Background: NTRK gene fusion resulting from NTRK1/2/3 genetic alterations occurs in various adult and pediatric cancers, which is one of the most defined driving factors of carcinogenesis. Patients with NTRK fusion positive cancers treated by earlier generation TRK inhibitors achieve rapid and durable responses but can develop on-target resistance. ICP-723 is a highly selective next-generation TRK inhibitor. In preclinical studies, ICP-723 not only markedly inhibits the activity of the wild type TRKA/B/C, but also shows robust activity against resistant mutations, e.g., G595R, F589L or G667C/A/S. A first-in-human clinical study is currently ongoing to evaluate the safety, tolerability, pharmacokinetics (PK) characteristics and efficacy of ICP-723. Methods: This is a multi-center, open-label phase I/II clinical trial, which includes a phase I dose escalation part and a phase II dose expansion part. In the phase I dose escalation, patients with advanced solid tumor, who failed from clinical standard of care or for whom there is currently no effective therapy, will be enrolled. The modified "3+3" method is followed for dose escalation. Results: As of 11Feb2022, a total of 17 patients in phase I dose escalation were treated with ICP-723 at doses of 1 mg QD to 8 mg QD. The median age of the enrolled patients was 54 yrs, (range: 31 to 69 yrs) and ECOG performance status was between 0-1 (58.8% had ECOG PS of 1). Six of 17 patients were confirmed as NTRK gene fusion positive tumors by either prior gene test reports or the central lab gene test. There is no DLT observed in the 6 dose groups. Most AEs were manageable and grade 1-2. The most common TRAEs (> 20%) were asthenia (23.5%), increased ALT (29.7%), increased AST (29.7%) and anemia (29.7%). Gr ≥3 TRAEs were increased ALT (5.9%), increased AST (5.9%), increased CPK (11.8%), neutrophil count decreased (5.9%) and pain (5.9%). The plasma exposure to ICP-723 increased in a dose proportional manner across the observed dosage levels. According to RECIST 1.1 criteria, among the 6 patients with NTRK fusion, the overall response rate (ORR) was 66.7% (4 patients with partial response (PR)), the disease control rate (DCR) was 100%. It is worth noting that one patient with measurable brain metastasis achieved PR with the target brain lesion shrunk from 10 mm to 3 mm. All patients who achieved PR responded to ICP-723 at the first tumor assessment after 4-week treatment and maintained sustained responses to the date of data cutoff. Conclusions: ICP-723 is safe and well-tolerated in patients with advanced solid tumors. Encouraging clinical efficacy including intracranial activity was demonstrated in patients with NTRK gene fusion in various tumor types. Enrollment in phase I is ongoing until the final RP2D is determined, then phase II expansion will be conducted in patients with defined gene alterations. Clinical trial information: NCT04685226.