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Ref Type Journal Article
PMID (32958578)
Authors Pascual J, Lim JSJ, Macpherson IRJ, Armstrong AC, Ring A, Okines AF, Cutts RJ, Herrera-Abreu MT, Garcia-Murillas I, Pearson A, Hrebien S, Gevensleben H, Proszek PZ, Hubank M, Hills M, King J, Parmar M, Prout T, Finneran L, Malia J, Swales KE, Ruddle R, Raynaud FI, Turner A, Hall E, Yap TA, Lopez JS, Turner NC
Title Triplet therapy with palbociclib, taselisib and fulvestrant in PIK3CA mutant breast cancer and doublet palbociclib and taselisib in pathway mutant solid cancers.
Journal Cancer discovery
Vol
Issue
Date 2020 Sep 21
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
PIK3CA I1058F missense unknown PIK3CA I1058F lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). I1058F has been identified in sequencing studies (PMID: 17062663, PMID: 21266528, PMID: 32958578), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Dec 2021).
PIK3CA I1058L missense unknown PIK3CA I1058L lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). I1058L has been identified in sequencing studies (PMID: 32958578), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Dec 2021).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA act mut estrogen-receptor positive breast cancer predicted - sensitive Palbociclib + Taselisib Phase I Actionable In a Phase Ib trial (PIPA), the combination of Ibrance (palbociclib) with Taselisib (GDC-0032) was well tolerated in estrogen-receptor negative breast cancer patients harboring PIK3CA activating mutations and resulted in an objective response rate of 10% (1/10), a clinical benefit rate of 30% (4/10), and a median progression-free survival of 3.6 months (PMID: 32958578; NCT02389842). 32958578
PIK3CA act mut Advanced Solid Tumor predicted - sensitive Palbociclib + Taselisib Phase I Actionable In a Phase Ib trial (PIPA), the combination of Ibrance (palbociclib) with Taselisib (GDC-0032) was well tolerated in patients with advanced solid tumors harboring PIK3CA activating mutations and resulted in an objective response rate of 0% (0/12), a clinical benefit rate of 16.7% (2/12), and a median progression-free survival of 3.8 months (PMID: 32958578; NCT02389842). 32958578