M4205 (IDRX-42) is a highly selective and potent inhibitor of relevant oncogenic driver and resistance variants of KIT in cancer.

Abstract

Primary activating mutations in KIT (exons 9/11) are key driver alterations in about 80% of gastrointestinal stromal tumors (GIST). Imatinib, a small molecule tyrosine kinase inhibitor, is used successfully as first-line therapy for unresectable metastatic or recurrent GIST patients, but secondary resistance mutations in the KIT kinase domains frequently occur. Currently approved later-line therapies target these mutations incompletely with limited clinical benefit. M4205, a kinome-selective KIT inhibitor, was designed to address this high unmet medical need by inhibiting all relevant KIT driver and resistance mutations. Compared to imatinib, M4205 shows stronger antitumor activity in preclinical GIST models driven by oncogenic KIT driver mutations. M4205 demonstrates clinically relevant efficacy in a range of preclinical GIST models expressing different secondary KIT resistance mutations. The kinase selectivity profile of M4205 is superior to registered standard of care and investigational agents. M4205, now IDRX-42, is currently being investigated in a Phase 1 first-in-human study in participants with GIST.