Reference Detail

Ref Type

Journal Article

PMID

(32958578)

Authors

Pascual J, Lim JSJ, Macpherson IR, Armstrong AC, Ring A, Okines AFC, 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	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	11	1	2021 Jan	92-107	Cancer Discov

URL

Abstract Text

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 .

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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 does not lie within any known functional domains 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 2023).
PIK3CA	I1058L	missense	unknown	PIK3CA I1058L does not lie within any known functional domains 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 2023).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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
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