count decreased (55.3%), nausea (46.8%), alanine aminotransferase increased (44.0%), anaemia (44.0%), fatigue (43.3%), lipase increased (42.6%), decreased appetite (35.9%), stomatitis (30.3%), vomiting (28.5%), weight decreased (27.8%), hypocalcaemia (27.8%), plasma glucose decreased (26.8%), activated partial thromboplastin time (aPTT) prolonged (22.2%) and alopecia (20.4%).

The most common grade 3 or 4 ADRs (reported at a frequency ≥ 2%) were plasma glucose increased (39.1%), rash (19.4%), gamma-glutamyltransferase increased (12.0%), lymphocyte count decreased (9.2%), diarrhoea (7.0%), lipase increased (7.0%), hypokalaemia (6.3%), fatigue (5.6%), weight decreased (5.3%), anaemia (4.9%), hypertension (4.6%), alanine aminotransferase increased (4.2%), nausea (2.8%), creatinine increased (2.8%), stomatitis (2.5%), hypocalcaemia (2.1%) and mucosal inflammation (2.1%).

The most common ADRs leading to treatment discontinuation were hyperglycaemia (6.3%), rash (4.2%), diarrhoea (2.8%) and fatigue (2.5%).

CBYL719X2402 (BYLieve)

Additional safety evaluations were performed in the Phase II, multicenter, open-label, three-cohort, non-comparative study of alpelisib plus endocrine therapy (either fulvestrant or letrozole) in patients (pre- and post-menopausal women, and men) with HR-positive, HER2-negative advanced breast cancer harbouring PIK3CA mutation(s) in the tumour, and whose disease has progressed on or after prior treatments.

In the cohort of patients who had progressed on or after a CDK4/6 inhibitor plus an aromatase inhibitor before treatment with alpelisib plus fulvestrant (Cohort A; n=127 patients), ADRs that were reported in ≥ 20% of patients were diarrhoea (59.8%), hyperglycaemia (58.3%), nausea (45.7%), rash (39.4%), fatigue (29.1%), decreased appetite (28.3%), stomatitis (26.8%) and vomiting (23.6%).

Grade 3 or grade 4 ADRs that were reported in ≥ 5% of patients were hyperglycaemia (28.3%), rash (18.9%), and diarrhoea (5.5%).

The most common serious adverse drug reactions (ADRs), reported in ≥ 2% of patients were hyperglycaemia (5.5%) and rash (3.1%). Serious adverse events reported in ≥ 2% of patients were dyspnoea (2.4%) and pleural effusion (2.4%). Serious adverse events related to the gastrointestinal tract included colitis and erosive oesophagitis (each 0.8%).

Tabulated list of adverse reactions

ADRs from the phase III clinical study and post-marketing experience (Table 7) are listed by MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, ADRs are presented in order of decreasing seriousness. In addition, 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 the available data).

Table 7 ADRs observed in phase III clinical study and during post-marketing experience

Description of selected ADRs

Hyperglycaemia

Hyperglycaemia (FPG >160 mg/dl) was reported in 190 (66.9%) patients; grade 2 (FPG 160-250 mg/dl), 3 (FPG >250-500 mg/dl) and 4 (FPG >500 mg/dl) events were reported in 16.2%, 33.8% and 4.6% of patients, respectively.

Based on baseline FPG and HbA1c values, 56% of patients were considered pre-diabetic (FPG >100-126 mg/dl [5.6 to 6.9 mmol/l] and/or HbA1c 5.7-6.4%) and 4.2% of patients were considered diabetic (FPG ≥ 126 mg/dl [≥ 7.0 mmol/l] and/or HbA1c ≥ 6.5%). 74.8% of patients who were pre-diabetic at baseline experienced hyperglycaemia (any grade) when treated with alpelisib. Among all patients with hyperglycaemia of grade ≥ 2 (FPG ≥ 160 mg/dl), the median time to first occurrence was 15 days (range: 5 days to 900 days) (based on laboratory findings). The median duration of grade ≥ 2 hyperglycaemia was 10 days (95% CI: 8 to 13 days). In patients with grade ≥ 2 hyperglycaemia, median time to improvement (at least one grade from the first event) was 8 days (95% CI: 8 to 10 days). In all patients who continued on fulvestrant after discontinuing Piqray, FPG levels returned to baseline (normal).

