Subunit-Selective PI3K Inhibition to Reverse Immunotherapy Resistance: Phase I/II Study of PI3Kβ and Pembrolizumab in Advanced Solid Tumors with PTEN Loss

Abstract Overcoming resistance to immune checkpoint blockade (ICB) remains a critical unmet need for most cancer patients. Loss of the PTEN tumor suppressor gene activates the PI3K-AKT pathway in multiple cancer types. In melanoma, PTEN loss reduces ICB efficacy in preclinical models and correlates with decreased response rates in patients. The PI3Kβ inhibitor GSK2636771 blocked PI3K-AKT activation, increased immune infiltration, and improved ICB efficacy in PTEN-null melanoma preclinical models. Thus, we conducted a phase I/II study (NCT01458067) to evaluate the safety and efficacy of GSK2636771 with pembrolizumab in patients with advanced cancer and PTEN loss. Of the twenty-seven treated patients, 41% experienced grade 3-4 treatment related adverse events. The overall response rate (ORR) by RECIST 1.1 was 12% and 20% experienced clinical benefit. We present the clinical and translational results from this trial and preclinical experiments comparing PI3K isoforms which identifies PI3Kα as an alternative strategy to reverse resistance to ICB.