4616 - Alpelisib (ALP) + Endocrine Therapy (ET) by Last Prior Therapy in Patients (pts) With PIK3CA-Mutated Hormone-Receptor Positive (HR+) Human Epidermal Growth Factor Receptor-2-Negative (HER2–) Advanced Breast Cancer (ABC): Additional Study Cohort in BYLieve

Background

Approximately 40% of pts with HR+, HER2– ABC have mutations (mut) in PIK3CA, which encodes α-PI3K and leads to PI3K pathway hyperactivation and potentially ET resistance. ALP is a selective inhibitor of α-PI3K that, in combination with fulvestrant (FUL), significantly improved median progression-free survival (PFS) vs placebo + FUL in pts with PIK3CA-mut, HR+ HER2– ABC in the phase 3 SOLAR-1 trial (11.0 vs 5.7 mo, respectively; HR 0.65; 95% CI, 0.50-0.85; P < 0.001). BYLieve is an ongoing phase 2, multicenter, open-label, noncomparative study assessing ALP + ET (FUL or letrozole [LET]) in pts with PIK3CA-mut HR+, HER2– ABC who progressed on/after prior treatments (tx).

Trial design

BYLieve includes women (any menopausal status) and men with PIK3CA-mut, HR+, HER2– ABC and evidence of tumor progression on prior tx. Cohorts A and B comprise pts who received a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + ET as their last tx. With the adoption of Amendment 3, a new cohort (C) enrolls pts who had systemic chemotherapy or ET as last prior tx and who failed aromatase inhibitor (AI) in the adjuvant or metastatic setting. In the advanced setting, ≤2 anticancer tx (including ≤1 chemotherapy) are allowed. Pts must have ≥1 measurable lesion per RECIST criteria or ≥ 1 predominantly lytic bone lesion. Key exclusion criteria include prior PI3Ki tx and type 1 or uncontrolled type 2 diabetes. Study tx comprises: Cohort A (prior CDK 4/6i + AI), ALP 300 mg once daily (qd) + FUL 500 mg Q28d + C1d15; Cohort B (prior CDK 4/6i + FUL), ALP 300 mg qd + LET 2.5 mg qd; Cohort C, ALP 300 mg qd + FUL 500 mg Q28d + C1d15. The primary endpoint is the proportion of pts free of progression at 6 mo per local investigator assessment for each cohort. Secondary endpoints include PFS, PFS2, ORR, and CBR. Safety and tolerability will also be assessed, including fasted or random blood glucose levels (non-fasted). Tumor tissue and circulating tumor DNA are collected for biomarker assessments. The study is ongoing and currently recruiting pts, with increase in planned overall enrollment from 160 to 340 pts.

Clinical trial identification

NCT03056755.

Editorial acknowledgement

Medical editorial assistance was provided by Joe Hodgson of Healthcare Consultancy Group, LLC, and funded by Novartis Pharmaceuticals Corporation.

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation.

Funding

Novartis Pharmaceuticals Corporation.

Disclosure

E. Ciruelos: Advisory / Consultancy, Speaker and consultant fee: Novartis, Roche, Pfzier, Lilly. T. Bachelot: Research grant / Funding (self), Research grant: Novartis; Research grant / Funding (self): Roche; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Pfzier. S. Chia: Advisory / Consultancy, Research grant / Funding (institution), Payment to the institution for conducting clinical trials. Honorarium to myself for advisory boards.: Novartis; Advisory / Consultancy, Research grant / Funding (institution), Payment to the institution for conducting clinical trials. Honorarium to myself for advisory boards.: Pfzier. D. Juric: Advisory / Consultancy, Scientific Advisory Board: Novartis, Genentech, Eisai, Ipsen, EMD Serono. N. Turner: Advisory / Consultancy: AstraZeneca, BMS, Lilly, MSD, Novartis, Pfizer, Roche/Genentech, Tesaro, Bicycle Therapeutics; Research grant / Funding (self): AstraZeneca, BioRad, Pfizer, Roche/Genentech, Clovis, Guardant Health. A. Ridolfi: Full / Part-time employment: Novartis. N. Sophos: Full / Part-time employment: Novartis. B. Cooper: Full / Part-time employment: Novartis. A. Thuerigen: Full / Part-time employment: Novartis. H.S. Rugo: Research grant / Funding (institution): Pfizer, Merck, Novartis, Lilly, Genentech, OBI, Odonate, Daiichi, Eisai, Seattle Genetics and Macrogenics; Travel / Accommodation / Expenses: Lilly, Mylan, Pfizer, Amgen, Merck and Puma. All other authors have declared no conflicts of interest.