Phosphatidylinositol 3-kinase α-selective inhibition with alpelisib (BYL719) in PIK3CA-altered solid tumors: Results from the first-in-human study Journal Article


Authors: Juric, D.; Rodon, J.; Tabernero, J.; Janku, F.; Burris, H. A.; Schellens, J. H. M.; Middleton, M. R.; Berlin, J.; Schuler, M.; Gil-Martin, M.; Rugo, H. S.; Seggewiss-Bernhardt, R.; Huang, A.; Bootle, D.; Demanse, D.; Blumenstein, L.; Coughlin, C.; Quadt, C.; Baselga, J.
Article Title: Phosphatidylinositol 3-kinase α-selective inhibition with alpelisib (BYL719) in PIK3CA-altered solid tumors: Results from the first-in-human study
Abstract: PurposeWe report the first-in-human phase Ia study to our knowledge (ClinicalTrials.gov identifier: NCT01219699) identifying the maximum tolerated dose and assessing safety and preliminary efficacy of single-agent alpelisib (BYL719), an oral phosphatidylinositol 3-kinase (PI3K)-selective inhibitor.Patients and MethodsIn 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.ResultsOne 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%).ConclusionAlpelisib demonstrated a tolerable safety profile and encouraging preliminary activity in patients with PIK3CA-altered solid tumors, supporting the rationale for selective PI3K inhibition in combination with other agents for the treatment of PIK3CA-mutant tumors.
Keywords: mutation; breast-cancer; growth; pathway; frequent; phase-i; ovarian; trials; metastatic breast; i pi3k inhibitor; multipotency
Journal Title: Journal of Clinical Oncology
Volume: 36
Issue: 13
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2018-05-01
Start Page: 1291
End Page: 1299
Language: English
ACCESSION: WOS:000433528700005
DOI: 10.1200/jco.2017.72.7107
PROVIDER: wos
PMCID: PMC5920739
PUBMED: 29401002
Notes: Article -- Source: Wos
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MSK Authors
  1. Jose T Baselga
    389 Baselga