Alpelisib Plus Fulvestrant in PIK3CA -Altered and PIK3CA -Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer: A Phase 1b Clinical Trial

Dejan Juric, Filip Janku, Jordi Rodon Ahnert, Howard A. Burris, Ingrid A. Mayer, Martin Schuler, Ruth Seggewiss-Bernhardt, Marta Gil-Martin, Mark R. Middleton, José Baselga, Douglas Bootle, David Demanse, Lars Blumenstein, Karl Schumacher, Alan Huang, Cornelia Quadt, Hope S. Rugo

Research output: Contribution to journalArticle

Abstract

Importance: The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in patients with estrogen receptor-positive (ER+), endocrine therapy-resistant breast cancers. Objective: To assess the maximum tolerated dose (MTD), safety, and activity of alpelisib, an oral, PI3Kα-specific inhibitor, plus fulvestrant in patients with ER+ advanced breast cancer (ABC). Design, Setting, and Participants: An open-label, single-arm, phase 1b study of alpelisib plus fulvestrant was conducted at 10 centers in 5 countries. Participants were 87 postmenopausal women with PIK3CA-altered or PIK3CA-wild-type ER+ ABC, whose cancer progressed during or after antiestrogen therapy. The study began enrolling patients October 5, 2010, and the data cutoff was March 22, 2017. Interventions: Escalating doses of alpelisib were administered once daily, starting at 300 mg, plus fixed-dose fulvestrant, 500 mg, in the dose-escalation phase; alpelisib at the recommended phase 2 dose plus fulvestrant in the dose-expansion phase. Main Outcomes and Measures: The primary end point was determination of the MTD of once-daily alpelisib plus fulvestrant. Secondary end points included safety and preliminary activity. Results: From October 5, 2010, to March 22, 2017, 87 women (median age: 58 years [range, 37-79 years]; median of 5 prior lines of antineoplastic therapy) received escalating once-daily doses of alpelisib (300 mg, n = 9; 350 mg, n = 8; 400 mg, n = 70) plus fixed-dose fulvestrant (500 mg). During dose escalation, dose-limiting toxic effects were reported in 1 patient (alpelisib, 400 mg): diarrhea (grade 2), vomiting, fatigue, and decreased appetite (all grade 3). The MTD of alpelisib when combined with fulvestrant was 400 mg once daily, and the recommended phase 2 dose was 300 mg once daily. Overall, the most frequent grade 3/4 adverse events with alpelisib, 400 mg, once daily (≥10% of patients), regardless of causality, were hyperglycemia (19 [22%]) and maculopapular rash (11 [13%]); 9 patients permanently discontinued therapy owing to adverse events. Median progression-free survival at the MTD was 5.4 months (95% CI, 4.6-9.0 months). Median progression-free survival with alpelisib, 300 to 400 mg, once daily plus fulvestrant was longer in patients with PIK3CA-altered tumors (9.1 months; 95% CI, 6.6-14.6 months) vs wild-type tumors (4.7 months; 95% CI, 1.9-5.6 months). Overall response rate in the PIK3CA-altered group was 29% (95% CI, 17%-43%), with no objective tumor responses in the wild-type group. Conclusions and Relevance: Alpelisib plus fulvestrant has a manageable safety profile in patients with ER+ ABC, and data suggest that this combination may have greater clinical activity in PIK3CA-altered vs wild-type tumors. Trial Registration: ClinicalTrials.gov identifier: NCT01219699.

