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

• DOI: 10.1200/jco.2017.72.7107
• Publication Date: 2018-02-05T21:00:54Z
• Authors: Dejan Juric; Jordi Rodon; Josep Tabernero; Filip Janku; Howard A. Burris; Jan H.M. Schellens; Mark R. Middleton; Jordan Berlin; Martin Schuler; Marta Gil-Martin; Hope S. Rugo; Ruth Seggewiss-Be...; Alan Huang; Douglas Bootle; David Demanse; Lars Blumenstein; Christina Coughlin; Cornelia Quadt; José Baselga
• Keywords: Oral; Adult; Class I Phosphatidylinositol 3-Kinases; Clinical Sciences; Oncology and Carcinogenesis; Medizin; Administration, Oral; Breast Neoplasms; Drug Administration Schedule; Càncer de mama; Dose-Response Relationship; Tiazoles; 03 medical and health sciences; Breast cancer; Clinical trials; Breast Cancer; 80 and over; Humans; Oncology & Carcinogenesis; 6.2 Cellular and gene therapies; Cancer; Aged; Aged, 80 and over; 0303 health sciences; Biomedical and Clinical Sciences; Dose-Response Relationship, Drug; Evaluation of treatments and therapeutic interventions; Oncology and carcinogenesis; Middle Aged; 3. Good health; Thiazoles; Treatment Outcome; 6.1 Pharmaceuticals; Administration; Female; Patient Safety; Drug; Assaigs clínics

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