Study: Alpelisib Plus Endocrine Therapy Effective in PIK3CA-mutated, HR+, HER2– Advanced Breast Cancer

In an analysis of data from 2 cohorts included in the phase 2 BYLieve study, investigators found that the lower median circulating tumor DNA (ctDNA) fraction and the lower mutational complexity in Cohort A’s less than 6-month group versus the more than 6-month group was associated with longer median progression-free survival (mPFS), potentially indicating an increased dependence on the mutant PI3K-α, according to a poster presentation at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

Additionally, author Dejan Juric noted that in cohort B, both groups—the less than 6-month group and more than 6-month group—had high median ctDNA fractions with similar tumor mutation profiles.

In primary analyses of the phase 2 BYLieve trial, data demonstrated the efficacy and safety of alpelisib (Piqray, Novartis) plus endocrine therapy (ET) in patients with PIK3CA-mutated (mut), hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) in the post-cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) setting. Approved for patients with HR+, HER2– ABC and a tumor mutation in PIK3CA, the combination of alpelisib plus ET was also assessed in post hoc analyses of patients with disease progression within 6 months of CDK4/6i + ET treatment (Tx), the results of which confirmed the benefit of alpelisib regardless of the duration of prior CDK4/6i, according to the study.

During the BYLieve study, patients with PIK3CA-mut, HR+, HER2– ABC were given CDK4/6i plus aromatase inhibitor in cohort A or given plus FUL in cohort B as immediate prior treatment to receiving alpelisib plus FUL and alpelisib plus letrozole (LET), respectively. By the data cutoff points, patients had 18 months or more of follow up in cohort A and 6 months or more of follow up in cohort B, with patients grouped in each cohort based on the duration of prior CDK4/6i Tx (either 6 months or less or more than 6 months).

To detect alterations on ctDNA, investigators used the next-generation sequencing PanCancer V2 Panel. Additionally, progression-free survival (PFS) was assessed in each cohort, as well as assessed by the duration of prior CDK4/6i treatment.

Juric explained that among the 127 patients enrolled in cohort A and the 126 patients enrolled in cohort B, 98 (≤ 6-mo: 24; >6-mo: 74) in cohort A and 94 (≤ 6-mo: 28; >6-mo: 66) cohort B were included in their analysis based on the availability of ctDNA samples, data on duration of prior CDK4/6i, and centrally confirmed PIK3CA-mut disease. In this population in the 2 cohorts, the median PFS (mPFS [95% CI]) was 8.2 months (5.6 - 9.5) and 5.6 months (3.7 - 7.1) in cohorts A and B, respectively.

In cohort A, the mPFS (95% CI) was 12 months (5.5-non estimable) in the 6-months or less group and 6.2 months (5.4 - 8.5) in the greater than 6-months group. The OncoPrint genomic profiles showed that patients in the 6-month or less group versus the more than 6-month group had a lower median ctDNA fraction and fewer detected gene alterations, including in genes associated with ET and/or CDK4/6i resistance, as well as fewer chromosomes 8/11 amplifications, which can be linked to early relapse.

In cohort B, investigators found the mPFS was 5.9 months (3.5 - 11.0) in the 6-months or less group and 5.6 months (3.7 - 7.1) in the greater than 6-months group. However, in this cohort, both groups were found to have high median ctDNA fractions and complex tumor mutation profiles, which Juric explained may reflect a more extensive treatment history.

For future investigations, Juric noted that ctDNA and tissue analyses are necessary to clarify the correlation between alpelisib plus ET efficacy and treatment timing and baseline genomic complexity.

Reference

Juric D. 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. 2022 ASCO Annual Meeting. Accessed June 9, 2022. https://meetings.asco.org/abstracts-presentations/209428