Original languageEnglish (US)
JournalJAMA Oncology
Volume5
Issue number2
DOIs
StatePublished - Feb 1 2019

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Estrogen Receptors
Clinical Trials
Breast Neoplasms
Maximum Tolerated Dose
Phosphatidylinositol 3-Kinase
Neoplasms
Safety
Disease-Free Survival
Endpoint Determination
fulvestrant
Estrogen Receptor Modulators
Poisons
Appetite
Therapeutics
Exanthema
Hyperglycemia
Causality
Antineoplastic Agents
Vomiting
Fatigue

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Alpelisib Plus Fulvestrant in PIK3CA -Altered and PIK3CA -Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer : A Phase 1b Clinical Trial. / Juric, Dejan; Janku, Filip; Rodon Ahnert, Jordi; Burris, Howard A.; Mayer, Ingrid A.; Schuler, Martin; Seggewiss-Bernhardt, Ruth; Gil-Martin, Marta; Middleton, Mark R.; Baselga, José; Bootle, Douglas; Demanse, David; Blumenstein, Lars; Schumacher, Karl; Huang, Alan; Quadt, Cornelia; Rugo, Hope S.

In: JAMA Oncology, Vol. 5, No. 2, 01.02.2019.

Research output: Contribution to journalArticle

Juric, D, Janku, F, Rodon Ahnert, J, Burris, HA, Mayer, IA, Schuler, M, Seggewiss-Bernhardt, R, Gil-Martin, M, Middleton, MR, Baselga, J, Bootle, D, Demanse, D, Blumenstein, L, Schumacher, K, Huang, A, Quadt, C & Rugo, HS 2019, 'Alpelisib Plus Fulvestrant in PIK3CA -Altered and PIK3CA -Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer: A Phase 1b Clinical Trial' JAMA Oncology, vol. 5, no. 2. https://doi.org/10.1001/jamaoncol.2018.4475
Juric, Dejan ; Janku, Filip ; Rodon Ahnert, Jordi ; Burris, Howard A. ; Mayer, Ingrid A. ; Schuler, Martin ; Seggewiss-Bernhardt, Ruth ; Gil-Martin, Marta ; Middleton, Mark R. ; Baselga, José ; Bootle, Douglas ; Demanse, David ; Blumenstein, Lars ; Schumacher, Karl ; Huang, Alan ; Quadt, Cornelia ; Rugo, Hope S. / Alpelisib Plus Fulvestrant in PIK3CA -Altered and PIK3CA -Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer : A Phase 1b Clinical Trial. In: JAMA Oncology. 2019 ; Vol. 5, No. 2.
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title = "Alpelisib Plus Fulvestrant in PIK3CA -Altered and PIK3CA -Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer: A Phase 1b Clinical Trial",
abstract = "Importance: The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in patients with estrogen receptor-positive (ER+), endocrine therapy-resistant breast cancers. Objective: To assess the maximum tolerated dose (MTD), safety, and activity of alpelisib, an oral, PI3Kα-specific inhibitor, plus fulvestrant in patients with ER+ advanced breast cancer (ABC). Design, Setting, and Participants: An open-label, single-arm, phase 1b study of alpelisib plus fulvestrant was conducted at 10 centers in 5 countries. Participants were 87 postmenopausal women with PIK3CA-altered or PIK3CA-wild-type ER+ ABC, whose cancer progressed during or after antiestrogen therapy. The study began enrolling patients October 5, 2010, and the data cutoff was March 22, 2017. Interventions: Escalating doses of alpelisib were administered once daily, starting at 300 mg, plus fixed-dose fulvestrant, 500 mg, in the dose-escalation phase; alpelisib at the recommended phase 2 dose plus fulvestrant in the dose-expansion phase. Main Outcomes and Measures: The primary end point was determination of the MTD of once-daily alpelisib plus fulvestrant. Secondary end points included safety and preliminary activity. Results: From October 5, 2010, to March 22, 2017, 87 women (median age: 58 years [range, 37-79 years]; median of 5 prior lines of antineoplastic therapy) received escalating once-daily doses of alpelisib (300 mg, n = 9; 350 mg, n = 8; 400 mg, n = 70) plus fixed-dose fulvestrant (500 mg). During dose escalation, dose-limiting toxic effects were reported in 1 patient (alpelisib, 400 mg): diarrhea (grade 2), vomiting, fatigue, and decreased appetite (all grade 3). The MTD of alpelisib when combined with fulvestrant was 400 mg once daily, and the recommended phase 2 dose was 300 mg once daily. Overall, the most frequent grade 3/4 adverse events with alpelisib, 400 mg, once daily (≥10{\%} of patients), regardless of causality, were hyperglycemia (19 [22{\%}]) and maculopapular rash (11 [13{\%}]); 9 patients permanently discontinued therapy owing to adverse events. Median progression-free survival at the MTD was 5.4 months (95{\%} CI, 4.6-9.0 months). Median progression-free survival with alpelisib, 300 to 400 mg, once daily plus fulvestrant was longer in patients with PIK3CA-altered tumors (9.1 months; 95{\%} CI, 6.6-14.6 months) vs wild-type tumors (4.7 months; 95{\%} CI, 1.9-5.6 months). Overall response rate in the PIK3CA-altered group was 29{\%} (95{\%} CI, 17{\%}-43{\%}), with no objective tumor responses in the wild-type group. Conclusions and Relevance: Alpelisib plus fulvestrant has a manageable safety profile in patients with ER+ ABC, and data suggest that this combination may have greater clinical activity in PIK3CA-altered vs wild-type tumors. Trial Registration: ClinicalTrials.gov identifier: NCT01219699.",
author = "Dejan Juric and Filip Janku and {Rodon Ahnert}, Jordi and Burris, {Howard A.} and Mayer, {Ingrid A.} and Martin Schuler and Ruth Seggewiss-Bernhardt and Marta Gil-Martin and Middleton, {Mark R.} and Jos{\'e} Baselga and Douglas Bootle and David Demanse and Lars Blumenstein and Karl Schumacher and Alan Huang and Cornelia Quadt and Rugo, {Hope S.}",
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TY - JOUR

