Background: KC1036 is a novel and selective multi-kinase inhibitor that targets cell proliferation, angiogenesis, metastasis and drug resistance by inhibiting receptor tyrosine kinases (AXLs and VEGFRs) involved in the tumor microenvironment. KC1036 has demonstrated anti-tumor activity in preclinical models of solid tumors, including non-small cell lung cancer (NSCLC). Methods: This phase I, first-in-human study of KC1036 (NCT04387916) enrolled adult patients (pts) with advanced or metastatic solid tumors. This study was comprised of dose escalation (Part A: With the accelerated titration of the 10 mg QD, in which only one patient was enrolled, a standard 3+3 design was applied for 20, 40, 60, and 80 mg QD) followed by dose expansion (Part B) and recommended phase II dose (RP2D) expansion (Part C). The primary safety endpoints were to determine dose limiting toxicities (DLTs) and RP2D. Secondary endpoints included pharmacokinetics (PK) and preliminary efficacy evaluated per RECIST v1.1 criterion. Results: As of November 30, 2022, a total of 41 pts had received at least 1 dose of KC1036 orally with 13 pts in Part A (10 mg [n = 1], 20 mg [n = 3], 40 mg [n = 3], 60 mg [n = 4], 80 mg [n = 3]) and 28 pts in Part B (60 mg [n = 21], 80 mg [n = 7]). In Part A, no DLTs were observed, and the maximum tolerated dose (MTD) has not been reached. Consequently, 60 mg and 80 mg were recommended for Part B. Pts most commonly had NSCLC (31.7%, 13/41), esophageal cancer (14.6%, 6/41), colorectal cancer (12.1%, 5/41). All pts were heavily pre-treated with 65% (27/41) receiving three or more lines of therapy, and average targeted tumor size was 58.7 mm with the largest 162 mm. Of the 41 pts, the median duration of KC1036 exposure was 105.0 days (range, 51.0-168.0). Any-grade TRAEs occurred in 39 pts (95.1%), with 16 pts (39.0%) reported with ≥ Grade 3. The most commonly reported ≥ Grade 3 TRAEs at 60 mg was hypertension (16.7%, 4/24), and that at 80 mg was diarrhea (30.0%, 3/10). PK analysis showed that KC1036 exhibited with dose-proportional increases in exposure over the range of 10 to 40 mg, but increased less proportionally within the range of 40-80 mg. Of 36 pts who had at least one efficacy evaluation, 5 (13.9%) had a best response of partial response (PR) and 24 (66.7%) had stable disease (SD). Thus, ORR was 13.9% (95% CI: 4.7, 29.5) and DCR was 80.6% (95% CI: 64.0, 91.2). Among the 9 evaluable pts with lung adenocarcinoma (6 on 60 mg and 3 on 80 mg), 2 pts had PR, 5 had SD and 2 had progressive disease (PD) as best response. Sustainable PR for 42 weeks was observed in 1 patient with lung adenocarcinoma on 60 mg. Conclusions: KC1036 demonstrated a manageable safety profile and preliminary antitumor activity in pts with advanced solid tumors. Taking safety, efficacy and clinical PK into consideration, 60 mg QD was recommended as RP2D for Part C, and this part was ongoing. Further studies in pts with lung adenocarcinoma would be considered promising. Clinical trial information: NCT04387916.