Triplet Therapy with Palbociclib, Taselisib, and Fulvestrant in PIK3CA-Mutant Breast Cancer and Doublet Palbociclib and Taselisib in Pathway-Mutant Solid Cancers.
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Authors
Pascual, J
Lim, JSJ
Macpherson, IR
Armstrong, AC
Ring, A
Okines, AFC
Cutts, RJ
Herrera-Abreu, MT
Garcia-Murillas, I
Pearson, A
Hrebien, S
Gevensleben, H
Proszek, PZ
Hubank, M
Hills, M
King, J
Parmar, M
Prout, T
Finneran, L
Malia, J
Swales, KE
Ruddle, R
Raynaud, FI
Turner, A
Hall, E
Yap, TA
Lopez, JS
Turner, NC
Lim, JSJ
Macpherson, IR
Armstrong, AC
Ring, A
Okines, AFC
Cutts, RJ
Herrera-Abreu, MT
Garcia-Murillas, I
Pearson, A
Hrebien, S
Gevensleben, H
Proszek, PZ
Hubank, M
Hills, M
King, J
Parmar, M
Prout, T
Finneran, L
Malia, J
Swales, KE
Ruddle, R
Raynaud, FI
Turner, A
Hall, E
Yap, TA
Lopez, JS
Turner, NC
Document Type
Journal Article
Date
2021-01-01
Date Accepted
2020-09-16
Abstract
Cyclin-dependent kinase 4/6 (CDK4/6) and PI3K inhibitors synergize in PIK3CA-mutant ER-positive HER2-negative breast cancer models. We conducted a phase Ib trial investigating the safety and efficacy of doublet CDK4/6 inhibitor palbociclib plus selective PI3K inhibitor taselisib in advanced solid tumors, and triplet palbociclib plus taselisib plus fulvestrant in 25 patients with PIK3CA-mutant, ER-positive HER2-negative advanced breast cancer. The triplet therapy response rate in PIK3CA-mutant, ER-positive HER2-negative cancer was 37.5% [95% confidence interval (CI), 18.8-59.4]. Durable disease control was observed in PIK3CA-mutant ER-negative breast cancer and other solid tumors with doublet therapy. Both combinations were well tolerated at pharmacodynamically active doses. In the triplet group, high baseline cyclin E1 expression associated with shorter progression-free survival (PFS; HR = 4.2; 95% CI, 1.3-13.1; P = 0.02). Early circulating tumor DNA (ctDNA) dynamics demonstrated high on-treatment ctDNA association with shorter PFS (HR = 5.2; 95% CI, 1.4-19.4; P = 0.04). Longitudinal plasma ctDNA sequencing provided genomic evolution evidence during triplet therapy. SIGNIFICANCE: The triplet of palbociclib, taselisib, and fulvestrant has promising efficacy in patients with heavily pretreated PIK3CA-mutant ER-positive HER2-negative advanced breast cancer. A subset of patients with PIK3CA-mutant triple-negative breast cancer derived clinical benefit from palbociclib and taselisib doublet, suggesting a potential nonchemotherapy targeted approach for this population.This article is highlighted in the In This Issue feature, p. 1.
Citation
Cancer discovery, 2020
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
2159-8274
eISSN
2159-8290
Research Team
Molecular Oncology
Medicine (de Bono Prostate)
Clinical PD Biomarker Group
ICR-CTSU Urology and Head and Neck Trials Team
Translational Genomics
Medicine (de Bono Prostate)
Clinical PD Biomarker Group
ICR-CTSU Urology and Head and Neck Trials Team
Translational Genomics