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Ref Type Abstract
PMID
Authors Anna Travesa; Mai Johnson; Peter King; Praveen Nair; Jason Funt; Sarah Kolitz; Kevin D Fowler; John Brothers II; Amy Axel; Scott Barrett; Benjamin J Zeskind; Brett Hall
Title Abstract A093: 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
URL https://aacrjournals.org/mct/article/22/12_Supplement/A093/730686
Abstract Text Introduction: A significant proportion of cancer patients have tumors addicted to uncontrolled MAPK signaling. Activating mutations in RAS or RAF are often directly responsible and have been observed in over 20% of human tumors1. Because MEK is downstream of RAS and RAF, it is an appealing drug target. However, MEK inhibitors have historically suffered from poor clinical durability, high toxicity and a susceptibility to pathway reactivation that has limited monotherapy activity in the RAS mutant setting. Unlike other MEK inhibitors, IMM-1-104 [NCT05585320] and IMM-6-415 are designed with distinctive features including both (1.) a unique target engagement mechanism that helps resist MAPK pathway reactivation and (2.) a pharmacokinetic (PK) profile that enables fast cadence deep cyclic inhibition (DCI). DCI drives pulsatile targeted inhibition that deprives tumor cells of a critical oncogenic pathway while limiting drug-related toxicities by affording normal cells an adequate PK recovery window between drug doses. To our knowledge, IMM-6-415’s preclinical activity is driven by the shortest drug plasma half-life (0.3-hours in mice) of any MEK inhibitor developed to date. Experimental Procedures: IMM-6-415 has already demonstrated promising activity in RAS-mutant xenograft tumor models (SITC 2022). Here, the antitumor activity of IMM-6-415 was evaluated in over 60 humanized 3D tumor growth assays (3D-TGA), which included 30 BRAF class I-mutant tumor models. Additionally, multiple 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 BRAFV600E melanoma and colorectal subcutaneous tumor xenograft models in female BALB/c nude mice. Summary of New Data: As monotherapy, IMM-6-415 demonstrated antitumor 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. Therefore, we further explored both monotherapy and combination activity of IMM-6-415 in the A-375 (melanoma) and HT-29 (colorectal) BRAF V600E tumor xenograft models. Monotherapy treatment with encorafenib or IMM-6-415 displayed superior tumor growth inhibition (TGI) when compared to binimetinib. Furthermore, the combination of IMM-6-415 plus encorafenib prompted greater TGI with superior durability of response when tested head-to-head against the combination of binimetinib plus encorafenib in vivo at human equivalent doses for registered drugs. Conclusions: IMM-6-415 demonstrated promising activity and tolerability in preclinical models alone and in combination with encorafenib. In combination with encorafenib, IMM-6-415 achieved a greater TGI in vivo than the combination of encorafenib plus binimetinib in BRAFV600E colorectal cancer and melanoma tumor models, suggesting an opportunity for IMM-6-415 as monotherapy or in combination in BRAF mutant tumors.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
IMM-6-415 IMM-6-415 2 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
IMM-6-415 IMM6415|IMM 6415|IMM-6415 MEK inhibitor (Pan) 26 IMM-6-415 is a MEK inhibitor, which potentially reduces tumor growth (Mol Cancer Ther (2023) 22 (12_Supplement): A093).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E colorectal cancer predicted - sensitive Encorafenib + IMM-6-415 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with the combination of Braftovi (encorafenib) and IMM-6-415 resulted in increased tumor growth inhibition compared to the combination of Mektovi (binimetinib) and Braftovi (encorafenib) in a cell line xenograft model of colorectal cancer harboring BRAF V600E (Mol Cancer Ther (2023) 22 (12_Supplement): A093). detail...
BRAF V600E colorectal cancer predicted - sensitive IMM-6-415 Preclinical - Cell line xenograft Actionable In a preclinical study, IMM-6-415 treatment inhibited tumor growth in a cell line xenograft model of colorectal cancer harboring BRAF V600E (Mol Cancer Ther (2023) 22 (12_Supplement): A093). detail...
BRAF V600E melanoma predicted - sensitive Encorafenib + IMM-6-415 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with the combination of Braftovi (encorafenib) and IMM-6-415 resulted in increased tumor growth inhibition compared to the combination of Mektovi (binimetinib) and Braftovi (encorafenib) in a cell line xenograft model of melanoma harboring BRAF V600E (Mol Cancer Ther (2023) 22 (12_Supplement): A093). detail...
BRAF V600E melanoma predicted - sensitive IMM-6-415 Preclinical - Cell line xenograft Actionable In a preclinical study, IMM-6-415 treatment inhibited tumor growth in a cell line xenograft model of melanoma harboring BRAF V600E (Mol Cancer Ther (2023) 22 (12_Supplement): A093). detail...