Abstract 4393: RAF/MEK clamp avutometinib combined with a pan-RAF inhibitor induces nearly complete MAPK pathway inhibition with deep tumor regressions in NRAS or BRAF class III mutant models

Abstract Although there are targeted therapies currently approved for cancers with KRAS G12C and BRAF V600E (class I) mutations, there is still significant unmet medical need for patients harboring NRAS or BRAF class II/III alterations which are found in a range of cancers including melanoma and lung cancer. Avutometinib is a first-in-class orally available RAF/MEK clamp that potently inhibits MEK1/2 kinase activities and induces formation of dominant negative RAF/MEK complexes thereby blocking compensatory activation of MEK by RAF. The combination of avutometinib with the focal adhesion kinase (FAK) inhibitor defactinib has shown clinical activity for patients with low-grade serous ovarian cancer and is currently being investigated in a Phase 3 confirmatory study (RAMP 301; NCT06072781). Here, we tested the combination of avutometinib with a pan-RAF inhibitor (pan-RAFi) in cancer models harboring NRAS or BRAF class III mutations. In 3D proliferation assays, avutometinib inhibited cell proliferation across multiple MAPK pathway alterations including NRAS, and BRAF class II and III. Combination strategies of avutometinib with inhibitors of upstream MAPK pathway signaling, including pan-HER, SOS1 and pan-RAF inhibitors, were explored and striking synergy was observed between avutometinib and pan-RAF inhibitors in reducing viability of tumor cells in vitro. In a BRAF class III non-small cell lung cancer patient-derived xenograft (PDX) model (LU3057), the combination of avutometinib with the pan-RAFi exarafenib induced strong tumor regressions in all the mice, whereas avutometinib alone induced tumor stasis. In an NRAS mutant melanoma PDX model (ME9518), the combination of avutometinib and exarafenib showed deep tumor regression, whereas avutometinib or exarafenib single agents did not induce tumor regression. In contrast to the tumor regressions induced by avutometinib plus exarafenib in this ME9518 model, the combination of the MEK-only inhibitor binimetinib with exarafenib caused substantial body weight loss and failed to show tumor regression. Strong tumor regressions in all mice were also observed with the combination of avutometinib and the pan-RAFi belvarafenib in an NRAS mutant xenograft model (SKMEL2). Mechanistically, the deep tumor regressions observed with the combination of avutometinib plus exarafenib corresponded with virtually complete elimination of MAPK pathway markers such as pMEK, DUSP4 and pS6 in the tumors relative to avutometinib or exarafenib alone which conferred less complete inhibition. These results demonstrate that the combination of avutometinib with a pan-RAFi is especially efficacious and is well tolerated, indicating that clinical evaluation of avutometinib in combination with a pan-RAF inhibitor for treatment of patients with NRAS or BRAF class III mutations may be warranted. Citation Format: Silvia Coma, Poulikos I. Poulikakos, Jonathan A. Pachter. RAF/MEK clamp avutometinib combined with a pan-RAF inhibitor induces nearly complete MAPK pathway inhibition with deep tumor regressions in NRAS or BRAF class III mutant models [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 4393.