Hyperglycaemia was managed with antidiabetic medicinal products, see section 4.4.

Rash

Rash events (including rash maculopapular, macular, generalised, papular and pruritic, dermatitis and dermatitis acneiform) were reported in 153 (53.9%) patients. Rash was predominantly mild or moderate (grade 1 or 2) and responsive to therapy, and in some cases rash was accompanied by pruritus and dry skin. Grade 2 and 3 events were reported in 13.7% and 20.1% of patients, respectively, with a median time to first onset of 12 days (range: 2 days to 220 days).

Among patients who received prophylactic antirash treatment including antihistamines, rash was reported less frequently than in the overall population; 26.1% vs 53.9% for all grades, 11.4% vs 20.1% for grade 3, and 3.4% vs 4.2% for rash leading to the permanent discontinuation of Piqray. Accordingly, antihistamines may be initiated prophylactically, at the time of initiation of treatment with Piqray.

Gastrointestinal toxicity (nausea, diarrhoea, vomiting)

Diarrhoea, nausea and vomiting were reported in 59.5%, 46.8% and 28.5% of the patients, respectively (see Table 7).

Grade 2 and 3 diarrhoea events were reported in 19.7% and 7.0% of patients, respectively, with a median time to onset of grade ≥ 2 diarrhoea of 50 days (range: 1 day to 954 days).

Severe diarrhoea and clinical consequences, such as dehydration and acute kidney injury, have been reported during treatment with Piqray and resolved with appropriate intervention (see Table 4). Antiemetics (e.g. ondansetron) and antidiarrhoeal medicinal products (e.g. loperamide) were used in 28/153 (17.6%) and 109/169 (64.5%) patients, respectively, to manage symptoms.

Osteonecrosis of the jaw (ONJ)

ONJ was reported in 5.6% patients (16/284) in the Piqray plus fulvestrant arm. Fifteen patients experiencing ONJ were exposed to concomitant bisphosphonates (e.g. zoledronic acid) or RANK-ligand inhibitors (e.g. denosumab). Therefore, in patients receiving Piqray and bisphosphonates or RANK-ligand inhibitors, an increased risk of development of ONJ cannot be excluded.

Elderly

In patients ≥ 65 years of age treated with alpelisib plus fulvestrant, there was a higher incidence of grade 3-4 hyperglycaemia (45.3%) compared to patients <65 years of age (33.5%), while in patients <75 years of age, grade 3-4 hyperglycaemia was 36% compared to 55.9% in patients ≥ 75 years of age.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms

The adverse reactions associated with overdose have been consistent with the safety profile of Piqray and included hyperglycaemia, nausea, asthenia and rash.

Management

General symptomatic and supportive measures should be initiated in all cases of overdose where necessary. There is no known antidote for Piqray.

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XX65

Mechanism of action

Alpelisib is an α -specific class I phosphatidylinositol3kinase (PI3Kα ) inhibitor. Gain-of-function mutations in the gene encoding the catalytic α -subunit of PI3K (PIK3CA) lead to activation of PI3Kα and AKT-signalling, cellular transformation and the generation of tumours in in vitro and in vivo models.

In breast cancer cell lines, alpelisib inhibited the phosphorylation of PI3K downstream targets including AKT, and showed activity in cell lines harbouring a PIK3CA mutation.

In vivo, alpelisib inhibited the PI3K/AKT signalling pathway and reduced tumour growth in xenograft models, including models of breast cancer.

PI3K inhibition by alpelisib treatment has been shown to induce an increase in oestrogen receptor (ER) transcription in breast cancer cells. The combination of alpelisib and fulvestrant demonstrated increased anti-tumour activity compared to either treatment alone in xenograft models derived from ER-positive, PIK3CA mutated breast cancer cell lines.

The PI3K/AKT signalling pathway is responsible for glucose homeostasis, and hyperglycaemia is an expected on-target adverse reaction of PI3K inhibition.

