PIK3CB Inhibitor GSK2636771 in Cancers With <i>PTEN</i> Mutation/Deletion or Loss of PTEN Protein Expression: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocols N and P.

Abstract

PTEN loss contributes to aberrant signaling of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin pathway and may confer sensitivity to therapies targeting the PI3K pathway. The PIK3CB inhibitor GSK2636771 demonstrated efficacy in tumors with <i>PIK3CB</i> mutations and may similarly show efficacy in patients with PTEN loss. Two nonrandomized, open-label phase II subprotocols within the context of the NCI-MATCH trial targeted PTEN tumor alterations in patients with advanced relapsed/refractory solid tumors, lymphoma, or myeloma: <i>PTEN</i> mutation/deletion (arm N) or loss of PTEN protein expression (arm P). Patients were treated with oral GSK2636771 at 400 mg once per day on 28-day cycles. The primary outcome was objective response (OR); secondary outcomes included progression-free survival (PFS) ≥ 6 months, PFS, and overall survival. Of the 59 patients enrolled across both subprotocols (arm N = 24, arm P = 35), 54 were eligible and treated with GSK2636771. Among 24 patients whose tumors had <i>PTEN</i> mutation/deletion but retained PTEN expression (arm N), seven patients (32%) achieved stable disease (SD), with two (9%) experiencing SD ≥ 6 months (uterine leiomyosarcoma and uterine endometrial carcinoma); the median PFS was 1.8 months. Of the 32 patients whose tumors had loss of PTEN protein expression (arm P), seven patients (22%) achieved SD, with two (6%) experiencing SD ≥ 6 months (prostate cancer; squamous bladder cancer); the median PFS was 1.8 months. Most frequent ≥grade 3 treatment-related adverse events included fatigue (n = 4) and anemia (n = 2) in arm N and hypocalcemia (n = 3), anemia, fatigue, diarrhea, and hypokalemia (each n = 2) in arm P. Although the primary end point of OR was not met, GSK2636771 demonstrated modest single-agent activity among patients with relapsed/refractory cancer having <i>PTEN</i> mutation/deletion with PTEN expression or PTEN protein loss.