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J Clin Oncol. 2014 Apr 20;32(12):1202-9. doi: 10.1200/JCO.2013.54.0518. Epub 2014 Mar 24.

Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer.

Author information

  • 1Ingrid A. Mayer, Vandana G. Abramson, Justin M. Balko, María Gabriela Kuba, Melinda E. Sanders, and Carlos L. Arteaga, Vanderbilt University, Nashville, TN; Steven J. Isakoff, Massachusetts General Hospital, Boston, MA; Andres Forero, University of Alabama, Birmingham, AL; Jeffrey T. Yap, Huntsman Cancer Institute, Salt Lake City, UT; Annick D. Van den Abbeele and Eric Winer, Dana-Farber Cancer Institute, Boston, MA; Yisheng Li, MD Anderson Cancer Center, Houston, TX; and Lewis C. Cantley, Weill Cornell Medical College, New York, NY.

Abstract

PURPOSE:

Buparlisib, an oral reversible inhibitor of all class I phosphoinositide-3-kinases, has shown antitumoral activity against estrogen receptor (ER)-positive breast cancer cell lines and xenografts, alone and with endocrine therapy. This phase Ib study evaluated buparlisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER-positive breast cancer refractory to endocrine therapy.

PATIENTS AND METHODS:

Patients received letrozole and buparlisib in two different administration schedules. Outcomes were assessed by standard solid-tumor phase I methods. [(18)F]fluorodeoxyglucose-positron emission tomography/computed tomography ([(18)F]FDG-PET/CT) scans were done at baseline and 2 weeks after treatment initiation. Tumor blocks were collected for phosphoinositide-3-kinase pathway mutation analysis.

RESULTS:

Fifty-one patients were allocated sequentially to continuous or intermittent (five on/two off days) buparlisib administration on an every-4-week schedule. Buparlisib's maximum-tolerated dose (MTD) was 100 mg/d. Common drug-related adverse events included ≤ grade 2 hyperglycemia, nausea, fatigue, transaminitis, and mood disorders. The clinical benefit rate (lack of progression ≥ 6 months) among all patients treated at the MTD was 31%, including two objective responses in the continuous dose arm. Of seven patients remaining on treatment ≥ 12 months, three had tumors with PIK3CA hot-spot mutation. Patients exhibiting metabolic disease progression by [(18)F]FDG-PET/CT scan at 2 weeks progressed rapidly on therapy.

CONCLUSION:

The letrozole and buparlisib combination was safe, with reversible toxicities regardless of schedule administration. Clinical activity was observed independent of PIK3CA mutation status. No metabolic response by [(18)F]FDG-PET/CT scan at 2 weeks was associated with rapid disease progression. Phase III trials of buparlisib and endocrine therapy in patients with ER-positive breast cancer are ongoing.

PMID:
24663045
PMCID:
PMC3986383
DOI:
10.1200/JCO.2013.54.0518
[PubMed - indexed for MEDLINE]
Free PMC Article

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