공고 • Jul 22
Immuneering Corporation Publishes Preclinical Findings on Atebimetinib’S Broad Activity and Tolerability Across Ras- and Raf-Mutant Tumors
Immuneering Corporation announced the publication of new findings in Cancer Research, characterizing the differentiated mechanism and broad preclinical activity of atebimetinib. Atebimetinib showed broad antitumor activity across KRAS-, NRAS-, and BRAF-mutant models, including colorectal, lung, and melanoma, by resisting the RAF-mediated bypass signaling that has constrained other MEK inhibitors. In head-to-head in vivo studies, atebimetinib produced deeper, more durable tumor growth inhibition than the FDA-approved MEK inhibitor binimetinib. Atebimetinib was associated with favorable tolerability in preclinical models, consistent with Deep Cyclic Inhibitor technology's design to decouple antitumor activity from the toxicity of continuous MAPK suppression. In a preclinical cancer cachexia model, atebimetinib-treated animals sustained body weight near baseline through approximately two weeks of dosing, while untreated controls lost a median of more than 20% of body weight. The article reports that atebimetinib demonstrated broad antitumor activity across RAS- and RAF-mutant models while resisting RAF-mediated bypass signaling, a key mechanism associated with resistance to other MEK inhibitors. Because the activity observed spanned a range of KRAS, NRAS, and BRAF alterations, the findings support the potential of atebimetinib to address RAS- and RAF-mutant cancers broadly. The article describes how atebimetinib combines a novel dual-MEK mechanism with a short half-life designed to achieve Deep Cyclic Inhibition (DCI) of the MAPK pathway. Unlike other MEK inhibitors that chronically suppress signaling and are prone to RAF-mediated bypass, atebimetinib was shown to produce profound but transient inhibition of MAPK signaling followed by recovery periods that allow normal tissue to rest between doses – an approach designed to improve tolerability while maintaining antitumor activity. Key findings include: Atebimetinib demonstrated potent inhibition of both pERK and pMEK across multiple KRAS-, NRAS-, and BRAF-mutant tumor models, including colorectal, lung, and melanoma models. Whereas other MEK inhibitors reduced pERK but allowed pMEK to accumulate - the molecular signature of RAF-mediated pathway reactivation - atebimetinib reduced both pERK and pMEK, reflecting its resistance to CRAF-mediated bypass. Atebimetinib's short half-life enabled deep cyclic inhibition of the MAPK pathway, characterized by deep suppression during peak exposure followed by recovery toward physiologic baseline signaling between doses. In multiple head-to-head in vivo studies, atebimetinib demonstrated greater depth and durability of tumor growth inhibition than the FDA-approved MEK inhibitor binimetinib across KRAS-, NRAS-, and BRAF-mutant tumor models while remaining well tolerated. In the Colon-26 model, a syngeneic colon-carcinoma model widely used to study cancer cachexia, atebimetinib-treated animals maintained body weight near baseline (within approximately 5%) through roughly two weeks of dosing, while untreated control animals lost a median of more than 20% of body weight by approximately day 14. Across the in vivo models more broadly, atebimetinib-treated mice maintained body weight within a median of 3-5% over up to four weeks of chronic dosing. Immuneering is currently recruiting patients in MAPKeeper 301 (NCT07562152), a global randomized Phase 3 pivotal trial evaluating atebimetinib plus mGnP versus standard-of-care gemcitabine/nab-paclitaxel in first-line metastatic pancreatic cancer. In the second half of the year, the company expects to dose the first patient in a Phase 2 trial of atebimetinib plus Libtayo (cemiplimab) in patients with first-line RAS-mutant non-small cell lung cancer. Immuneering's lead product candidate, atebimetinib, is an investigational, oral, once-daily Deep Cyclic Inhibitor of MEK, designed to improve survival across many cancer indications. The company is conducting a global randomized pivotal trial, MAPKeeper 301, evaluating atebimetinib in combination with chemotherapy in first-line pancreatic cancer patients. The company's development pipeline also includes additional combination opportunities and preclinical stage programs.