Abstract LB-214: FASN inhibitor TVB-2640 shows pharmacodynamic effect and evidence of clinical activity in KRAS-mutant NSCLC patients in a phase I study
Authors: O’Farrell Marie , Heuer Tim , Grimmer Katharine , Crowley Richard , Waszczuk Joanna , Fridlib Marina , Ventura Richard , Rubio Claudia , Lai Julie , Buckley Doug , McCulloch William , Kemble George 
Published: July 2016

TVB-2640 is an oral, first-in-class, selective and reversible inhibitor of fatty acid synthase (FASN) in Phase 1 testing in solid tumor patients (study 3V2640-CLIN-002).

FASN is a central mediator of neoplastic lipogenesis and uniquely catalyzes the production of palmitate, a key signaling molecule and the building block for long chain fatty acids. Tumor cells frequently increase FASN expression compared to normal cells to support an increased dependence on de novo lipogenesis to produce palmitate, phospholipids, lipid second messengers, membranes and lipid rafts for oncogenic signaling. High FASN correlates with poor prognosis in several tumor types including NSCLC. Palmitoylation, the reversible attachment of palmitate to proteins regulates membrane interactions and dynamically alters protein trafficking and function. RAS proteins require palmitoylation for plasma membrane localization and signaling, and KRAS4A mutated at G12 specifically requires palmitoylation for oncogenic activity. FASN inhibitors may therefore provide a novel approach to target KRAS which to date has eluded many drug development approaches.

In vitro viability assays showed that KRAS mutant NSCLC cell lines show greater sensitivity to FASN inhibitors than KRAS WT. Furthermore gene expression analysis of TCGA NSCLC tumors and PDX models showed that KRAS mutant cases are associated with a higher incidence of lipogenic features than KRAS WT.

The ongoing Phase 1 study includes 2 NSCLC expansion cohorts; TVB-2640 as monotherapy or in combination with paclitaxel. Several biomarker approaches are ongoing to investigate pharmacodynamic activity and patient enrichment strategies. Metabolomic profiling of serum from 12 NSCLC patients showed increased serum malonyl carnitine and decreased palmitate- derived lipids after 8 or 15 days of TVB-2640 treatment. These changes are consistent with FASN inhibition, and also observed in preclinical models. A novel non-invasive approach using Sebutape patches to collect forehead sebum showed inhibition of de novo lipogenesis in 7/7 patients including 2 NSCLC. Decreases in wax esters, saturated and monounsaturated triglycerides were observed, indicating that these lipids are not restored by diet.

To date, 16 NSCLC patients are considered evaluable for clinical activity; 6 have KRAS mutant tumors, 2 have wild type KRAS and 8 are unknown. Of the 6 known KRAS mutant patients, 3 are in the monotherapy cohort and all 3 have stable disease for 20, &gt;25 and &gt;37 weeks respectively. The remaining 3 KRAS mutant patients are on combination therapy; one achieved a partial response and remains on therapy (&gt;22 weeks), 1 had stable disease (24 weeks), and 1 progressed.

This study shows that TVB-2640 1) inhibits palmitate production and lipogenesis, and 2) shows evidence of clinical activity in KRAS mutant NSCLC patients. Additional biomarker and clinical analyses are ongoing in NSCLC and other tumor types.

Citation Format: Marie O’Farrell, Tim Heuer, Katharine Grimmer, Richard Crowley, Joanna Waszczuk, Marina Fridlib, Richard Ventura, Claudia Rubio, Julie Lai, Doug Buckley, William McCulloch, George Kemble. FASN inhibitor TVB-2640 shows pharmacodynamic effect and evidence of clinical activity in KRAS-mutant NSCLC patients in a phase I study. [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 LB-214.