Clinical efficacy and safety

Study CBYL719C2301 (SOLAR-1)

Piqray was evaluated in a pivotal phase III, randomised, double-blind, placebo-controlled study of alpelisib in combination with fulvestrant in postmenopausal women, and men, with HR+, HER2- advanced (locoregionally recurrent or metastatic) breast cancer whose disease had progressed or recurred on or after an aromatase-inhibitor-based treatment (with or without CDK4/6 inhibitor combination).

A total of 572 patients were enrolled into two cohorts, one cohort with PIK3CA mutation and one cohort without PIK3CA mutation breast cancer. Patients were randomised to receive either alpelisib 300 mg plus fulvestrant or placebo plus fulvestrant in a 1:1 ratio. Randomisation was stratified by presence of lung and/or liver metastasis and previous treatment with CDK4/6 inhibitor(s).

In the cohort with PIK3CA mutation, 169 patients with one or more PIK3CA mutations (C420R, E542K, E545A, E545D [1635G>T only], E545G, E545K, Q546E, Q546R, H1047L, H1047R or H1047Y) were randomised to receive alpelisib in combination with fulvestrant and 172 patients were randomised to receive placebo in combination with fulvestrant. In this cohort 170 (49.9%) patients had liver/lung metastases and 20 (5.9%) patients had received prior CDK4/6 inhibitor treatment.

Patients had a median age of 63 years (range: 25 to 92 years). 44.9% patients were 65 years of age or older and ≤ 85 years. The patients included were White (66.3%), Asian (21.7%) and Black or African American (1.2%). The study population included one male subject enrolled in the PIK3CA mutant cohort and treated with alpelisib and fulvestrant. 66.0% and 33.4% of subjects had an ECOG performance status of 0 and 1, respectively.

97.7% of patients had received prior endocrine therapy. In 67.7% of subjects, the last therapy prior to study enrollment was endocrine therapy. Letrozole and anastrozole were the most commonly used endocrine therapies. The setting of last endocrine therapy prior to study enrollment was therapeutic in 47.8% of subjects and adjuvant therapy in 51.9% of subjects. Overall, 85.6% of the patients were considered to have endocrine-resistant disease; primary endocrine resistance (de novo resistance) was observed in 13.2% and secondary endocrine resistance (relapse/progression following an initial response) in 72.4% of patients.

In both cohorts (with or without PIK3CA mutation), demographics and baseline disease characteristics, ECOG performance status, tumour burden and prior antineoplastic therapy were well balanced between the study arms.

During the randomised treatment phase, alpelisib 300 mg or placebo was administered orally once daily on a continuous basis. Fulvestrant 500 mg was administered intramuscularly on cycle 1 days 1 and 15 and then at day 1 of a 28-day cycle during treatment phase (administration ± 3 days).

Patients were not allowed to cross over from placebo to alpelisib during the study or after disease progression.

The primary endpoint for the study was progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1), based on the investigator assessment in patients harbouring a PIK3CA mutation. The key secondary endpoint was overall survival (OS) for patients with a PIK3CA mutation status.

Other secondary endpoints included PFS for patients without PIK3CA mutation, OS for patients without PIK3CA mutation.

Primary efficacy analysis

At the final PFS analysis, the median duration of follow-up (between randomisation and data cut-off date of 12-June 2018) was 20 months. The results demonstrated a statistically significant improvement in PFS by investigator assessment in the PIK3CA mutant cohort for patients receiving alpelisib plus fulvestrant, compared to patients receiving placebo plus fulvestrant with an estimated 35% risk reduction of disease progression or death in favour of treatment with alpelisib plus fulvestrant.

Primary PFS results were supported by consistent results from a blinded independent review committee (BIRC) assessment in this cohort, from a randomly selected subset of 50% of randomised patients.

Table 8 Study C2301 - Summary of efficacy results (cohort with PIK3CA mutation)

In the cohort with PIK3CA mutation, PFS subgroup analyses per investigator assessment by randomisation stratification factors showed a generally consistent treatment effect in favour of the alpelisib arm, irrespective of presence or absence of lung/liver metastases.

