Abstract 5606: The novel brain-penetrant paradox breaker BRAF inhibitor RG6344 manifests exceptional activity in BRAF mutant colorectal cancers

Abstract Despite the approval of the combination Encorafenib/Cetuximab in metastatic colorectal cancers (CRC) harboring BRAF V600E mutations, the therapeutic benefits offered by this regimen remains limited and short lived. We developed a next generation brain permeable, paradox breaker BRAFi (RG6344, previously identified as Compound Ia in Wichmann et al., Clin Cancer Res 2022) currently undergoing clinical testing (ISRCTN13713551). Here we present its preclinical activity for BRAF mutated CRC. RG6344 proves paradox breaking properties by not triggering MAPK over-activation in BRAF WT contexts at all levels. For in vivo testing regimens covering IC80 (60 mg/kg) and IC95 (140 mg/kg) p-ERK inhibition were used. RG6344 was highly tolerated in all studies as a single agent and in all combination regimens tested clearly highlighting that the lack of paradoxical MAPK activation allows superior target inhibition in vivo. In BRAFi naïve xenograft models (LS411N, HT29) RG6344 as monotherapy outperformed Encorafenib/Cetuximab at all doses tested indicating higher activity of this agent even at doses targeting only IC80 p-ERK inhibition, the same BRAF inhibition levels reached by Encorafenib in CRC approved clinical regimens. RG6344 activity was further strengthened in combination with cetuximab and demonstrated long-lasting responses in PDX models derived from patients that progressed to Encorafenib/Cetuximab therapy supporting the use of RG6344 even in BRAFi experienced patients. Additional combination studies of RG6344 with FOLFOX in BRAFi naive models resulted in tumor regression and dramatic superiority compared to the same combination with Encorafenib. These data collectively provide strong preclinical translational evidence for the potentially transformative activity of RG6344 in BRAF mutated CRC. Citation Format: Florian Renner, Jan Eckmann, Cornelia Handl, Nicole Kratochwil, Jürgen Wichmann, Gabriel Schnetzler, Nino Keshelava, Héctor G. Palmer, Jordi Martinez-Quintanilla, Irene Chicote, Jordi Vergés, Piergiorgio Pettazzoni. The novel brain-penetrant paradox breaker BRAF inhibitor RG6344 manifests exceptional activity in BRAF mutant colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5606.