Triplet Therapy with Palbociclib, Taselisib, and Fulvestrant inPIK3CA-Mutant Breast Cancer and Doublet Palbociclib and Taselisib in Pathway-Mutant Solid Cancers
| Autor: | Heidrun Gevensleben, Alistair Ring, Toby Prout, Nicholas C. Turner, Alison Turner, Iain R. Macpherson, Paula Proszek, Alex Pearson, Mike Hubank, Rosalind J. Cutts, Karen E Swales, Sarah Hrebien, Javier Pascual, Margaret Hills, Maria Teresa Herrera-Abreu, Jenny King, Jason Malia, Anne C Armstrong, Ruth Ruddle, Alicia Okines, Isaac Garcia-Murillas, Emma Hall, Mona Parmar, Laura Finneran, Florence I. Raynaud, Timothy A. Yap, Juanita Lopez, Joline S.J. Lim |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Oncology medicine.medical_specialty education.field_of_study Fulvestrant Kinase business.industry Population Cancer Palbociclib medicine.disease 03 medical and health sciences Cyclin E1 030104 developmental biology 0302 clinical medicine Breast cancer 030220 oncology & carcinogenesis Internal medicine medicine education business neoplasms PI3K/AKT/mTOR pathway medicine.drug |
| Zdroj: | Cancer Discovery. 11:92-107 |
| ISSN: | 2159-8290 2159-8274 |
| DOI: | 10.1158/2159-8290.cd-20-0553 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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