In the subgroup of 170 patients with presence of lung/liver metastases, the PFS HR (95% CI) was 0.56 (0.40, 0.79); median PFS was 3.7 months (95% CI: 2.9, 6.1) in the placebo plus fulvestrant arm and 9.0 months (95% CI: 5.6, 14.5) in the alpelisib plus fulvestrant arm.

Among 20 patients with prior CDK4/6 inhibitor use the hazard ratio (HR) for PFS was 0.48 (95% CI: 0.17, 1.36); median PFS was 1.8 months (95% CI: 1.7, 3.6) in the placebo plus fulvestrant arm and 5.5 months (95% CI: 1.6, 16.8) in the alpelisib plus fulvestrant arm.

Overall response rates are summarized in Table 9.

Table 9 Overall response rate and clinical benefit rate in the PIK3CA mutant cohort per investigator assessment (Data cut-off date: 18-Jun-2018)

Figure 1 Kaplan-Meier plot of progression free survival in the PIK3CA mutant cohort per investigator assessment (Data cut-off date: 18-Jun-2018)

Final overall survival analysis

The final OS analysis was conducted using a data cut-off date of 23-Apr-2020.

With a median duration from randomisation to data cut-off of approximately 42 months, a total of 87 (51.5%) deaths were reported in the alpelisib plus fulvestrant arm and 94 (54.7%) in the placebo plus fulvestrant arm, the HR was 0.86 (95% CI: 0.64, 1.15; p = 0.15, one-sided) and the pre-specified O'Brien-Fleming efficacy boundary of p ≤ 0.0161 was not crossed. Median OS was 31.4 months (95% CI: 26.8, 41.3) in the placebo plus fulvestrant arm and 39.3 months (95% CI: 34.1, 44.9) in the alpelisib plus fulvestrant arm.

Figure 2 Kaplan-Meier plot of overall survival in cohort with PIK3CA mutation (cut-off date of 23-Apr-2020)

OS subgroup analyses by randomisation stratification factors demonstrated a generally consistent treatment effect.

Cohort without PIK3CA mutation

No PFS benefit was observed in patients whose tumours did not have a PIK3CA tissue mutation.

CBYL719X2402 (BYLieve)

Alpelisib was evaluated in a Phase II, multicenter, open-label, three-cohort, non-comparative study in combination with endocrine therapy (either fulvestrant or letrozole) in adult patients (pre- and post-menopausal women and men), 18 years or older, with HR-positive, HER2-negative locally advanced or metastatic breast cancer harbouring PIK3CA mutation(s), and whose disease has progressed on or after prior treatments.

Table 10 CBYL719X2402 Patients assignment based on most recent prior therapy and treatment regimen

Patients were treated until disease progression, intolerable toxicity, or until 18 months after last subject first treatment. Treatment crossover between cohorts was not permitted in this study

The primary objective of the study was to assess the proportion of patients who were alive without disease progression at 6 months based on local Investigator assessment per RECIST 1.1. Analysis of the primary endpoint was to be performed separately for each cohort.

Using a data cut-off date of 17 December 2019, data for Cohort A only are available. The primary analysis was performed for the modified Full analysis set (mFAS), defined as all subjects in Cohort A with a PIK3CA mutation confirmed by a Novartis-designated laboratory who received at least one dose of study treatment (n=121). With a median duration of follow-up of 11.7 months (calculated from the start of treatment to the date of data cut-off), 61/121 patients (50.4%, 95% CI: 41.2, 59.6) were alive without disease progression at 6 months.

Median progression-free survival (PFS), one of the secondary endpoints was 7.3 months (95% CI: 5.6, 8.3) in Cohort A, based on investigator assessment.

Figure 3 Kaplan-Meier plot of time of PFS per local Investigator assessment (Cohort A) – mFAS (cut-off date of 17-Dec-2019)

Prior use of fulvestrant in study CBYL719X2102

Patients with prior fulvestrant use were not included in the pivotal study. In the phase I study CBYL719X2101, 39 subjects reported prior fulvestrant use. The best overall responses to treatment with alpelisib plus fulvestrant for the 21 subjects with PIK3CA mutations and measurable disease at baseline were partial response in 7 subjects, stable disease in 11 subjects, and progressive disease in 2 subjects. Hence, the evidence of efficacy of this treatment in patients previously treated with fulvestrant is not established due to the limited data at this time (see section 4.4).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Piqray in all subsets of the paediatric population in breast cancer (see section 4.2 for information on paediatric use).

