Abstract 2672: ERAS-007 is a selective ERK1/2 inhibitor with preclinical activity across RAS/MAPK pathway-driven CRC models

Abstract

Colorectal cancer (CRC) remains an unmet medical need where more than 50% off patients have tumors that are driven by somatic mutations in the RAS/MAPK signaling pathway. Targeted therapies, such as anti-EGFR inhibitors for patients with BRAFwt/RASwt CRC tumors and encorafenib + cetuximab for patients with BRAFV600E CRC tumors, are available treatment options but demonstrate both limited overall response rates and duration of response (Yaeger, 2018). In particular, in the previously treated setting, overall survival is typically less than a year (Grothey, 2013; Mayer, 2015; Kopetz, 2019). In addition, targeted treatment options are limited for patients harboring KRAS or NRAS mutations as emergence of these mutations is a predictive biomarker to anti-EGFR therapy resistance in metastatic CRC. ERAS-007 is a selective ERK1/2 inhibitor targeting the terminal node of the RAS/MAPK signaling pathway. In addition, ERAS-007 demonstrates single digit nanomolar biochemical ERK1/2 inhibition as well as a durable target residence time, thus making it a promising combination partner in RAS/MAPK pathway activated or altered CRC. To this end, ERAS-007 was evaluated in preclinical models in combination with encorafenib + cetuximab in BRAFV600E CRC and with palbociclib in KRASmut CRC. ERAS-007 demonstrated monotherapy activity and combination benefit in cell-based assays as well as superior combination efficacy in vivo relative to respective monotherapy control arms. In summary, ERAS-007 demonstrates promising preclinical activity across a wide range of RAS/MAPK pathway-driven CRC models both as a monotherapy and in combination that support further exploration in the clinic. Accordingly, ERAS-007 combinations with encorafenib + cetuximab in BRAFV600E CRC and with palbociclib in KRASmut CRC are currently being evaluated in the HERKULES-3 phase 1b/2 master protocol (NCT05039177). Citation Format: Erin D. Lew, Joanne Oh, Taylor Congdon, Jingchuan Zhang, Robert F. Shoemaker. ERAS-007 is a selective ERK1/2 inhibitor with preclinical activity across RAS/MAPK pathway-driven CRC 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 2672.

Advances and prospects of drug clinical research in colorectal cancer in 2022

“…At the 2022 American Association For Cancer Research annual meeting, the most noteworthy new drugs in the field of CRC were the ERK1/2 inhibitor ERAS‐007 and the SHP2 inhibitor ERAS‐601 from ERASCA company [ 46 ]. When combined with encorafenib plus cetuximab, ERAS‐007 showed superior antitumor activity in patients with BRAF V600E mutations compared with dual‐target regimens.…”