Found 1 Presentation For Request "1085p"
1085P - Ph I/II study of PI3K-β inhibitor GSK2636771 (G771) in combination with pembrolizumab (P) in patients (pts) with PTEN loss and melanoma or other advanced solid tumors
- Elizabeth Burton (Houston, United States of America)
Abstract
Background
Immune checkpoint blockade (ICB) improves survival in metastatic melanoma (MM), but many pts progress or recur and ultimately die from this disease. PTEN loss, which occurs in up to 30% of MM pts, activates the PI3K-AKT pathway and correlates with decreased tumor infiltrating lymphocytes (TIL) and lower response rate (RR) to ICB. In preclinical models of PTEN-null melanoma selective inhibition of PI3Kβ with G771 combined with ICB increased CD4+/8+ TIL and survival. Thus, we conducted a phase I/II study (NCT01458067) of PI3Kβi + P in pts w/ PTEN loss, including PD-1 refractory MM.
Methods
Ph I primary objective (obj) was determining the Recommended Phase II Dose (RP2D) of G771 + P (3+3 design). P was given at 200 mg IV and dose escalation started at 300mg PO qd of G771 for 21 days. Ph II primary objs were safety, tolerability, and RR by RECIST 1.1. Secondary obj included PKs of the G771 and PD effects in tumor and blood. MM pts must have progressed on PD1 or not achieved response after 6 mos of therapy. PD1-naïve pts with advanced prostate, triple-negative breast (TNBC), colorectal or endometrial cancer were also eligible. PTEN loss was defined by mutation or loss of protein expression by IHC.
Results
Ten pts were accrued to the dose escalation phase (300mg and 400mg), but RP2D was set at 200 mg of G771 due to a DLT of acute kidney injury and data from other ongoing studies. A total of 27 pts (of 41 planned) were treated: 10 MM, 12 prostate, 2 TNBC, 1 each of endometrial, lung, colon. Study accrual stopped due to sponsor decision to cease development of G771. PRs were achieved in 3 pts (12%) and clinical benefit rate (CR/PR/SD) was 52%, including 3 pts with >1 yr on therapy. Median PFS was 3.4 mos (95% CI: 2.5-6.0). 44% pts experienced gr 3/4 toxicities, 3 pts discontinued due to toxicity. Paired biopsies were obtained when safe/feasible; RR and translational studies will be presented at the conference.
Conclusions
G771 (200 mg PO QD) + P was tolerable, but response was modest. Translational studies will be critical to understanding mechanisms of response and resistance to G771 + P and to develop additional strategies to overcome resistance to ICB due to PTEN loss.
Clinical trial identification
NCT01458067.
Legal entity responsible for the study
The University of Texas MD Anderson Cancer Center.
Funding
Merck, GSK.
Disclosure
S.A. Piha-Paul: Financial Interests, Institutional, Funding: AbbVie Inc; Financial Interests, Institutional, Funding: ABM Therapeutics; Financial Interests, Institutional, Funding: Alkermes; Financial Interests, Institutional, Funding: Aminex Therapeutics; Financial Interests, Institutional, Funding: Amphivena Therapeutics; Financial Interests, Institutional, Funding: biomarin pharmaceutical; Financial Interests, Institutional, Funding: Boehringer Ingelheim; Financial Interests, Institutional, Funding: BMS; Financial Interests, Institutional, Funding: Cerulean; Financial Interests, Institutional, Funding: Chugai; Financial Interests, Institutional, Funding: Curis; Financial Interests, Institutional, Funding: Daiichi Sankyo; Financial Interests, Institutional, Funding: Eli Lily; Financial Interests, Institutional, Funding: ENB Therapeutics; Financial Interests, Institutional, Funding: Five Prime Therapeutics; Financial Interests, Institutional, Funding: F Star therapeutics; Financial Interests, Institutional, Funding: Gene Quantum; Financial Interests, Institutional, Funding: Genmab; Financial Interests, Institutional, Funding: GSK; Financial Interests, Institutional, Funding: Helix Biopharma; Financial Interests, Institutional, Funding: Incyte corp; Financial Interests, Institutional, Funding: Jacobio; Financial Interests, Institutional, Funding: Medimmune; Financial Interests, Institutional, Funding: Medivation; Financial Interests, Institutional, Funding: Merck; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Pieris; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: Principia Biopharma; Financial Interests, Institutional, Funding: Puma Biotechnology; Financial Interests, Institutional, Funding: Rapt Therapeutics; Financial Interests, Institutional, Funding: Seattle Genetics; Financial Interests, Institutional, Funding: Silverback Therapeutics; Financial Interests, Institutional, Funding: Taiho Oncology; Financial Interests, Institutional, Funding: Tesaro Inc; Financial Interests, Institutional, Funding: Transthera Bio. H.A. Tawbi: Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Genentech; Financial Interests, Personal, Advisory Role: Eisai; Financial Interests, Personal, Advisory Role: Iovance; Financial Interests, Institutional, Funding: BMS; Financial Interests, Institutional, Funding: Merck; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Genentech; Financial Interests, Institutional, Funding: GSK; Financial Interests, Institutional, Funding: Celgene; Financial Interests, Institutional, Funding: Dragonfly. All other authors have declared no conflicts of interest.