Phase I Basket Study of Taselisib, an Isoform-Selective PI3K Inhibitor, in Patients with PIK3CA -Mutant Cancers

• Published in: Clinical cancer research Vol. 27; no. 2; pp. 447 - 459
• Main Authors: Jhaveri, Komal, Chang, Matthew T., Juric, Dejan, Saura, Cristina, Gambardella, Valentina, Melnyk, Anton, Patel, Manish R., Ribrag, Vincent, Ma, Cynthia X., Aljumaily, Raid, Bedard, Philippe L., Sachdev, Jasgit C., Dunn, Lara, Won, Helen, Bond, John, Jones, Surai, Savage, Heidi M., Scaltriti, Maurizio, Wilson, Timothy R., Wei, Michael C., Hyman, David M.
• Format: Journal Article
• Language: English
• Published: United States 15.01.2021
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - therapeutic use; Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Class I Phosphatidylinositol 3-Kinases - genetics; Class I Phosphatidylinositol 3-Kinases - metabolism; Cohort Studies; Female; Humans; Imidazoles - therapeutic use; Male; Middle Aged; Mutation; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Oxazepines - therapeutic use; Progression-Free Survival; Treatment Outcome; Young Adult
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-20-2657

Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ( ), which encodes the p110α catalytic subunit of PI3K, are found in multiple human cancers. While recurrent mutations in 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 -mutant cancers with the isoform-specific PI3K inhibitor taselisib. Patients were enrolled on the basis of local 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 -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 ( and ) and postprogression through reactivation of the PI3K pathway ( , and ). 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 -mutant tumors.