Antineoplastic agents, other antineoplastic agents. ATC code:
Pharmacology: Pharmacodynamics: 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
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.
, 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:
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 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.
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 with PIK3CA mutation advanced breast cancer. The key secondary endpoint was overall survival (OS) for patients with PIK3CA mutation status.
Other secondary endpoints included PFS for patients without PIK3CA mutation, OS for patients without PIK3CA mutation.
The median duration of follow-up (between randomisation and data cut-off date of 12-June-2018) in the cohort with PIK3CA mutation was 20 months.
The efficacy results in the cohort with PIK3CA mutation demonstrated a statistically significant improvement in PFS in patients receiving alpelisib plus fulvestrant, compared to patients receiving placebo plus fulvestrant with an estimated 35% risk reduction of disease progression or death. (See Table 1.)
Click on icon to see table/diagram/image
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.
Among 20 patients with prior CDK4/6 inhibitor use the hazard ratio (HR) 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.
Using a data cut-off date of 12-Jun-2018, PFS results for the subgroup of endocrine resistant patients (HR=0.64; 95% CI: 0.49, 0.85, n=292) and endocrine sensitive patients (HR=0.87; 95% CI: 0.35, 2.17, n=39) were in favour of the alpelisib plus fulvestrant arm. The number of endocrine sensitive patients with a PIK3CA mutation was limited (n=39) and the results should be interpreted with caution.
Using a data cut-off date of 12-Jun-2018, the overall response rate in patients with measurable disease at baseline was 35.7% (95% CI: 27.4, 44.7) in the alpelisib plus fulvestrant arm and 16.2% (95% CI: 10.4, 23.5) in the placebo plus fulvestrant arm. (See figure.)
Click on icon to see table/diagram/image
Cohort without PIK3CA mutation: No PFS benefit was observed in patients whose tumours did not have a PIK3CA tissue mutation.
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 Precautions).
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 Dosage & Administration 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 pharmacokinetics were comparable in both oncology patients and healthy subjects.
Following oral administration of alpelisib, median time to reach peak plasma concentration (Tmax
) 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 AUCinf
by 73% and Cmax
by 84%, and a LFLC meal (334 calories with 8.7 g of fat) increased AUCinf
by 77% and Cmax
by 145%. No significant difference was found for AUCinf
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.
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% 46%).
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 minor contribution of CYP3A4. 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 absorbed fraction of the dose was excreted as alpelisib.
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 excreted in the faeces (81.0%), mainly through hepatobiliary export and/or intestinal secretion of alpelisib, or metabolised to 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.
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.
CYP3A4 substrates: In a drug-drug interaction study with the sensitive CYP3A4 substrate everolimus, AUC increased by 11.2%. No clinically meaningful change is expected as a result of drug interaction with CYP3A4 substrates.
CYP3A4 inducers and inhibitors: The effects of CPY3A4 inducers or inhibitors have not been evaluated in clinical studies. No clinically meaningful changes in overall exposure are expected as a result of the low fraction (<15%) metabolised by CYP3A4.
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.
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 Dosage & Administration).
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 Dosage & Administration).
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 Dosage & Administration). The mean exposure for alpelisib was increased 1.26-fold in patients with severe (GMR: 1.00 for Cmax
; 1.26 for AUClast
) 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 Dosage & Administration).
Toxicology: Preclinical safety data:
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.
Cardiovascular safety pharmacology: In vitro
inhibition of hERG channels (IC50
of 9.4 μM) 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 studies with alpelisib were negative. In a repeated-dose rat toxicity study, where micronucleus analysis was integrated, exposure levels of alpelisib were 1.4-fold higher in males and 2-fold higher in females than therapeutic exposure in adult humans treated with the recommended dose. Therefore, the genotoxicity potential of alpelisib in humans cannot be ruled out.
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.
A fertility study in rats has not been performed. However, 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.
Phototoxicity: An in vitro
phototoxicity test on the mouse Balb/c 3T3 fibroblast cell line did not identify a relevant phototoxicity potential for alpelisib.