Triplet therapy with palbociclib, taselisib and fulvestrant in PIK3CA mutant breast cancer and doublet palbociclib and taselisib in pathway mutant solid cancers

Pascual, J. et al. (2021) Triplet therapy with palbociclib, taselisib and fulvestrant in PIK3CA mutant breast cancer and doublet palbociclib and taselisib in pathway mutant solid cancers. Cancer Discovery, 11(1), pp. 92-107. (doi: 10.1158/2159-8290.CD-20-0553) (PMID:32958578)

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Abstract

Cyclin-dependent kinase-4/6 (CDK4/6) and phosphatidylinositol 3-kinase (PI3K) inhibitors synergise in PIK3CA mutant ER-positive HER2-negative breast cancer models. We conducted a phase Ib trial investigating 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 was 37.5% (95% 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 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacPherson, Professor Iain
Authors: Pascual, J., Lim, J. S.J., Macpherson, I. R.J., Armstrong, A. C., Ring, A., Okines, A. F.C., Cutts, R. J., Herrera-Abreu, M. T., Garcia-Murillas, I., Pearson, A., Hrebien, S., Gevensleben, H., Proszek, P. Z., Hubank, M., Hills, M., King, J., Parmar, M., Prout, T., Finneran, L., Malia, J., Swales, K. E., Ruddle, R., Raynaud, F. I., Turner, A., Hall, E., Yap, T. A., Lopez, J. S., and Turner, N. C.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cancer Discovery
Publisher:American Association for Cancer Research
ISSN:2159-8274
ISSN (Online):2159-8290
Published Online:21 September 2020
Copyright Holders:Copyright © 2020 American Association for Cancer Research
First Published:First published in Cancer Discovery 11(1):92-107
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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