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

PURPOSE 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 PIK3CB mutations and may similarly show efficacy in patients with PTEN loss. METHODS 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: PTEN 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. RESULTS 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 PTEN 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. CONCLUSION Although the primary end point of OR was not met, GSK2636771 demonstrated modest single-agent activity among patients with relapsed/refractory cancer having PTEN mutation/deletion with PTEN expression or PTEN protein loss.