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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Juric has reported a paid consultant role with Novartis, EMD Serono, Eisai, and Genentech. Dr Janku has reported grant funding from Novartis, Piqur, BioMed Valley Discoveries, Deciphera, FujiFilm, Astellas, Agios, Plexxikon, Symphogen, Trovagene, Biocartis, Guardant Health, Genentech, and Foundation Medicine; and personal fees for advisory board participation from Novartis, Deciphera, Trovagene, Guardant Health, Foundation Medicine, and Sequenom. Dr Rodón reported advisory board fees from Novartis during the course of the study. Dr Mayer reported serving in a consultant or advisory role with Novartis and Genentech and receiving research grants from Novartis and Pfizer. Dr Schuler reported receiving personal fees for consulting from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Novartis, and Roche; honoraria from Alexion, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, MSD, and Novartis; and having patents with Universität Duisburg-Essen. Dr Seggewiss-Bernhardt has reported a consultant or advisory role with AstraZeneca, Roche, and Novartis; and has reported travel, accommodation, and/or expenses paid by Astellas, Bristol-Myers Squibb, Novartis, Roche, and Celgene. Dr Middleton reported grant funding from Roche, AstraZeneca (paid to his institution), and GSK; personal fees for serving on advisory boards and consulting from Amgen, Roche, GSK, Novartis, Bristol-Myers Squibb, Merck, Rigontec, and Eisai (member of independent data safety monitoring committee); travel fees from Immunocore; and study fees (paid to his institution) from Novartis, Astellas, Millennium, Immunocore, Bristol-Myers Squibb, Vertex, Eisai, AbbVie, Clovis, Pfizer, and Merck; and is supported by the National Institute for Health Research Oxford Biomedical Research Centre. Dr Baselga reports nonfinancial support and reasonable reimbursement for travel from Roche/Genentech; receiving fees from and stock ownership in the following companies: Aura Biosciences (including serving on the board of directors from 2013-2017), Infinity Pharmaceuticals (including serving on the board of directors from 2013-2017), PMV Pharma Biotechnologies (including serving on the scientific advisory board from 2014-present), Juno Therapeutics (acquired by Celgene) (including serving on the scientific advisory board from 2014-2017), Grail (including serving as member or chair of the scientific advisory board from 2016-2018), Varian Medical Systems (including serving on the board of directors from 2017-2018), Bristol-Myers Squibb (including serving on the board of directors from March to September 2018), Seragon (acquired by Roche) (including serving on the scientific advisory board from 2013-2014); stock ownership in ApoGen Biotechnologies (including serving on the scientific advisory board from 2014-present), and Foghorn Therapeutics (including serving on the board from 2017-present); serving as cofounder, receiving fees from, and stock ownership in Tango (formerly Synthetic Lethal) from 2016-present and Northern Biologics (formerly Mosaic Biomedicals) (including serving on the scientific advisory board from 2013-present); receiving consulting and travel fees from Novartis and Eli Lilly; serving as cofounder of Venthera; and serving as investigator on a patent licensed to Memorial Sloan Kettering for use of phosphoinositide 3-kinase inhibitors for treatment of vascular malformations and serving as investigator for patents pending assignment to Memorial Sloan Kettering for combination therapy using PDK1 and PI3K inhibitors and inhibition of KMT2D for the treatment of breast cancer. Mr Bootle is an employee of Novartis Pharmaceuticals Corporation. Dr Demanse is an employee of Novartis Pharmaceuticals Corporation. Dr Blumenstein is an employee of and reports stock ownership in Novartis. Dr Schumacher is an employee of and reports stock ownership in Novartis. Dr Huang was a Novartis employee at the time of the study. Ms Quadt is an employee of and reports stock ownership in Novartis. Dr Rugo has reported research support (paid to institution) from Novartis, Genentech, Eli Lilly, Pfizer, Macrogenics, and Merck. No other conflicts were reported.

Figures

Figure 1.. Patient Enrollment and Disposition

Between October 10, 2010, and March 22, 2017, this open-label, phase 1b study screened 117 patients for eligibility, 87 of whom were enrolled and received treatment with alpelisib plus fulvestrant.

Figure 2.. Progression-Free Survival in Patients With PIK3CA-Altered and PIK3CA-Wild-Type Tumors

Data cutoff date was March 22, 2017. aPatients with PIK3CA-altered tumors received alpelisib, 300 to 400 mg, once daily plus fulvestrant. bPatients with PIK3CA-wild-type tumors received alpelisib, 400 mg, once daily plus fulvestrant.

Figure 3.. Best Percentage Change From Baseline in Sum of Longest Diameters and Best Overall Response in Patients With Estrogen Receptor–Positive Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer

A, PIK3CA-altered tumors. Forty-three patients excluded from missing best percentage change from baseline because of no postbaseline assessment or nonmeasurable lesion at baseline. B, PIK3CA-wild-type tumor. Seventeen patients excluded from missing best percentage change from baseline because of no postbaseline assessment or nonmeasurable lesion at baseline. Data cutoff point was March 22, 2017. CR indicates complete response; mTOR, mammalian target of rapamycin; PD, progressive disease; PR, partial response; SD, stable disease; and UNK, unknown. The dotted lines correspond to a +20% and −30% change from baseline. aIncludes 3 patients with human epidermal growth factor receptor 2–positive, estrogen receptor–positive, locally advanced or metastatic breast cancer.