The pharmacokinetics of alpelisib were investigated in patients under an oral dosing regimen ranging from 30 to 450 mg daily. Healthy subjects received single oral doses ranging from 300 to 400 mg. The pharmcokinetics were comparable in both oncology patients and healthy subjects.

Absorption

Following oral administration of alpelisib, median time to reach peak plasma concentration (T_max) ranged between 2.0 to 4.0 hours, independent of dose, time or regimen. Based on absorption modelling bioavailability was estimated to be very high (>99%) under fed conditions but lower under fasted conditions (~68.7% at a 300 mg dose). Steady-state plasma levels of alpelisib after daily dosing can be expected to be reached on day 3 following onset of therapy in most patients.

Food effect

Alpelisib absorption is affected by food. In healthy volunteers after a single 300 mg oral dose of alpelisib, compared to the fasted state, a high-fat high-calorie (HFHC) meal (985 calories with 58.1 g of fat) increased AUC_inf by 73% and C_max by 84%, and a LFLC meal (334 calories with 8.7 g of fat) increased AUC_inf by 77% and C_max by 145%. No significant difference was found for AUC_inf between LFLC and HFHC with a geometric mean ratio of 0.978 (CI: 0.876, 1.09), showing that neither fat content nor overall calorific intake has a considerable impact on absorption. The increase in gastrointestinal solubility by bile, secreted in response to food intake, is the potential cause of the food effect. Hence, Piqray should be taken immediately after food at approximately same time each day.

Distribution

Alpelisib moderately binds to protein with a free fraction of 10.8% regardless of concentration. Alpelisib was equally distributed between red blood cells and plasma with a mean in vivo blood-to-plasma ratio of 1.03. As alpelisib is a substrate of human efflux transporters, penetration of the blood-brain barrier is not expected to occur in humans. The volume of distribution of alpelisib at steady state (Vss/F) is estimated at 114 litres (intersubject CV% 49%).

Biotransformation

In vitro studies demonstrated that formation of the hydrolysis metabolite BZG791 by chemical and enzymatic amide hydrolysis was a major metabolic pathway, followed by CYP3A4-mediated hydroxylation. Alpelisib hydrolysis occurs systemically by both chemical decomposition and enzymatic hydrolysis via ubiquitously expressed, high-capacity enzymes (esterases, amidases, choline esterase) not limited to the liver. CYP3A4-mediated metabolites and glucuronides amounted to ~15% of the dose; BZG791 accounted for ~40-45% of the dose. The rest of the dose, which was found as unchanged alpelisib in urine and faeces, was either excreted as alpelisib or not absorbed.

Elimination

Alpelisib exhibits low clearance with 9.2 l/h (CV% 21%) based on population pharmacokinetic analysis under fed conditions. The population-derived half-life, independent of dose and time, was 8 to 9 hours at steady state with 300 mg once daily.

In a human mass-balance study, after oral administration, alpelisib and its metabolites were primarily found in the faeces (81.0%) as alpelisib, or metabolised as BZG791. Excretion in the urine is minor (13.5%), with unchanged alpelisib (2%). Following a single oral dose of [14C] alpelisib, 94.5% of the total administered radioactive dose was recovered within 8 days.

Linearity/non-linearity

The pharmacokinetics were found to be linear with respect to dose and time under fed conditions between 30 and 450 mg. After multiple doses, alpelisib exposure (AUC) at steady state is only slightly higher than that of a single dose, with an average accumulation of 1.3 to 1.5 with a daily dosing regimen.

Metabolic interaction

CYP3A4, CYP2C8, CYP2C9, CYP2C19 and CYP2B6 substrates

In a drug-drug interaction study, co-administration of repeated doses of alpelisib 300 mg with a single dose of sensitive substrates of CYP3A4 (midazolam), CYP2C8 (repaglinide), CYP2C9 (warfarin), CYP2C19 (omeprazole) and CYP2B6 (bupropion), administered as a cocktail, showed that there is no clinically signficant pharmacokinetic interaction. The data from CYP2B6 substrate (bupropion) should be interpreted with caution due to the small sample size.

