Abstract 1376: Dosing frequency/PD/efficacy relationship of MEN1611 in HER2 amplified, PIK3CA mutated, and refractory to Trastuzumab xenograft model of breast cancer
Authors: Fiascarelli Alessio , Merlino Giuseppe , Capano Stefania , Bressan Alessandro , Bigioni Mario , Pellacani Andrea , Binaschi Monica , Salerno Massimiliano 
Published: July 2021

The PI3K-AKT-mTOR pathway is one of the most dysregulated pathways in human cancers, with PIK3CA, the gene encoding the p110α catalytic isoform of PI3K, representing the most frequently mutated gene of this network. In breast tumors, PIK3CA mutations occur in about 20% to 40% of HER2-positive and HER2-negative respectively. The lack of driver oncogenic function, hypothesized for PIK3CA mutations, paralleled by the poor clinical benefit showed by monotherapy with PI3K inhibitors in solid tumors, suggests the use of rational combinations with optimized dosing to improve PI3K inhibitor efficacy. Here we investigate the activity of the PI3K α/β selective and δ-sparing inhibitor MEN1611 in once-daily (QD) at 3.2 mg/kg versus twice-daily (BID) dosing at 1.6 mg/kg, both as a single agent and in combination with trastuzumab, to examine the correlation between drug regimen, target effect, and tumor response. The in vivo studies were investigated with the HER2 amplified, PIK3CA mutated (p.C420R), and trastuzumab-resistant JIMT-1 breast cancer cell line. To compare the effect of QD versus BID MEN1611 treatment, we evaluated the magnitude of PI3K signaling at the tumor site, by measuring the levels of pAKT and pS6 at different time points, at the beginning and the end of treatment. Anti-tumor activity was evaluated in terms of tumor volume inhibition (TVI) and by the modified response evaluation criteria in solid tumors (mRECIST). In monotherapy, although QD dosing produced a slightly longer pathway inhibition (10 vs 8 hours) than the BID, the maximum magnitude achieved was comparable. The analysis of anti-tumor efficacy, showed non-significant differences between the two schedules in terms of tumor volume inhibition (52% versus 45% for the QD and the BID respectively), confirming the PD data. In combo, BID administration was able to keep the pathway efficiently downregulated, counteracting a rebound effect observed at the 24 hour time point in the QD group of animals. Moreover, efficacy evaluation showed significant tumor-regression activity in the BID group of animals compared to the QD (79% versus 43% respectively). Although further studies are needed to evaluate time-dependent drug exposure in tumor and plasma samples, these preliminary findings support the BID clinical schedule of MEN1611 in the B-PRECISE-01 clinical trial (NCT03767335).

Citation Format: Alessio Fiascarelli, Giuseppe Merlino, Stefania Capano, Alessandro Bressan, Mario Bigioni, Andrea Pellacani, Monica Binaschi, Massimiliano Salerno. Dosing frequency/PD/efficacy relationship of MEN1611 in HER2 amplified, PIK3CA mutated, and refractory to Trastuzumab xenograft model of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1376.