Abstract A68: Activity of the TORC 1/2 kinase inhibitor, CC-223, in hormone receptor positive (HR+) breast cancer cell lines and patients (pts) with genetically characterized HR+ breast cancer in a Phase I clinical trial.
Authors: Mita Monica M. , Arkenau Hendrik-Tobias , Bendell Johanna C. , Munster Pamela N. , Mahipal Amit , Delord Jean-Pierre , Paz-Ares Luis G. , Soria Jean-Charles , Xu Shuichan , Tran Tam , Shi Tao , Wu Xiaoling , Chopra Rajesh , Hege Kristen , Varga Andrea 
Published: August 2014

Abstract
Introduction: PIK3CA and PTEN are among the top five most frequently mutated genes in breast cancer. Activating mutation of PIK3CA or loss of function mutation in PTEN leads to constitutive activation of AKT and mTOR driving multiple downstream metabolic and proliferative pathways important to oncogenesis. There is also cross-talk between the PI3K/AKT/mTOR pathway and ER signaling and activation of the PI3K/AKT/mTOR pathway is associated with resistance to endocrine therapy. CC-223 is a potent and selective ATP-competitive mTOR kinase inhibitor, targeting both TORC1 and TORC2 complexes.
Results: Pre-clinically, CC-223 potently inhibits the growth of breast cancer cell lines with GI50 values below 1 uM in 38 of 43 lines. Luminal-derived cell lines are more sensitive to CC-223 than basal-derived lines. Within the luminal subset, ER+, HER2+, PIK3CA mutant, or wild-type TP53 cell lines are more sensitive to CC-223; PTEN loss is not associated with increased CC-223 sensitivity. During the dose escalation part of the phase I clinical trial, 3 pts with breast cancer were enrolled. One pt with HR+/Her2- breast cancer had a durable PR (31 weeks). An expansion cohort of HR+/Her2- breast cancer enrolled 17 pts at a CC-223 dose of 45 mg QD in 28-day cycles and 13 pts were evaluable for tumor response. Deep sequencing of tumors for multiple cancer-related genes was performed. The most common (&gt; 20%) related adverse events (all grades) reported in the breast cancer cohort were nausea, stomatitis, fatigue, anorexia, diarrhea, vomiting, hyperglycemia, rash, and thrombocytopenia. Exposure-dependent TORC1 (p4EBP1) and TORC2 (pAKT) inhibition was observed in blood cells; analysis of paired tumor biopsies is ongoing. Reduction in glucose uptake (&gt; 25% decrease in SUV) on PET imaging at day 15 was observed in 4 of 8 patients with PET imaging data currently available. Three pts demonstrated RECIST PR in target lesions (one categorized as PD due to a new bone lesion); PIK3CA mutations were present in all 3 subjects. Of the two additional pts with PIK3CA mutations, one had SD &gt; 6 months. The one PIK3CA mutated subject with PD at first restaging had a concurrent p53 mutation. Additional genetic abnormalities in mTOR and related pathways in subjects with target lesion PR involved PTEN, Rictor, and IGFR1 genes. Six subjects had SD after 2 cycles, with minor target lesion regression (0 to -30%) in 5 of 6, and with SD &gt; 24 weeks in 1 of 6.
Conclusion: The safety profile of CC-223 is typical for drugs targeting the mTOR pathway. Preclinical and clinical data support the activity of CC-223 in HR+ positive breast cancer, particularly in tumors with PIK3CA mutations.
Breast Cancer Accrual: Cedars-Sinai (Mita): 4; SCRIL (Arkenau): 4; IGR (Varga): 4; SCRI (Bendell): 3 (all Part A); Moffitt (Mahipal): 2; UCSF (Munster): 1; JSOM (Paz-Ares): 1; ICR (DeLord): 1.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A68.
Citation Format: Monica M. Mita, Hendrik-Tobias Arkenau, Johanna C. Bendell, Pamela N. Munster, Amit Mahipal, Jean-Pierre Delord, Luis G. Paz-Ares, Jean-Charles Soria, Shuichan Xu, Tam Tran, Tao Shi, Xiaoling Wu, Rajesh Chopra, Kristen Hege, Andrea Varga. Activity of the TORC 1/2 kinase inhibitor, CC-223, in hormone receptor positive (HR+) breast cancer cell lines and patients (pts) with genetically characterized HR+ breast cancer in a Phase I clinical trial. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A68.