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2018-01-01
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/172648

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

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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.

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Càncer de mama, Tiazoles, Assaigs clínics

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Breast cancer, Thiazoles, Clinical trials

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Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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JURIC, Dejan, RODON, Jordi, TABERNERO CATURLA, Josep, JANKU, Filip, BURRIS, Howard a., SCHELLENS, Jan h. m., MIDDLETON, Mark r., BERLIN, Jordan, SCHULER, Martin, GIL-MARTÍN, Marta, RUGO, Hope s., SEGGEWISS BERNHARDT, Ruth, HUANG, Alan, BOOTLE, Douglas, DEMANSE, David, BLUMENSTEIN, Lars, COUGHLIN, Christina, QUADT, Cornelia, BASELGA TORRES, Josep. Phosphatidylinositol 3-Kinase -Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study. _Journal of Clinical Oncology_. 2018. Vol. 36, núm. 13, pàgs. 1291-1299. [consulta: 24 de novembre de 2025]. [Disponible a: https://hdl.handle.net/2445/172648]

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