In healthy subjects, co-administration of a CYP2C9 substrate (S-warfarin) -with repeated doses of 300 mg alpelisib at steady state, increased S-warfarin exposure on average by 34% and 19% for AUC_inf and C_max respectively, compared to administration of S-warfarin alone. This indicates that alpesilib is a mild inhibitor of CYP2C9.

In a drug-drug interaction study with the sensitive CYP3A4 and P-gp substrate everolimus, in patients with advanced solid tumours, AUC increased by 11.2%. No clinically meaningful change is expected as a result of drug interaction with CYP3A4 substrates.

CYP3A4 inducers

In a drug-drug interaction study co-administration of alpelisib and rifampin, a strong CYP3A4 inducer, confirmed that there is a clinically significant pharmacokinetic interaction between alpelisib and strong CYP3A4 inducers (see section 4.5).

Transporter-based interaction

Based on in vitro data, inhibition of the renal organic anion transporter OAT3 by alpelisib (and/or its metabolite BZG791) cannot be discarded in patients at the therapeutic dose.

Alpelisib showed only weak in vitro inhibition towards the ubiquitously expressed efflux transporters (P-gp, BCRP, MRP2, BSEP), solute carrier transporters at the liver inlet (OATP1B1, OATP1B3, OCT1) and solute carrier transporters in the kidney (OAT1, OCT2, MATE1, MATE2K). As unbound systemic steady-state concentrations (or concentrations at the liver inlet) at both the therapeutic dose and maximum tolerated dose are significantly lower than the experimentally determined unbound inhibition constants or IC₅₀, the inhibition will not translate into clinical significance. Due to high alpelisib concentrations in the intestinal lumen, an effect on intestinal P-gp and BCRP cannot be fully excluded.

Special populations

Effect of age, weight and gender

The population pharmacokinetic analysis showed that there are no clinically relevant effects of age, body weight, or gender on the systemic exposure of alpelisib that would require Piqray dose adjustment.

Paediatric patients (below 18 years)

The pharmacokinetics of Piqray in children aged 0-18 years have not been established. No data are available.

Elderly (age 65 years or above)

Of 284 patients who received Piqray in the phase III study (in the alpelisib plus fulvestrant arm), 117 patients were ≥ 65 years of age and 34 patients were between 75 and 87 years of age. No overall differences in exposure of Piqray were observed between these patients and younger patients (see section 4.2).

Race/Ethnicity

Population pharmacokinetic analyses and pharmacokinetic analyses from a phase I study in Japanese cancer patients showed that there are no clinically relevant effects of ethnicity on the systemic exposure of Piqray.

Non-compartmental pharmacokinetic parameters after single and multiple daily doses of Piqray for Japanese patients were very similar to those reported in the Caucasian population.

Renal impairment

Based on a population pharmacokinetic analysis that included 117 patients with normal renal function (eGFR ≥ 90 ml/min/1.73 m²) / (CLcr ≥ 90 ml/min), 108 patients with mild renal impairment (eGFR 60 to <90 ml/min/1.73 m²)/ (CLcr 60 to <90 ml/min), and 45 patients with moderate renal impairment (eGFR 30 to <60 ml/min/1.73 m²), mild and moderate renal impairment had no effect on the exposure of alpelisib (see section 4.2).

Hepatic impairment

Based on a pharmacokinetic study in patients with hepatic impairment, moderate and severe hepatic impairment had negligible effect on the exposure of alpelisib (see section 4.2). The mean exposure for alpelisib was increased 1.26-fold in patients with severe (GMR: 1.00 for C_max; 1.26 for AUC_last/AUC_inf) hepatic impairment.

Based on a population pharmacokinetic analysis that included 230 patients with normal hepatic function, 41 patients with mild hepatic impairment and no patients with moderate hepatic impairment, further supporting the findings from the dedicated hepatic impairment study, mild and moderate hepatic impairment had no effect on the exposure of alpelisib (see section 4.2).

