Raf Dimer Inhibitor Lifirafenib Enhances The Antitumor Activity Of Mek Inhibitor Mirdametinib In Ras Mutant Tumors

K-RAS mutation represents one of the most frequent genetic alterations in cancers. Monotherapy approaches targeting RAS downstream effectors such as MEK and ERK have had limited clinical success in patients with K-RAS-mutated cancers. The reduced sensitivity of K-RAS-mutated cells to certain MEK inhibitors is associated with feedback phosphorylation of MEK and reactivation of mitogen-activated protein kinase (MAPK) signaling. Herein, we report that RAF dimer inhibitor lifirafenib (BGB-283) shows strong synergistic effect with MEK inhibitor mirdametinib (PD-0325901) in suppressing proliferation of K-RAS-mutated cancer cell lines. This synergistic effect was not observed using vemurafenib, a first-generation B-RAFV600E selective inhibitor. Mechanistic analysis revealed that RAF dimer inhibition could suppress RAF-dependent MEK reactivation and led to sustained inhibition of MAPK signaling in K-RAS-mutated cells. Furthermore, combination synergy was observed in K-RAS mutant xenograft models. Pharmacodynamic analysis supported the role of synergistic phospho-ERK blockade in enhancing the antitumor activity in the K-RAS mutant models. These findings support the rationale to combine a RAF dimer inhibitor and a MEK inhibitor to treat K-RAS-mutated cancers and led to the ongoing a Phase Ib/II clinical trial of lifirafenib and mirdametinib in patients with K-RAS mutations or other MAPK pathway aberrations (Clinical Trial ID: NCT03905148). Citation Format: Xi Yuan, Xinwen Zhang, Rong Du, Shing-Hu Cheung, Min Wei, Changyou Zhou, Lai Wang, Todd Shearer, Badreddin Edris, Mary Smith, Zhan Yao, Claire N. Thant, Neal Rosen, Lusong Luo. RAF dimer inhibitor lifirafenib enhances the antitumor activity of MEK inhibitor mirdametinib in RAS mutant tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6415.