Abstract 1057: Significant efficacy demonstrated with the combination of ulixertinib (ERK1/2 inhibitor) and CDK4/6 inhibitors in MAPK altered models
Authors: Emery Caroline M. , Corgiat Brian , Davis Justin , Sorrell David , Johnson Mitch , Kreider Brent , Knoerzer Deborah 
Published: June 2022

Abstract
Ulixertinib (BVD-523) is a first-in-class small molecule inhibitor of ERK1/2 currently being investigated in several oncology clinical trials, both as a single agent and in combination with other anti-cancer therapeutics. Palbociclib and ribociclib are FDA approved orally active, potent, and highly selective reversible inhibitors of the CDK4 and CDK6 kinases. As it is well established that ERK activation increases cyclin D levels and entry into the cell cycle, we hypothesized that the combination of ERK1/2 and CDK4/6 inhibition would have synergistic antitumor activity and cause tumor regression in vivo.
Initial in vitro work combined ulixertinib with CDK4/6 inhibitors across a small panel of lung cancer cell lines. Cell lines carrying a KRAS mutation were more sensitive to ulixertinib relative to KRAS wild type cell lines based on single agent IC50 values. The single agent IC50 values for the CDK4/6 inhibitors were dependent on whether a metabolic or non-metabolic readout for cell viability was used. The combination interactions across a dose matrix of concentrations were determined by the Loewe Additivity and Bliss Independence models. The results of combining ulixertinib and CDK4/6 inhibitors ranged from additive to potentially synergistic.
The combination of ulixertinib and palbociclib was then assessed against four xenograft models representing colorectal, melanoma, and pancreatic tumor types, each harboring an alteration within a component of the MAPK pathway. Palbociclib monotherapy across all models showed limited tumor growth inhibition (TGI) while ulixertinib monotherapy demonstrated modest TGI across all models. The combination groups demonstrated significant responses ranging from 75% - 90% TGIs. All treatment regimens were well tolerated across all models. Downstream assays were completed including reverse phase protein arrays (RPPA). Using RPPA, treatment effects on protein signaling was evaluated in the MAPK family, cell cycle regulation, and other associated feedback and compensatory pathways. Notably, suppression of protein targets downstream of ERK1/2 were seen with both ulixertinib monotherapy and combination therapy. Similarly, the combination therapy group reduced protein levels involved in cell cycle progression, which was not seen in either monotherapy group alone.
The efficacy demonstrated with this preclinical work has proven to be translatable to the clinic as the combination of ulixertinib and palbociclib recently achieved MTD in a Phase I trial in advanced solid tumors including pancreatic cancer (NCT 03454035).
Citation Format: Caroline M. Emery, Brian Corgiat, Justin Davis, David Sorrell, Mitch Johnson, Brent Kreider, Deborah Knoerzer. Significant efficacy demonstrated with the combination of ulixertinib (ERK1/2 inhibitor) and CDK4/6 inhibitors in MAPK altered models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1057.