Alpelisib (ALP) + endocrine therapy (ET) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–), PIK3CA-mutated (mut) advanced breast cancer (ABC): Baseline biomarker analysis and progression-free survival (PFS) by duration of prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy in the BYLieve study.

Dejan Juric Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA info_outline Dejan Juric, Hope S. Rugo, Stephen K.L. Chia, Florence Lerebours, Manuel Ruiz-Borrego, Pamela Drullinsky, Eva M. Ciruelos, Patrick Neven, Yeon Hee Park, Christina H. Arce, Ennan Gu, Mukta Joshi, Estelle Roux, Murat Akdere, Nicholas C. Turner

Authors Dejan Juric Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA info_outline Dejan Juric, Hope S. Rugo, Stephen K.L. Chia, Florence Lerebours, Manuel Ruiz-Borrego, Pamela Drullinsky, Eva M. Ciruelos, Patrick Neven, Yeon Hee Park, Christina H. Arce, Ennan Gu, Mukta Joshi, Estelle Roux, Murat Akdere, Nicholas C. Turner Organizations Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, British Columbia Cancer Agency, University of British Columbia, Vancouver, BC, Canada, Institut Curie, PSL Research University, Saint-Cloud, France, Hospital Virgen del Rocio de Sevilla, Seville, Spain, Memorial Sloan Kettering Cancer Center, New York, NY, Hospital Universitario 12 de Octubre, Madrid, Spain, University Hospitals, Leuven, Belgium, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea, Novartis Pharmaceuticals Corporation, East Hanover, NJ, Novartis Institutes for BioMedical Research, Cambridge, MA, Novartis Pharma AG, Basel, Switzerland, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, United Kingdom Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: ALP (PI3K-α selective inhibitor and degrader) + fulvestrant (FUL) is approved for pts with HR+, HER2– ABC and a tumor mutation in PIK3CA (̃ 40% of these pts). Primary analyses from the Phase 2 BYLieve study demonstrated efficacy and safety of ALP + ET in pts with PIK3CA -mut, HR+, HER2– ABC in the post-CDK4/6i setting. Post hoc analyses, including pts with disease progression within 6 mo of CDK4/6i + ET treatment (Tx), confirmed ALP benefit regardless of duration of prior CDK4/6i. Here we assess baseline biomarkers in circulating tumor DNA (ctDNA) by duration of prior CDK4/6i Tx and PFS in pts from BYLieve Cohorts A and B. Methods: In the BYLieve study, pts with PIK3CA -mut, HR+, HER2– ABC had CDK4/6i + aromatase inhibitor (Cohort A) or + FUL (Cohort B) as immediate prior Tx to receiving ALP + FUL and ALP + letrozole (LET), respectively. At data cutoff dates, pts had ≥ 18-mo follow-up in Cohort A and ≥ 6-mo in Cohort B. In each cohort, pts were grouped based on duration of prior CDK4/6i Tx (≤ 6 mo or >6 mo). Alterations were detected on ctDNA using next-generation sequencing (PanCancer V2 Panel). PFS was assessed in each cohort and by duration of prior CDK4/6i Tx. Results: Of 127 and 126 pts enrolled in Cohorts A and B, respectively, 98 (≤ 6-mo: 24; >6-mo: 74) and 94 (≤ 6-mo: 28; >6-mo: 66) were included in this analysis based on availability of ctDNA samples, data on duration of prior CDK4/6i, and centrally confirmed PIK3CA -mut disease. In this population, median (m) PFS (95% CI) was 8.2 mo (5.6 - 9.5) and 5.6 mo (3.7 - 7.1) in Cohorts A and B, respectively. In Cohort A, mPFS (95% CI) was 12.0 mo (5.5-non estimable) and 6.2 mo (5.4 - 8.5) in the ≤ 6-mo and >6-mo groups, respectively. The OncoPrint genomic profiles showed that pts in the ≤ 6-mo vs >6-mo group had a lower median ctDNA fraction and fewer detected gene alterations, including in genes associated with ET and/or CDK4/6i resistance, and fewer chromosomes 8/11 amplifications (linked to early relapse). In Cohort B, mPFS was 5.9 mo (3.5 - 11.0) and 5.6 mo (3.7 - 7.1) in the ≤ 6-mo and >6-mo groups, respectively. Both groups had high median ctDNA fractions and complex tumor mutation profiles reflecting more extensive treatment history. Conclusions: Lower median ctDNA fraction and lower mutational complexity observed in Cohort A ≤ 6-mo vs >6-mo group was associated with numerically longer mPFS, potentially indicating increased dependence on the mutant PI3K-α. In Cohort B, both ≤ 6-mo and >6-mo groups had high median ctDNA fractions and similar tumor mutation profiles. Additional ctDNA and tissue analyses are needed to elucidate the correlation between ALP + ET efficacy and treatment timing and baseline genomic complexity.