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

Ingrid A. Mayer, Vandana G. Abramson, Steven J. Isakoff, Andres Forero, Justin M. Balko, María Gabriela Kuba, Melinda E. Sanders, Jeffrey T. Yap, Annick D. Van Den Abbeele, Yisheng Li, Lewis C. Cantley, Eric Winer, Carlos L. Arteaga

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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. [18F]fluorodeoxyglucose-positron emission tomography/computed tomography ([18F]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 [18F]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 [ 18F]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.

Original languageEnglish (US)
Pages (from-to)1202-1209
Number of pages8
JournalJournal of Clinical Oncology
Volume32
Issue number12
DOIs
StatePublished - Apr 20 2014

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letrozole
1-Phosphatidylinositol 4-Kinase
Estrogen Receptors
Breast Neoplasms
Fluorodeoxyglucose F18
Neoplasms
Appointments and Schedules
Maximum Tolerated Dose
Mutation
Disease Progression
Therapeutics
NVP-BKM120
human ERBB2 protein
Metabolic Diseases
Drug-Related Side Effects and Adverse Reactions
Mood Disorders
Heterografts
Hyperglycemia

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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. / Mayer, Ingrid A.; Abramson, Vandana G.; Isakoff, Steven J.; Forero, Andres; Balko, Justin M.; Kuba, María Gabriela; Sanders, Melinda E.; Yap, Jeffrey T.; Van Den Abbeele, Annick D.; Li, Yisheng; Cantley, Lewis C.; Winer, Eric; Arteaga, Carlos L.

In: Journal of Clinical Oncology, Vol. 32, No. 12, 20.04.2014, p. 1202-1209.

Research output: Contribution to journalArticle

Mayer, Ingrid A. ; Abramson, Vandana G. ; Isakoff, Steven J. ; Forero, Andres ; Balko, Justin M. ; Kuba, María Gabriela ; Sanders, Melinda E. ; Yap, Jeffrey T. ; Van Den Abbeele, Annick D. ; Li, Yisheng ; Cantley, Lewis C. ; Winer, Eric ; Arteaga, Carlos L. / 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. In: Journal of Clinical Oncology. 2014 ; Vol. 32, No. 12. pp. 1202-1209.
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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. [18F]fluorodeoxyglucose-positron emission tomography/computed tomography ([18F]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 [18F]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 [ 18F]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.",
author = "Mayer, {Ingrid A.} and Abramson, {Vandana G.} and Isakoff, {Steven J.} and Andres Forero and Balko, {Justin M.} and Kuba, {Mar{\'i}a Gabriela} and Sanders, {Melinda E.} and Yap, {Jeffrey T.} and {Van Den Abbeele}, {Annick D.} and Yisheng Li and Cantley, {Lewis C.} and Eric Winer and Arteaga, {Carlos L.}",
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T1 - 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

AU - Mayer, Ingrid A.

AU - Abramson, Vandana G.

AU - Isakoff, Steven J.

AU - Forero, Andres

AU - Balko, Justin M.

AU - Kuba, María Gabriela

AU - Sanders, Melinda E.

AU - Yap, Jeffrey T.

AU - Van Den Abbeele, Annick D.

AU - Li, Yisheng

AU - Cantley, Lewis C.

AU - Winer, Eric

AU - Arteaga, Carlos L.

PY - 2014/4/20

Y1 - 2014/4/20

N2 - 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. [18F]fluorodeoxyglucose-positron emission tomography/computed tomography ([18F]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 [18F]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 [ 18F]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.

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