Triplet therapy with palbociclib, taselisib and fulvestrant in PIK3CA mutant breast cancer and doublet palbociclib and taselisib in pathway mutant solid cancers
Pascual, J. Lim, J. S. J. Macpherson, I. R. J. Armstrong, Anne C Ring, A. Okines, A. F. Cutts, R. J. Herrera-Abreu, M. T. Garcia-Murillas, I. Pearson, A.
Pascual, J.
Lim, J. S. J.
Macpherson, I. R. J.
Armstrong, Anne C
Ring, A.
Okines, A. F.
Cutts, R. J.
Herrera-Abreu, M. T.
Garcia-Murillas, I.
Pearson, A.
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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.
Authors
Pascual, J.
Lim, J. S. J.
Macpherson, I. R. J.
Armstrong, Anne C
Ring, A.
Okines, A. F.
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.
Turner, N. C.
Lim, J. S. J.
Macpherson, I. R. J.
Armstrong, Anne C
Ring, A.
Okines, A. F.
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.
Turner, N. C.
Description
Date
2020
Publisher
Collections
Keywords
Type
Article
Citation
Pascual J, Lim JSJ, Macpherson IRJ, Armstrong AC, Ring A, Okines AF, et al. Triplet therapy with palbociclib, taselisib and fulvestrant in PIK3CA mutant breast cancer and doublet palbociclib and taselisib in pathway mutant solid cancers. Cancer Discov. 2020.