Deep Cyclic Inhibition of the MAPK pathway with IMM-6-415, alone and in combination with encorafenib, demonstrates anti-tumor activity and tolerability in RAF mutant tumors in vivo

• A nti – tumor activity of IMM-6-415 was evaluated in more than 60 humanized 3D-TGA models , which included 30 BRAF class I-mutant tumor models. M ultiple drug-drug combinations have been explored, including vertical drug combinations with BRAF inhibitors.

• IMM-6-415, binimetinib and encorafenib were tested head-to-head as single agents and in combination with encorafenib in BRAF V600E melanoma and colorectal subcutaneous tumor xenograft models in female BALB/c nude mice.

• As monotherapy, IMM-6-415 demonstrated anti – tumor activity in over 50% (34 of 66) of the 3D-TGA models tested, including 30 BRAF mutant preclinical models in which 19 (63%) showed activity. Similar to IMM-1-104, resistant models either lacked an obvious MAPK pathway driver mutation or displayed parallel oncogenic activation events. S ensitive and intermediate responses were also strongly enriched for models harboring an activation mutation in RAS or RAF .

• Monotherapy treatment with encorafenib or IMM-6-415 displayed superior TGI when compared to binimetinib in the A-375 (melanoma) and HT-29 (colorectal) BRAF V600E tumor models .

• In combination with encorafenib , IMM – 6 – 415 achieved a greater TGI in vivo than the combination of encorafenib plus binimetinib in BRAF V600E colorectal cancer and melanoma tumor models, suggesting an opportunity for IMM-6-415 as monotherapy or in combination regimens for the treatment of BRAF mutant tumors.