Show simple item record

dc.contributor.advisorTurner, N
dc.contributor.authorPascual, J
dc.date.accessioned2021-10-29T14:41:23Z
dc.date.available2022-03-30T00:00:00Z
dc.date.issued2021-09-30
dc.identifier.citation2021
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4858
dc.description.abstractTargeting the commonly upregulated cell-cycle and PI3-kinase pathway in breast cancer are two of the most novel approaches to tackle the disease, with both strategies having led to clinically meaningful results and licensed drugs to use in the clinic. However, resistance to drugs inhibiting these pathways inevitably occurs and alternative strategies to delay this resistance and prolong survival are needed. CDK4/6 and PI3-kinase inhibitors synergise in PIK3CA mutant ER-positive and negative breast cancer pre-clinical models. A two-stage phase Ib trial was conducted to investigate safety and preliminary efficacy for the doublet CDK4/6 inhibitor palbociclib plus selective PI3-kinase inhibitor taselisib in solid tumours and the triplet palbociclib plus taselisib plus fulvestrant in patients with PIK3CA mutant ER positive HER2 negative advanced breast cancer. The escalation phase defined the recommended dose for phase 2 (RDP2) and subsequent patients were enrolled in the expansion phase and treated with the RDP2, which required a dose reduction in taselisib (from the 4mg to 2mg dose PO QD). There was evidence of AKT pathway modulation in pharmacodynamics studies conducted in platelet rich plasma, suggesting inhibition of PI3K by taselisib at this dose. However, increased AKT phosphorylation 24h post-dose suggested rebound were neutropenia (88%), thrombocytopenia (57%), anaemia (48%), fatigue (45%), leukopenia (36%) and diarrhoea (34%). Most common grade 3/4 AEs in expansion phase were neutropenia (53%) and leukopenia (19%). The study recruited 25 patients with ER positive HER2 negative PIK3CA mutant advanced breast cancer with an objective response rate of 37.5% (95% Cl 18.8-59.4) and clinical benefit rate of 58.3% (95% Cl 36.6-77.9). In addition, there was durable disease control for some PIK3CA mutant ER negative patients and other solid tumours with the doublet taselisib plus palbociclib, with particularly long-lasting stabilizations in TNBC with high expression of androgen receptor. In the biomarker analysis in PIK3CA mutant triplet arm, high baseline cyclin E1 expression levels were associated with short progression free survival (PFS) (HR 4.16, 95% Cl 1.32-13.11, p=0.02), and early ctDNA dynamics were associated with PFS (high on treatment ctDNA HR 5.23, 95% Cl 1.41-19.42, p=0.04). High-depth error-corrected paired plasma ctDNA sequencing provided evidence of ongoing cancer genomic evolution through triplet therapy, with evidence of ESR1 and FAT1 mutation acquisition under therapy. In conclusion, 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. Our study further supports high expression of cyclin E1 as a poor prognostic marker on palbociclib combinations and reinforces the evidence of early ctDNA changes predicting treatment efficacy. These findings provide preliminary proof-of-concept that supports future combination approaches involving both PI3K and cyclin-dependent pathway.
dc.languageeng
dc.language.isoeng
dc.publisherInstitute of Cancer Research (University Of London)
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectTheses, Doctoral
dc.subjectBreast Cancer - Chemotherapy
dc.subjectBreast Cancer - Molecular Biology
dc.titleTriplet combination of palbociclib, taselisib and fulvestrant and biomarkers for CDK4/6 and PI3-kinase inhibition in breast cancer
dc.typeThesis or Dissertation
dcterms.accessRightsPublic
dcterms.licensehttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.versionAO
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2021-09-30
rioxxterms.typeThesis
pubs.notes6 months
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Molecular Oncology
pubs.embargo.terms6 months
pubs.embargo.date2022-03-30T00:00:00Z
icr.researchteamMolecular Oncology
dc.contributor.icrauthorPascual, Javieren_US
uketdterms.institutionInstitute of Cancer Research
uketdterms.qualificationlevelMasters
uketdterms.qualificationnameM.D.Res
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameM.D.Res


Files in this item

Thumbnail

This item appears in the following collection(s)

Show simple item record