(T-028) Pooled population PK of alpelisib in patients with PIK3CA-related overgrowth spectrum and breast cancer

Manuella Zimmermann, PhD – principal pharmacometrician, full development PMX, Novartis Pharmaceuticals Corporation, Basel, Switzerland; keroles Nakhla, PhD – Principal Scientist I, PKS, Novartis Institute of Biomedical Research, East Hanover, NJ, USA; Paul O'Connell, PhD – Associate director biostatistics, Analytics Computing & Engineering, Novartis Pharmaceuticals Corporation, Basel, Switzerland; Nathalie Fretault, PhD – Executive Director Biostatistics, Statistics, Novartis Pharma S.A.S, Rueil-Malmaison, France; Elise Burmeister Getz, PhD – Director, PKS, Novartis Institute of Biomedical Research, Emeryville, CA, USA; Yu-Yun Ho, PhD – Executive director pharmacometrics, full development PMX, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

Alpelisib is an PI3Kα inhibitor approved at 300 mg QD for the treatment of HR+, HER2-, PIK3CA-mutated breast cancer (BC). FDA granted approval2 for patients ≥2 yo with severe manifestations of PIK3CA-Related Overgrowth Spectrum (PROS) based on a compassionate use program at a QD dose of 50 mg for pediatrics and 250 mg for adults. PROS is an orphan disease characterized by tissue overgrowth which may be debilitating and may cause early mortality.

EPIK-P2 is an on-going randomized, double-blind, placebo-controlled study to assess the efficacy, safety and pharmacokinetics (PK) of alpelisib in pediatric and adult patients with PROS at a starting dose of 50 mg and 125 mg respectively, allowing dose increase to 250 mg QD for patients >= 6yo.

EPIK-P2 provides the first alpelisib PK data in PROS and in pediatric patients. EPIK-P2 allows dose titration to a maximum dose of 250 mg QD for patients 6 years old and older.

Objectives: To assess the influence of intrinsic and extrinsic factors on alpelisib PK to guide dose recommendations for pediatric and adult PROS patients.

Methods: Given the limited alpelisib PK data available in PROS, a pooled PK dataset with solid tumor, breast cancer PROS trials data was created. A popPK model was build to describe alpelisib PK. The influence of intrinsic patient characteristics such as age, weight, sex and extrinsic factors (such as co-administration with fulvestrant) were illustrated via simulations. Initial results, presented here, will be updated for ACOP with arising data from EPIK-P2.

Results: The alpelisib plasma PK dataset comprised 495 adult cancer patients (8265 observations) and 116 PROS patients (358 observations). Approximately 2300 observations from EPIK-P2 will be available in June 2024.
A single 1-compartment model with delayed 0-order absorption and linear elimination was found to adequately describe all adult cancer and adult and pediatric PROS PK data (with random effects on all parameters). PK behavior of alpelisib in PROS was not found to be different than in BC. A weight effect on volume (exponent of 0.7) and clearance (exponent of 0.5) was selected, along with sex and renal impairment effects on clearance, and fulvestrant co-administration on volume. Race and age were not significant. Results are consistent with prior results from the BC-only population. GOF plots indicated an adequate description of the data (individual fits, VPCs) with a stable convergence.

Conclusion: The final model illustrates the impact of covariates on steady state exposure, relative to a typical adult PROS female following a stable 125 mg QD dose:
No effect of disease type or race
10% lower exposure in males
15% higher exposure in patients with renal impairment
10% lower exposure with fulvestrant
35% and 55% lower exposure respectively in children and adolescents treated with 50 mg QD
These preliminary results indicate that the RWE-based EPIK-P2 starting doses require no adjustment for patient intrinsic-factor subgroups.

Citations: [1] Piqray USPI (2021) Highlights of prescribing information. Piqray (alpelisib) tablets. Novartis Pharmaceuticals Corporation, East Hanover, NJ. Revised 7/2021.: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212526s000lbl.pdf
[2] Vijoice USPI (2024) Highlights of prescribing information. Vijoice (alpelisib) tablets. Novartis Pharmaceuticals Corporation, East Hanover, NJ. Revised 4/2024.https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218466s000lbl.pdf
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[4] Keppler-Noreuil KM, Rios JJ, Parker VE, Semple RK, Lindhurst MJ, Sapp JC, Alomari A, Ezaki M, Dobyns W, Biesecker LG. PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet A. 2015 Feb;167A(2):287-95. doi: 10.1002/ajmg.a.36836. Epub 2014 Dec 31. PMID: 25557259; PMCID: PMC4480633.
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[6] EPIK-P2: NCT04589650: Study Assessing the Efficacy, Safety and PK of Alpelisib (BYL719) in Pediatric and Adult Patients With PIK3CA-related Overgrowth Spectrum (EPIK-P2).
[7] NCT01387321: A Study of BYL719 in Adult Patients With Advanced Solid Malignancies
[8] NCT01219699: A Study of BYL719 in Adult Patients With Advanced Solid Malignancies, Whose Tumors Have an Alteration of the PIK3CA Gene.
[9] NCT02437318: SOLAR-1: A phase III randomized double-blind, placebo controlled study of alpelisib in combination with fulvestrant for men and postmenopausal women with hormone receptor positive, HER2-negative advanced breast cancer which progressed on or after aromatase inhibitor treatment.
[10] Monolix 2023R1, Lixoft SAS, a Simulations Plus company