SO-10 An open-label, multi-centre, phase Ib/II study of PI3Kβ selective inhibitor GSK2636771 administered in combination with paclitaxel in patients with advanced gastric cancer having alterations in PI3K/Akt pathway

Abstract

Loss of PTEN expression accompanied with activation of PI3K/AKT pathway commonly occurs in gastric cancer. GSK2636771 is a potent, orally bioavailable, adenosine triphosphate-competitive selective inhibitor of PI3Kβ with minimal off-target effects. Here, we conducted a dose-finding study with safety and efficacy analysis of GSK2636771 combined with paclitaxel in patients with advanced gastric cancer (AGC) who progressed from first-line chemotherapy. In this multi-center phase Ib/II study, patients with PTEN-deficient AGC who failed to respond to first-line chemotherapy with fluoropyrimidine and platinum were eligible. PTEN expression was evaluated by immunohistochemistry and the PTEN-deficient was defined by < 100 of PTEN histoscore (PTEN H-score). A standard 3+3 design included two dose levels of GSK2636771 (300mg once daily and 200mg once daily) in combination with paclitaxel (80mg/m2 on days 1, 8, and 15) during phase Ib study to determine the recommended phase II dose (RP2D). Phase II study was subsequently conducted based on the RP2D derived from phase Ib study to assess safety and antitumor activity. Primary objectives included defining RP2D and assessment of progression-free survival (PFS) in patients administered with RP2D. Secondary objectives included overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, and biomarker analysis incorporating investigation of PTEN H-score (0 vs. 1-99) and somatic alteration of cancer by next-generation sequencing (NGS). This trial is registered with ClinicalTrials.gov, number NCT02615730. A total of 42 patients were enrolled, median age was 59 years old (range: 32-88 years old) and most patients were male (34/42). During phase Ib study, grade 3 hypocalcemia was observed in 2 out of 5 patients with GSK2636771 300mg once daily combined with paclitaxel. The RP2D was GSK2636771 200mg once daily combined with paclitaxel (80mg/m2 on days 1, 8, and 15). The median follow-up duration of 29.9 months [95% confidential interval (CI), 21.5-38.3 weeks]. Among 37 patients treated with RP2D with and 33.4 weeks (95% CI, 26.2-40.7 weeks), median PFS and OS were 12.1 (95% CI, 11.1-13.2 weeks) and 33.4 weeks (95% CI, 26.2-40.7 weeks), respectively. Among 28 patients with measurable disease and administered with RP2D, confirmed response and disease control was observed in 5 patients (ORR=17.9%) and 19 patients (DCR=67.9%), respectively. Patients with PTENnull tumors (H-score 0) exhibited favorable PFS (18.9 vs. 11.6 weeks, P=0.026) compared to those with PTENpartial loss tumors (H-score 1-99). Most common any grade of adverse events (AEs) were neutropenia (38.1%), peripheral neuropathy (28.8%), anorexia (21.4%), diarrhea (16.7%), and myalgia (14.3%). No treatment related death or unexpected AEs resulting in treatment cessation were observed with the RP2D. GSK2636771 combined with paclitaxel revealed manageable toxicities and antitumor activity in patients with PTEN-deficient AGC who progressed after first-line chemotherapy. Complete loss of PTEN expression may be associated with clinical benefit from GSK2636771 and paclitaxel. Further analysis of the association with biomarkers and clinical outcomes is underway.