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Ref Type Journal Article
PMID (40865033)
Authors Janku F, Jegede OA, Puhalla SL, Konstantinopoulos PA, Meric-Bernstam F, Zwiebel JA, Gray RJ, Wang XV, McShane LM, Rubinstein LV, Patton DR, Williams PM, Hamilton SR, Takebe N, Ghani S, Tricoli JV, Conley BA, Arteaga CL, Harris LN, O'Dwyer PJ, Chen AP, Flaherty KT
Title 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.
Journal Vol Issue Date Pages Journal Short Title
JCO precision oncology 9 2025 Aug e2500265 JCO Precis Oncol
URL
Abstract Text 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.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.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PTEN negative Advanced Solid Tumor no benefit GSK2636771 Phase II Actionable In a Phase II trial (MATCH), GSK2636771 treatment did not meet the primary endpoint of objective response in patients with advanced solid tumors with PTEN protein loss (n=35), resulting in stable disease in 22% (7/35) of the patients, a median progression-free survival of 1.8 months, and a median overall survival of 5.9 months (PMID: 40865033; NCT02465060). 40865033
PTEN mutant Advanced Solid Tumor no benefit GSK2636771 Phase II Actionable In a Phase II trial (MATCH), GSK2636771 treatment did not meet the primary endpoint of objective response in patients with advanced solid tumors harboring PTEN mutation or deletion but retained protein expression, resulting in stable disease in 32% (7/24) of the patients, a median progression-free survival of 1.8 months, and a median overall survival of 7.5 months (PMID: 40865033; NCT02465060). 40865033