T1 - Alpelisib Plus Fulvestrant in PIK3CA -Altered and PIK3CA -Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer

T2 - A Phase 1b Clinical Trial

AU - Juric, Dejan

AU - Janku, Filip

AU - Rodon Ahnert, Jordi

AU - Burris, Howard A.

AU - Mayer, Ingrid A.

AU - Schuler, Martin

AU - Seggewiss-Bernhardt, Ruth

AU - Gil-Martin, Marta

AU - Middleton, Mark R.

AU - Baselga, José

AU - Bootle, Douglas

AU - Demanse, David

AU - Blumenstein, Lars

AU - Schumacher, Karl

AU - Huang, Alan

AU - Quadt, Cornelia

AU - Rugo, Hope S.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Importance: The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in patients with estrogen receptor-positive (ER+), endocrine therapy-resistant breast cancers. Objective: To assess the maximum tolerated dose (MTD), safety, and activity of alpelisib, an oral, PI3Kα-specific inhibitor, plus fulvestrant in patients with ER+ advanced breast cancer (ABC). Design, Setting, and Participants: An open-label, single-arm, phase 1b study of alpelisib plus fulvestrant was conducted at 10 centers in 5 countries. Participants were 87 postmenopausal women with PIK3CA-altered or PIK3CA-wild-type ER+ ABC, whose cancer progressed during or after antiestrogen therapy. The study began enrolling patients October 5, 2010, and the data cutoff was March 22, 2017. Interventions: Escalating doses of alpelisib were administered once daily, starting at 300 mg, plus fixed-dose fulvestrant, 500 mg, in the dose-escalation phase; alpelisib at the recommended phase 2 dose plus fulvestrant in the dose-expansion phase. Main Outcomes and Measures: The primary end point was determination of the MTD of once-daily alpelisib plus fulvestrant. Secondary end points included safety and preliminary activity. Results: From October 5, 2010, to March 22, 2017, 87 women (median age: 58 years [range, 37-79 years]; median of 5 prior lines of antineoplastic therapy) received escalating once-daily doses of alpelisib (300 mg, n = 9; 350 mg, n = 8; 400 mg, n = 70) plus fixed-dose fulvestrant (500 mg). During dose escalation, dose-limiting toxic effects were reported in 1 patient (alpelisib, 400 mg): diarrhea (grade 2), vomiting, fatigue, and decreased appetite (all grade 3). The MTD of alpelisib when combined with fulvestrant was 400 mg once daily, and the recommended phase 2 dose was 300 mg once daily. Overall, the most frequent grade 3/4 adverse events with alpelisib, 400 mg, once daily (≥10% of patients), regardless of causality, were hyperglycemia (19 [22%]) and maculopapular rash (11 [13%]); 9 patients permanently discontinued therapy owing to adverse events. Median progression-free survival at the MTD was 5.4 months (95% CI, 4.6-9.0 months). Median progression-free survival with alpelisib, 300 to 400 mg, once daily plus fulvestrant was longer in patients with PIK3CA-altered tumors (9.1 months; 95% CI, 6.6-14.6 months) vs wild-type tumors (4.7 months; 95% CI, 1.9-5.6 months). Overall response rate in the PIK3CA-altered group was 29% (95% CI, 17%-43%), with no objective tumor responses in the wild-type group. Conclusions and Relevance: Alpelisib plus fulvestrant has a manageable safety profile in patients with ER+ ABC, and data suggest that this combination may have greater clinical activity in PIK3CA-altered vs wild-type tumors. Trial Registration: ClinicalTrials.gov identifier: NCT01219699.

