Clinical Efficacy and Whole Exome Sequencing of Liquid Biopsies in a Phase IB/II study of Bazedoxifene and Palbociclib in Hormone Receptor-Positive Breast Cancer

Tsuji J*, Li T, Grinshpun A, Coorens T, Russo D, Anderson L, Rees R, Nardone A, Patterson C, Lennon NJ, Cibulskis C, Leshchiner I, Tayob N, Tolaney SM, Tung N, McDonnell DP, Krop IE, Winer EP, Stewart C, Getz G#^, Jeselsohn R#^
Clinical Cancer Research (2022)


Purpose: Sensitivity to endocrine therapy (ET) is critical for the clinical benefit from the combination of palbociclib plus ET in hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer. Bazedoxifene is a third-generation selective ER modulator and selective ER degrader with activity in preclinical models of endocrine-resistant breast cancer, including models harboring ESR1 mutations. Clinical trials in healthy women showed that bazedoxifene is well tolerated.

Patients and methods: We conducted a phase Ib/II study of bazedoxifene plus palbociclib in patients with HR+/HER2- advanced breast cancer who progressed on prior ET (N=36) (NCT02448771).

Results: The study met its primary endpoint, with a clinical benefit rate of 33.3%, and the safety profile was consistent with what has previously been seen with palbociclib monotherapy. The median progression free survival (PFS) was 3.6 months (CI95% 2.0-7.2). An activating PIK3CA mutation at baseline was associated with a shorter PFS (HR = 4.4, CI95% 1.5-13, P = 0.0026) but activating ESR1 mutations did not impact the PFS. Longitudinal plasma circulating tumor DNA whole exome sequencing (WES) (N=68 plasma samples) provided an overview of the tumor heterogeneity, the sub-clonal genetic evolution and identified actionable mutations acquired during treatment.

Conclusions: The combination of palbocilib and bazedoxifene has clinical efficacy and an acceptable safety profile in a heavily pre-treated patient population with advanced HR+/HER2- breast cancer. These results merit continued investigation of bazedoxifene in breast cancer.

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