Preclinical evaluation and phase 1 study of the PI3Kα/δ inhibitor TQ‐B3525 in Chinese patients with advanced cancers

Abstract

AbstractBackgroundPhosphatidylinositol 3‐kinase (PI3K) inhibitors transformed management of various malignancies. This study preclinically characterized TQ‐B3525 (dual PI3Kα/δ inhibitor) and assessed the recommended phase 2 dose (RP2D), safety, efficacy, and pharmacokinetics in relapsed or refractory (R/R) lymphoma or advanced solid tumors (STs).MethodsOral TQ‐B3525 was given at eight dose levels on a 28‐day cycle. Primary end points were dose‐limiting toxicity (DLT), maximum tolerated dose (MTD), and safety.ResultsTQ‐B3525 showed high selectivity and suppressed tumor growth. Between June 12, 2018, and November 18, 2020, 80 patients were enrolled (63 in dose‐escalation cohort; 17 in dose‐expansion cohort). Two DLTs occurred in two (two of 63, 3.2%) DLT‐evaluable patients; MTD was not identified. TQ‐B3525 at 20 mg once daily was selected as RP2D. Grade 3 or worse treatment‐related adverse events mainly included hyperglycemia (16.3%), neutrophil count decreased (15.0%), and diarrhea (10.0%). Two (2.5%) treatment‐related deaths were reported. Sixty patients with R/R lymphoma and 11 advanced STs demonstrated objective response rates of 68.3% and 9.1%, disease control rates of 91.7% and 54.6%, median progression‐free survivals of 12.1 and 1.1 months; median overall survivals were not reached.ConclusionTQ‐B3525 exhibited rapid absorption and a nearly proportional increase in exposure. Acceptable safety and promising efficacy support further investigation of TQ‐B3525 (20 mg once daily) for R/R lymphoma.