AB - Importance: The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in patients with estrogen receptor-positive (ER+), endocrine therapy-resistant breast cancers. Objective: To assess the maximum tolerated dose (MTD), safety, and activity of alpelisib, an oral, PI3Kα-specific inhibitor, plus fulvestrant in patients with ER+ advanced breast cancer (ABC). Design, Setting, and Participants: An open-label, single-arm, phase 1b study of alpelisib plus fulvestrant was conducted at 10 centers in 5 countries. Participants were 87 postmenopausal women with PIK3CA-altered or PIK3CA-wild-type ER+ ABC, whose cancer progressed during or after antiestrogen therapy. The study began enrolling patients October 5, 2010, and the data cutoff was March 22, 2017. Interventions: Escalating doses of alpelisib were administered once daily, starting at 300 mg, plus fixed-dose fulvestrant, 500 mg, in the dose-escalation phase; alpelisib at the recommended phase 2 dose plus fulvestrant in the dose-expansion phase. Main Outcomes and Measures: The primary end point was determination of the MTD of once-daily alpelisib plus fulvestrant. Secondary end points included safety and preliminary activity. Results: From October 5, 2010, to March 22, 2017, 87 women (median age: 58 years [range, 37-79 years]; median of 5 prior lines of antineoplastic therapy) received escalating once-daily doses of alpelisib (300 mg, n = 9; 350 mg, n = 8; 400 mg, n = 70) plus fixed-dose fulvestrant (500 mg). During dose escalation, dose-limiting toxic effects were reported in 1 patient (alpelisib, 400 mg): diarrhea (grade 2), vomiting, fatigue, and decreased appetite (all grade 3). The MTD of alpelisib when combined with fulvestrant was 400 mg once daily, and the recommended phase 2 dose was 300 mg once daily. Overall, the most frequent grade 3/4 adverse events with alpelisib, 400 mg, once daily (≥10% of patients), regardless of causality, were hyperglycemia (19 [22%]) and maculopapular rash (11 [13%]); 9 patients permanently discontinued therapy owing to adverse events. Median progression-free survival at the MTD was 5.4 months (95% CI, 4.6-9.0 months). Median progression-free survival with alpelisib, 300 to 400 mg, once daily plus fulvestrant was longer in patients with PIK3CA-altered tumors (9.1 months; 95% CI, 6.6-14.6 months) vs wild-type tumors (4.7 months; 95% CI, 1.9-5.6 months). Overall response rate in the PIK3CA-altered group was 29% (95% CI, 17%-43%), with no objective tumor responses in the wild-type group. Conclusions and Relevance: Alpelisib plus fulvestrant has a manageable safety profile in patients with ER+ ABC, and data suggest that this combination may have greater clinical activity in PIK3CA-altered vs wild-type tumors. Trial Registration: ClinicalTrials.gov identifier: NCT01219699.

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