Phase I Basket Study of Taselisib, an Isoform-Selective PI3K Inhibitor, in Patients with PIK3CA-Mutant Cancers
| Autor: | Jhaveri K, Chang M, Juric D, Saura C, Gambardella V, Melnyk A, Patel M, Ribrag V, Ma C, Aljumaily R, Bedard P, Sachdev J, Dunn L, Won H, Bond J, Jones S, Savage H, Scaltriti M, Wilson T, Wei M, Hyman D |
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| Rok vydání: | 2021 |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA instname |
| ISSN: | 1557-3265 |
| Popis: | PURPOSE: Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), which encodes the p110alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3K), are found in multiple human cancers. While recurrent mutations in PIK3CA helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with PIK3CA-mutant cancers with the isoform-specific PI3K inhibitor, taselisib. PATIENTS AND METHODS: Patients were enrolled based on local PIK3CA mutation testing into 1 of 11 histology-specific cohorts and treated with taselisib at 6 mg or 4 mg daily until progression. Tumor DNA from baseline and progression (when available) was sequenced using a next-generation sequencing panel. Exploratory analyses correlating genomic alterations with treatment outcomes were performed. RESULTS: 166 patients with PIK3CA-mutant cancers were enrolled. The confirmed response rate was 9.0%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10.0%), and other cancers, plus tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront (TP53 and PTEN) and post-progression through reactivation of the PI3K pathway (PTEN, STK11, and PIK3R1). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index. CONCLUSIONS: Taselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target PIK3CA-mutant tumors. |
| Databáze: | OpenAIRE |
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