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Alpelisib (BYL719) plus Fulvestrant in PIK3CA-altered and PIK3CA wild-type ER+ advanced breast cancer. An open-label, phase 1b dose-escalation and expansion study

Juric, Dejan and Janku, Filip and Rodon, Jordi and Burris, Howard A. and Mayer, Ingrid A. and Schuler, Martin and Seggewiss-Bernhard, Ruth and Gil-Martin, Marta and Middleton, Mark R. and Baselga, Jose and Bootle, Douglas and Demanse, David and Blumenstein, Lars and Schumacher, Karl and Huang, Alan and Quadt, Cornelia and Rugo, Hope S. (2018) Alpelisib (BYL719) plus Fulvestrant in PIK3CA-altered and PIK3CA wild-type ER+ advanced breast cancer. An open-label, phase 1b dose-escalation and expansion study. JAMA oncology, Oncol.. E1-E9. ISSN 2374-2437

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: This was an open-label, single-arm, phase 1b study of alpelisib plus fulvestrant.
Setting: Eleven centers in 5 countries.
Participants: Postmenopausal women with PIK3CA-altered or PIK3CA-wild-type ER+ ABC, who progressed on or after anti-estrogen therapy.
Intervention: Escalating doses of alpelisib once daily (QD), starting from 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 endpoint was determination of the MTD of QD alpelisib plus fulvestrant. Secondary endpoints included safety and preliminary activity.
Results: From October 2010 to April 2014, 87 women (median age: 58; median 5 prior lines of antineoplastic therapy) received escalating doses of alpelisib QD (300 mg, n=9; 350 mg, n=8; 400-mg, n=70) plus fixed-dose fulvestrant (500 mg). During dose-escalation, dose-limiting toxicities were reported in 1 patient (alpelisib 400 mg): diarrhea (grade 2), vomiting, fatigue, and decreased appetite (all grade 3). The MTD of alpelisib (plus fulvestrant) was 400 mg QD, and the recommended phase 2 dose was 300 mg QD. Overall, the most frequent grade 3/4 adverse events with alpelisib 400 mg QD (≥10% of patients), regardless of causality, were hyperglycemia (22%) and maculopapular rash (13%); 9 patients permanently discontinued due to adverse events. Median progression-free survival (mPFS) at the MTD was 5.4 months (95% CI: 4.6–9.0). mPFS of alpelisib 300–400 mg QD plus fulvestrant was longer in patients with PIK3CA-altered tumors (9.1 months [95% CI: 6.6–14.6]) vs wild-type tumors (4.7 months [95% CI: 1.9–5.6]). Overall response rate in the PIK3CA-altered group was 29%, 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.

Item Type: Article
Keywords: Alpelisib, breast cancer, BYL719, PI3K, PIK3CA
Date Deposited: 26 Feb 2019 00:45
Last Modified: 26 Feb 2019 00:45
URI: https://oak.novartis.com/id/eprint/36898

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