Abstract 2278: Next-generation sequencing (NGS) analysis from a phase II single-agent gedatolisib study in patients with endometrial cancer
Authors: Pathan Nuzhat , English Patricia , Ching Keith , Huang Stephen , Jalaie Mehran , Pierce Kristen , Vermette Jennifer 
Published: July 2016

Genetic alterations in the PI3K pathway are abundant in endometrial cancer. Hence it is hypothesized that PI3K/mTOR inhibitors will have utility for treatment of endometrial cancer. Gedatolisib, also known as PF-384, is a potent and selective dual PI3K-mTOR inhibitor with broad anti-tumor activity in preclinical studies. Gedatolisib delivered weekly intravenously was investigated in a Phase II single-agent study of advanced endometrial cancer. The cumulative clinical benefit rate from 38 response evaluable patients was 39.5%, comparable to historical rates with mTOR inhibitors. A retrospective NGS analysis of archival biopsies from patients in the study was conducted using the Foundation Medicine Inc (FMI) Foundation One Test to explore potential predictive biomarkers for clinical benefit. Of the 26 patient samples submitted for analysis, data was obtained from 19 samples of which 17 had evaluable response data. Of these 17 samples, 6 were from patients who exhibited progressive disease (PD), 6 were from patients with stable disease (SD) and 5 were from patients that showed a partial response (PR) to treatment. In general, the best responders had a low mutation load while the worst responders had a higher mutation load. Whether large mutation burden was due to mismatch-repair defects determined by MSI status of the tumors is currently under investigation. PTEN alterations were found in tumors from patients that exhibited PD and SD, but not PR. Multiple genetic alterations in ARID1A were observed in 3 of 6 tumors from patients with PD. While PIK3CA alterations were frequently present, 2 of 5 patients with PR and 1 with SD exhibited an activating PIK3CA mutation at H1047R. Among 175 genes that were observed to be mutated in the analysis of 17 independent tumor samples, the top ranking genes associated with a reduction in tumor size (% change from baseline by RECIST 1.0; Wilcoxon rank sum test) were MAP3K1 (p = 0.027) and CTNNB1 (p = 0.050). Activating mutations in β-catenin were observed in tumor from 3 of 5 patients with PR and were not present in tumor from patients with PD or SD. Tumor from a patient who exhibited an outlier clinical response (stayed on study after 2 years on treatment) had an activating mutation in Akt at E17K and also a novel mutation in mTOR at F2184L. Computational modeling analysis revealed that the mutation did not have a significant impact on kinase structure or ligand binding. KRAS mutations did not appear to correlate with clinical response. This study highlights both the wealth of information provided by NGS analysis, but also the complexity of NGS data analysis and interpretation.

Citation Format: Nuzhat Pathan, Patricia English, Keith Ching, Stephen Huang, Mehran Jalaie, Kristen Pierce, Jennifer Vermette. Next-generation sequencing (NGS) analysis from a phase II single-agent gedatolisib study in patients with endometrial cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2278.