Phase I Basket Study of Taselisib, an Isoform-Selective PI3K Inhibitor, in Patients with <i>PIK3CA</i>-Mutant Cancers.

Abstract

Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (<i>PIK3CA</i>), which encodes the p110α catalytic subunit of PI3K, are found in multiple human cancers. While recurrent mutations in <i>PIK3CA</i> 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 <i>PIK3CA</i>-mutant cancers with the isoform-specific PI3K inhibitor taselisib. Patients were enrolled on the basis of local <i>PIK3CA</i> mutation testing into one of 11 histology-specific cohorts and treated with taselisib at 6 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. A total of 166 patients with <i>PIK3CA</i>-mutant cancers were enrolled. The confirmed response rate was 9%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10%), and other cancers, plus in tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront (<i>TP53</i> and <i>PTEN</i>) and postprogression through reactivation of the PI3K pathway (<i>PTEN, STK11</i>, and <i>PIK3R1</i>). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index. 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 <i>PIK3CA</i>-mutant tumors.