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Alpelisib Overcomes Resistance to CDK4/6 Inhibitors in HR-Positive/HER2-Negative Advanced Breast Cancer Patients

Conference Correspondent 

CDK4/6 inhibitors have been shown to improve progression-free survival (PFS) rates in patients with HR-positive/HER2-negative advanced-stage breast cancer. However, most HR-positive/HER2-negative patients develop resistance to CDK4/6 inhibitor therapy by activation of an unknown pathway. Approximately 40% of patients with HR-positive/HER2-negative advanced breast cancer present with PIK3CA mutations, which are associated with a poor prognosis.

Results from the phase 2 BYLieve study indicate alpelisib (ALP), a PI3K-alpha inhibitor, in combination with fulvestrant (FUL) or letrozole (LET) is a safe and effective treatment for HR-positive/HER2-negative advanced breast cancer patients treated with prior CDK4/6 inhibitor therapy. However, it has not been determined if the length of time of CDK4/6 inhibitor exposure influences the effectiveness of ALP + FUL or LET.

Current investigations are underway in pre- and postmenopausal women previously treated with CDK4/6 inhibitors in combination with an aromatase inhibitor or FUL. The women were divided into 2 cohorts (cohort A: ALP + FUL, n = 126; cohort B: ALP + LET, n = 123) and then 2 subgroups based on high (>380 days) or low (<380 days) duration of prior CDK4/6 inhibitor treatment. Both cohorts A and B exhibited similar efficacy and safety responses in HR-positive/HER2-negative advanced breast cancer patients when treated with ALP and FUL or LET. There was no significant difference in PFS between high and low duration of prior CDK4/6 inhibitor subgroups in either cohort. The researchers conclude ALP may rescue patients with HR-positive/HER2-negative advanced breast cancer from CDK4/6 inhibitor resistance if patients are exposed to a shorter duration of CDK4/6 inhibitor therapy.

Source: Chia SKL, Ruiz-Borrego M, Drullinsky P, et al. Impact of duration of prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy on alpelisib (ALP) benefit in patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor receptor-2–negative (HER2–), PIK3CA-mutated advanced breast cancer (ABC) from BYLieve. American Society of Clinical Oncology Virtual Meeting; June 4-8, 2021. Abstract 1060.

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