Abstract LB-65: Towards defining the genetic framework for clinical response to treatment with BYL719, a PI3Kalpha-specific inhibitor. (2013)

Abstract Defining predictive biomarkers and deriving appropriate patient populations for treatment are key areas of interest in the clinical development of phosphatidyl-inositol-3-kinase (PI3K) inhibitors, but currently most clinical trials do not pre-select patients using defined genetic markers. Pre-clinical studies indicated previously that in vitro sensitivity to BYL719, a potent and selective small molecule inhibitor of the α-isoform of PI3K, was increased in cell lines derived from a subset of indications, such as HER2-positive or luminal breast cancer. Moreover, BYL719 sensitivity in vitro was positively correlated with PIK3CA mutation or amplification and HER2 amplification. PTEN or BRAF mutation, on the other hand, was associated with BYL719 insensitivity. Consequently, presence of an activating PIK3CA alteration in the tumor was a pre-requisite for patients to enroll into the BYL719 first-in-human (FIM) clinical trial. In this study, we applied massive parallel sequencing to tumor specimens from patients enrolled in the BYL719 FIM trial to comprehensively assess the genetic determinants of clinical sensitivity to BYL719. Paraffin-embedded formalin-fixed archival or pre-treatment tumor specimens were obtained from 44 patients with advanced solid tumors upon enrolment into the clinical trial. DNA was isolated and then assayed by massive parallel sequencing covering either a panel of 182 cancer-related genes at Foundation Medicine or the whole exome at the Broad Institute. Mutations were identified by focusing on genes with alterations in the COSMIC data base and excluding germline variants and were subsequently correlated with clinical benefit as defined by stable disease ≥ 4 months, tumor shrinkage ≥ 20% or objective tumor response to BYL719 using a two-tailed Fisher's exact test. Focusing on a panel of 51 genes with known relevance to PI3K signaling, we observed that all pre-treatment tumor samples harbored at least one genetic abnormality and that each of the genes was altered in one or several tumor samples. TP53 (59%), APC (25%), KRAS (23%) and PTEN (18%) were the most frequently altered in addition to PIK3CA. Alterations in TP53 and KRAS were identified as statistically significant negative predictors of BYL719 sensitivity (p &amp;lt; 0.05), while mutations in the APC and PTEN genes were associated with a trend towards lack of benefit from treatment with BYL719. Our results suggest that definition of the genetic biomarkers that govern sensitivity to treatment with BYL719 and–most likely–other PI3Kα inhibitors in the clinic is possible upon analysis of patient's tumors by massive parallel sequencing. We also demonstrate that it is feasible to routinely obtain this information in the clinical trial setting. This implies that exploration of the genetic determinants driving sensitivity or primary resistance to targeted agents in general can now be undertaken clinically. Citation Format: Jordi Rodon, Dejan Juric, Ana-Maria Gonzalez-Angulo, Johanna Bendell, Jordan Berlin, Douglas Bootle, Kathlene Gravelin, Alan Huang, Adnan Derti, Joseph Lehar, Jens Würthner, Markus Boehm, Eliezer van Allen, Nikhil Wagle, Levi A. Garraway, Roman Yelensky, Philip J. Stephens, Vincent A. Miller, Robert Schlegel, Cornelia Quadt, José Baselga. Towards defining the genetic framework for clinical response to treatment with BYL719, a PI3Kalpha-specific inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-65. doi:10.1158/1538-7445.AM2013-LB-65