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J Clin Oncol. 2018 Feb 5:JCO2017727107. doi: 10.1200/JCO.2017.72.7107. [Epub ahead of print]

Phosphatidylinositol 3-Kinase α-Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study.

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Dejan Juric, Massachusetts General Hospital Cancer Center, Boston; Alan Huang, Novartis Institutes for BioMedical Research, Cambridge, MA; Jordi Rodon and Josep Tabernero, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona; Marta Gil-Martin, Catalan Institute of Oncology - Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; Filip Janku, The University of Texas MD Anderson Cancer Center, Houston, TX; Howard A. Burris, Sarah Cannon Research Institute and Tennessee Oncology; Jordan Berlin, Vanderbilt-Ingram Cancer Center, Nashville, TN; Jan H.M. Schellens, Netherlands Cancer Institute, Amsterdam, the Netherlands; Mark R. Middleton, National Institute for Health Research, Oxford Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom; Martin Schuler, West German Cancer Center, University Duisburg-Essen, and German Cancer Consortium, Partner Site University Hospital Essen, Essen; Ruth Seggewiss-Bernhardt, Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany; Hope S. Rugo, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; Douglas Bootle, David Demanse, Lars Blumenstein, and Cornelia Quadt, Novartis Pharma AG, Basel, Switzerland; Christina Coughlin, Novartis Pharmaceuticals Corporation, East Hanover, NJ; and José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY.


Purpose We report the first-in-human phase Ia study to our knowledge ( identifier: NCT01219699) identifying the maximum tolerated dose and assessing safety and preliminary efficacy of single-agent alpelisib (BYL719), an oral phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor. Patients and Methods In the dose-escalation phase, patients with PIK3CA-altered advanced solid tumors received once-daily or twice-daily oral alpelisib on a continuous schedule. In the dose-expansion phase, patients with PIK3CA-altered solid tumors and PIK3CA-wild-type, estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer received alpelisib 400 mg once daily. Results One hundred thirty-four patients received treatment. Alpelisib maximum tolerated doses were established as 400 mg once daily and 150 mg twice daily. Nine patients (13.2%) in the dose-escalation phase had dose-limiting toxicities of hyperglycemia (n = 6), nausea (n = 2), and both hyperglycemia and hypophosphatemia (n = 1). Frequent all-grade, treatment-related adverse events included hyperglycemia (51.5%), nausea (50.0%), decreased appetite (41.8%), diarrhea (40.3%), and vomiting (31.3%). Alpelisib was rapidly absorbed; half-life was 7.6 hours at 400 mg once daily with minimal accumulation. Objective tumor responses were observed at doses ≥ 270 mg once daily; overall response rate was 6.0% (n = 8; one patient with endometrial cancer had a complete response, and seven patients with cervical, breast, endometrial, colon, and rectal cancers had partial responses). Stable disease was achieved in 70 (52.2%) patients and was maintained > 24 weeks in 13 (9.7%) patients; disease control rate (complete and partial responses and stable disease) was 58.2%. In patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, median progression-free survival was 5.5 months. Frequently mutated genes (≥ 10% tumors) included TP53 (51.3%), APC (23.7%), KRAS (22.4%), ARID1A (13.2%), and FBXW7 (10.5%). Conclusion Alpelisib demonstrated a tolerable safety profile and encouraging preliminary activity in patients with PIK3CA-altered solid tumors, supporting the rationale for selective PI3Kα inhibition in combination with other agents for the treatment of PIK3CA-mutant tumors.

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