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Clin Cancer Res. 2017 Jan 1;23(1):26-34. doi: 10.1158/1078-0432.CCR-16-0134. Epub 2016 Apr 28.

A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer.

Author information

1
Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University, Nashville, Tennessee. ingrid.mayer@vanderbilt.edu carlos.arteaga@vanderbilt.edu.
2
Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University, Nashville, Tennessee.
3
Massachusetts General Hospital (MGH), Boston, Massachusetts.
4
Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York.
5
The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Weill Cornell Medical College, New York, New York.
7
Dana-Farber Cancer Institute (DFCI), Boston, Massachusetts.

Abstract

PURPOSE:

Alpelisib, a selective oral inhibitor of the class I PI3K catalytic subunit p110α, has shown synergistic antitumor activity with endocrine therapy against ER+/PIK3CA-mutated breast cancer cells. This phase Ib study evaluated alpelisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER+ breast cancer refractory to endocrine therapy.

EXPERIMENTAL DESIGN:

Twenty-six patients received letrozole and alpelisib daily. Outcomes were assessed by standard solid-tumor phase I methods. Tumor blocks were collected for DNA extraction and next-generation sequencing.

RESULTS:

Alpelisib's maximum-tolerated dose (MTD) in combination with letrozole was 300 mg/d. Common drug-related adverse events included hyperglycemia, nausea, fatigue, diarrhea, and rash with dose-limiting toxicity occurring at 350 mg/d of alpelisib. The clinical benefit rate (lack of progression ≥6 months) was 35% (44% in patients with PIK3CA-mutated and 20% in PIK3CA wild-type tumors; 95% CI, 17%-56%), including five objective responses. Of eight patients remaining on treatment ≥12 months, six had tumors with a PIK3CA mutation. Among evaluable tumors, those with FGFR1/2 amplification and KRAS and TP53 mutations did not derive clinical benefit. Overexpression of FGFR1 in ER+/PIK3CA mutant breast cancer cells attenuated the response to alpelisib in vitro CONCLUSIONS: The combination of letrozole and alpelisib was safe, with reversible toxicities. Clinical activity was observed independently of PIK3CA mutation status, although clinical benefit was seen in a higher proportion of patients with PIK3CA-mutated tumors. Phase II and III trials of alpelisib and endocrine therapy in patients with ER+ breast cancer are ongoing. Clin Cancer Res; 23(1); 26-34. ©2016 AACR.

PMID:
27126994
PMCID:
PMC5085926
DOI:
10.1158/1078-0432.CCR-16-0134
[Indexed for MEDLINE]
Free PMC Article

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