Juric, Dejan, Janku, Filip, Rodon, Jordi, Burris, Howard A., Mayer, Ingrid A., Schuler, Martin, Seggewiss-Bernhard, Ruth, Gil-Martin, Marta, Middleton, Mark R., Baselga, Jose, Bootle, Douglas, Demanse, David, Blumenstein, Lars, Schumacher, Karl, Huang, Alan, 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