Phase I/II study of the selective PI3Kβ inhibitor GSK2636771 in combination with pembrolizumab in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and PTEN loss.
Authors: Dumbrava Ecaterina Elena , Burton Elizabeth M. , Subudhi Sumit Kumar , Milton Denai R. , Aparicio Ana , Yap Timothy A. , Naing Aung , Corn Paul Gettys , Pilié Patrick Glen , Zurita Amado J. , Wang Jennifer , Amaria Rodabe Navroze , McQuade Jennifer Leigh , Glitza Isabella Claudia , Lazar Alexander J. , Meric-Bernstam Funda , Logothetis Christopher , Davies Michael A. , Hwu Patrick , Tawbi Hussein A. 
Published: June 2022

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Background: PTEN loss activates the PI3K/AKT signaling pathway, contributes to an immunosuppressive tumor microenvironment, resistance to androgen deprivation therapy and poor clinical outcome in pts with mCRPC. Treatment with anti-PD1 antibodies improves survival in many cancers, but efforts to harness its benefit in mCRPC have been unsuccessful. In preclinical PTEN loss models, selective PI3Kβ inhibitor enhanced survival and the frequency of intratumoral T cells. We hypothesized that the combination of PI3Kβ inhibitor and anti-PD-1 antibody is safe and promotes antitumor activity. To test this, we conducted a phase I/II study (NCT01458067) of PI3Kβ inh GSK2636771 and pembrolizumab in pts with solid tumors (including melanoma and mCRPC) with PTEN loss. We report the results from a cohort of pts with mCRPC and PTEN loss. Methods: The phase I primary objective was to determine the safety, tolerability, and recommended phase II dose (RP2D) of GSK2636771 + pembrolizumab using a 3+3 design. Pembrolizumab was given at 200 mg IV Q3W and dose escalation started at 300mg orally daily of GSK2636771 for 21 days cycle. The phase II primary objective was to evaluate the efficacy of the combination using RECIST 1.1. Secondary objectives were to evaluate PK and PD effects in tumor and blood. Tumoral PTEN loss was defined by loss of protein expression by IHC or by presence of an inactivating mutation identified by next-generation sequencing (NGS). Results: A total of 12 pts with mCRPC and PTEN loss were enrolled (2 pts in the dose escalation and 10 pts in the dose expansion cohorts). Median age was 67 years (range 55-80) and pts had a median of 4 lines of prior therapies with 83% of pts receiving prior taxane-based chemotherapy. The RP2D was identified at 200mg PO QD of GSK2636771 + pembrolizumab 200mg IV Q3W. Most treatment-related adverse events were grade (G) 1-2 with the most common being diarrhea (33%) and rash (42%). A total of 4 pts had G3 rash, including 2 pts with G3 immune-related bullous pemphigoid. Dose-limiting toxicities in pts with mCRPC included G3 hypophosphatemia and G3 rash. Treatment was discontinued because of G3 toxicity in 1 pt and 42% of pts required a dose reduction of GSK2636771. Among 11 evaluable pts at 200mg daily of GSK2636771, partial response (PR) was achieved in 2 pts (-56% and -59% as compared to baseline, per RECIST1.1), which was associated with ongoing progression free survival (PFS) > 12 months (24.1 and 13.6 months, respectively) and PSA > 50% reduction as compared to baseline. In addition, a pt with tumor reduction of 18% per RECIST1.1 has remained on treatment for 15.8 months. Conclusions: GSK2636771 plus pembrolizumab had an acceptable safety and tolerability profile. The combination showed promising preliminary antitumor activity and durable responses in a heavily pretreated population of pts with mCRPC. Clinical trial information: NCT01458067.