C4 Therapeutics, Inc. presented new pre-clinical data on CFT8919, a novel mutant-selective degrader of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) at the Keystone Symposium on Targeted Protein Degradation. The poster presentation shares pre-clinical data that suggests CFT8919 may be active as a single agent in patients with resistance to EGFR inhibitors due to secondary mutations in EGFR, including T790M and C797S, as well as in the front-line setting with the potential to avoid the emergence of resistance-causing secondary EGFR mutations seen with currently approved EGFR inhibitors. Summary of CFT8919 Pre-clinical Results: C4T conducted in vitro and in vivo studies that show CFT8919 is a potent and highly selective orally bioavailable degrader of EGFR L858R with broad coverage of on-target resistance mutations as well as intracranial activity. Notable observations include: In cancer cell lines, CFT8919 induces degradation of EGFR L858R at low nanomolar concentrations while no degradation of wild type is induced up to 10 µM. CFT8919 demonstrates equipotent activity against EGFR mutations resistant to EGFR inhibition, including L858R-C797S, L858R-T790M, and L858R-T790M-C797S compared to L858R single mutation in Ba/F3 cell models in vitro. Kinome profiling and global proteomic evaluation did not identify any significant off-target activity of CFT8919. CFT8919 does not induce degradation of known cereblon neo-substrates SALL4 or GSPT1, indicating that the potential associated toxicities will not be liabilities. Additionally, in vivo data demonstrates the following: CFT8919 degrades and inhibits mutant EGFR in tumors upon oral administration. In the NCI-H1975 EGFR-L858R-T790M xenograft model, after a single oral dose of CFT8919, up to 85% of mutant EGFR was degraded in tumors accompanied with near-complete inhibition of phospho-EGFR. In this model, twice-daily oral administration of CFT8919 showed dose-dependent anti-tumor activity and regressions comparable to osimertinib. In BaF3 allograft model expressing EGFR-L858R-T790M-C797S, CFT8919 demonstrates anti-tumor activity resulting in tumor regression, while osimertinib is inactive. CFT8919 demonstrates rapid and significant reductions in tumor burden in the H1975-LUC (EGFR L858R-T790M) brain metastasis model after oral dosing, indicating its potential to be active in the central nervous system. This promising pre-clinical data supports the Company’s decision to advance CFT8919 into investigational new drug (IND)-enabling studies this year. C4T anticipates filing an IND for CFT8919 by mid-2022, with the goal to initiate a Phase 1 clinical trial by year-end 2022.