Background: Mitogen-activated protein kinase (MAPK) pathway is a key regulator of cellular proliferation and survival, it is highly correlated with the occurrence of many cancers, JSI-1187 is a potent and reversible small molecule inhibitor of ERK1/2. This study is designed to assess the safety and efficacy of ERK Inhibitor JSI-1187 for advanced MAPK-mutant tumors patients. Methods: This is a phase 1 study included dose escalation and expansion (NCT06239623). The dose escalation study was conducted using a 3+3 escalation design to assess JSI-1187 16, 24, 32, 48,72, 80 and 96 mg BID, and 80, 128 and 152mg QD, repeated q 28 days. Dose limiting toxicities (DLTs) were predefined in the protocol. MAPK-mutant tumor patients whose disease progressed after existing standard treatment were treated. RAS and BRAF-mutated solid malignant tumors were explored in the dose-escalation phase. Results: As of December 23, 2023, 26 patients were enrolled, including 23 from the BID group and 3 from the 80mg QD group. No DLT was observed in QD group, 1 DLT (1 macular edema) and 2 DLTs (1 macular edema and 1 pneumonia) were observed at 96 and 80 mg BID, respectively. The most common JSI-1187 16-96mg BID related AEs were hypoalbuminemia (69.6%), rash (62.5%), and anemia (43.5%), while the most common JSI-1187 80mg QD related AEs were rash (100%), leukopenia (100%) and neutropenia (66.7%). The most common Grade 3 JSI-1187 16-96mg BID treatment-related AEs were anemia (17.4%) and thrombocytopenia (8.7%). Tumor response was evaluated in 18 of the total 26 patients. SD was noted as best response at doses of 16 – 96 mg BID and 80 mg QD including 29.8% tumor shrinkage in 1 NRAS-mutant melanoma patient treated at 32mg BID and 21.6% tumor shrinkage in 1 MEK1 K57N-mutant lung cancer patient treated at 72mg BID. Conclusions: JSI-1187 monotherapy is well-tolerated in advanced solid tumor patients and demonstrated preliminary antitumor effect. Current evidence supports future exploration of JSI-1187 as monotherapy, and in combination, in patients with MAPK-mutant tumors. Research Sponsor: JS Innopharm Clinical trial information: NCT06239623.