Safety pharmacology and repeated dose toxicity

The majority of the observed alpelisib effects were related to the pharmacological activity of alpelisib as a p110α -specific inhibitor of the PI3K pathway, such as the influence on the glucose homeostasis resulting in hyperglycaemia and the risk of increased blood pressure. The bone marrow and lymphoid tissue, pancreas and some reproductive organs of both genders were the main target organs for adverse effects. Effects on bone marrow and lymphoid tissue were generally reversible on cessation of treatment. Effects on the pancreas and reproductive organs did not fully reverse but showed a tendency towards reversion. In exploratory rat studies evidence of inflammatory changes of the skin was found.

Cardiovascular safety pharmacology

In vitro inhibition of hERG channels (IC₅₀ of 9.4 µ M) was shown at concentrations ~13-fold higher than the exposure in humans, at the recommended dose of 300 mg/day. No relevant electrophysiological effect was seen in dogs.

Carcinogenicity and mutagenicity

No carcinogenicity studies have been conducted.

Results of standard genotoxicity in vitro studies with alpelisib were negative. Alpelisib was not genotoxic in a repeated-dose rat toxicity study where micronucleus analysis was integrated, up to exposure levels approximately twice the estimated exposure (AUC) in humans at the recommended dose of 300 mg.

Reproductive toxicity

Embryo-foetal development studies in rats and rabbits have demonstrated that oral administration of alpelisib during organogenesis induced embryotoxicity, foetotoxicity and teratogenicity. In rats and rabbits, following prenatal exposure to alpelisib, increased incidences of pre- and post-implantation losses, reduced foetal weights and increased incidences of foetal abnormalities (enlarged brain ventricle, decreased bone ossification and skeletal malformations) were observed starting at exposures below those in humans at the highest recommended dose of 300 mg, indicating potential clinical relevance.

In repeated dose toxicity studies, adverse effects were observed in reproductive organs, such as vaginal or uterine atrophy and oestrus cycle variations in rats, decreases in prostate and testes weight in rats and dogs and prostate atrophy in dogs at clinically relevant doses based on AUC.

In fertility studies conducted in male and female rats, similar effects on fertility were observed. In females, increased pre- and post-implantation losses, which led to reduced numbers of implantation sites and live embryos, were observed at exposure levels (AUC) approximately twice the recommended human dose of 300 mg. In males, fertility and reproductive performance, including sperm count and motility parameters, were unaffected at exposure levels approximately twice the estimated exposure (AUC) in humans at the recommended dose of 300 mg. However, at exposure levels (AUC) at or below the recommended human dose of 300 mg, accessory gland weights (seminal vesicles, prostate) were reduced and correlated microscopically with atrophy and/or reduced secretion in prostate and seminal vesicles, respectively.

Phototoxicity

An in vitro phototoxicity test on the mouse Balb/c 3T3 fibroblast cell line did not identify a relevant phototoxicity potential for alpelisib.

Tablet core

Cellulose microcrystalline

Mannitol

Sodium starch glycolate

Hypromellose

Magnesium stearate

Film coating

Hypromellose

Iron oxide, black (E172)

Iron oxide, red (E172)

Titanium dioxide (E171)

Macrogol

Talc

Not applicable.

3 years.

This medical product does not require any special storage conditions.

PVC/PCTFE/alu (polyvinylchloride/polychlorotrifluoroethylene/aluminium) blister sealed into a blister card containing 14 film-coated tablets.

Piqray 50 mg and 200 mg film-coated tablets

Packs containing 28 film-coated tablets (14 of 50 mg and 14 of 200 mg) or 56 film-coated tablets (28 of 50 mg and 28 of 200 mg).

Multipacks containing 168 film-coated tablets (3x 56, each comprising 28 tablets of 50 mg and 28 tablets of 200 mg).

Piqray 150 mg film-coated tablets

Packs containing 28 or 56 film-coated tablets.

Multipacks containing 168 (3x 56) film-coated tablets.

Piqray 200 mg film-coated tablets

Packs containing 14 or 28 film-coated tablets.

Multipacks containing 84 (3x 28) film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.