Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents
ATC code: L01EM03
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.
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 a PIK3CA mutation. The key secondary endpoint was overall survival (OS) for patients with a PIK3CA mutation.
Other secondary endpoints included PFS for patients without a PIK3CA mutation, OS for patients without a PIK3CA mutation.
The study met its primary objective at the final PFS analysis (cut-off date 12-Jun-2018), demonstrating a statistically significant improvement in PFS per 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 (see Table 8).
Table 8. Study C2301 primary efficacy analysis – Summary of efficacy results based on RECIST (FAS, cohort with PIK3CA mutation). Data cut-off date: 12-Jun-2018:
| Piqray + fulvestrant (n=169) | Placebo + fulvestrant (n=172) | |
|---|---|---|
| Median progression free survival (PFS) (months, 95% CI) | ||
| Investigator radiological assessment# | ||
| PIK3CA mutant cohort (N=341) | 11.0 (7.5 to 14.5) | 5.7 (3.7 to 7.4) |
| Hazard ratio (95% CI) | 0.65 (0.50 to 0.85) | |
| p-valuea | 0.00065 | |
| Blinded independent review committee assessment*# | ||
| PIK3CA mutant cohort (N=173) | 11.1 (7.3 to 16.8) | 3.7 (2.1 to 5.6) |
| Hazard ratio (95% CI) | 0.48 (0.32 to 0.71) | |
| p-value | N/A | |
CI = confidence interval; N = number of patients; N/A = is not applicable
a p-value is obtained from the one-sided stratified log-rank test.
# Per RECIST 1.1
* Based on 50% sample-based audit approach
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) 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.
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.
At the time when the final OS analysis was conducted (data cut-off date of 23-Apr-2020) a descriptive follow-up efficacy analysis for PFS data was performed. With a median duration from randomisation to data cut-off of approximately 42 months, the reported PFS results were consistent with those from the primary PFS analysis. There was an estimated 36% risk reduction of progression or death in favour of treatment with alpelisib plus fulvestrant (HR=0.64; 95% CI: 0.50, 0.81) (Figure 1).
Figure 1. Study C2301 – Kaplan-Meier plot of PFS per investigator assessment (FAS, PIK3CA mutant cohort): descriptive update with data cut-off date of 23-Apr-2020:
At the final OS analysis, the study did not meet its key secondary objective. As of the data cut-off date of 23-Apr-2020, 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 39.3 months (95% CI: 34.1, 44.9) in the alpelisib plus fulvestrant arm and 31.4 months (95% CI: 26.8, 41.3) in the placebo plus fulvestrant arm (Figure 2).
Figure 2. Study C2301 key secondary analysis – Kaplan-Meier plot of OS (FAS, PIK3CA mutant cohort) with cut-off date of 23-Apr-2020:
In patients with prior CDK4/6i treatment (n=20), the median OS in the alpelisib plus fulvestrant arm was 29.8 months (95% CI: 6.7, 38.2) compared to 12.9 months (95% CI: 2.5, 34.6) in the placebo plus fulvestrant arm (HR=0.67; 95% CI: 0.21, 2.18).
No PFS benefit was observed in patients whose tumours did not have a PIK3CA tissue mutation.
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).
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.
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.
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% 49%).
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.
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.
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.
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 AUCinf and Cmax 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.
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).
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.
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.
The pharmacokinetics of Piqray in children aged 0-18 years have not been established. No data are available.
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).
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.
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).
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 Cmax; 1.26 for AUClast/AUCinf) 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).
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.
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.
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.
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.
An in vitro phototoxicity test on the mouse Balb/c 3T3 fibroblast cell line did not identify a relevant phototoxicity potential for alpelisib.
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