TY - JOUR
T1 - Triplet therapy with palbociclib, taselisib, and fulvestrant in pik3ca-mutant breast cancer and doublet palbociclib and taselisib in pathway-mutant solid cancers
AU - Pascual, Javier
AU - Lim, Joline S.J.
AU - Macpherson, Iain R.
AU - Armstrong, Anne C.
AU - Ring, Alistair
AU - Okines, Alicia F.C.
AU - Cutts, Rosalind J.
AU - Herrera-Abreu, Maria Teresa
AU - Garcia-Murillas, Isaac
AU - Pearson, Alex
AU - Hrebien, Sarah
AU - Gevensleben, Heidrun
AU - Proszek, Paula Z.
AU - Hubank, Michael
AU - Hills, Margaret
AU - King, Jenny
AU - Parmar, Mona
AU - Prout, Toby
AU - Finneran, Laura
AU - Malia, Jason
AU - Swales, Karen E.
AU - Ruddle, Ruth
AU - Raynaud, Florence I.
AU - Turner, Alison
AU - Hall, Emma
AU - Yap, Timothy A.
AU - Lopez, Juanita S.
AU - Turner, Nicholas C.
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85099709818&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-20-0553
DO - 10.1158/2159-8290.CD-20-0553
M3 - Article
C2 - 32958578
AN - SCOPUS:85099709818
SN - 2159-8274
VL - 11
SP - 92
EP - 107
JO - Cancer discovery
JF - Cancer discovery
IS - 1
ER -