Background: Liver metastases (LMs) are usually found in gastrointestinal tumors, such as colorectal cancer (mCRC), esophageal squamous cell carcinoma (ESCC) and gastric cancer. Currently, there is no formal option for such patients (pts) due to the different pathological characteristics, and more effective treatment regimens are needed. Anlotinib is an oral multi-targeted tyrosine kinase inhibitor targeting VEGFR1/2/3, FGFR1-4, PDGFRα/β and c-Kit, which effectively blocks tumor neovascularization and growth. Previous phase II clinical trials suggested that anlotinib plus chemotherapy as first-line therapy were well tolerated and showed clinical anti-tumor activity in mCRC and ESCC. It was demonstrated an objective response rate (ORR) of 76.7%, a disease control rate (DCR) of 93.3% and a median progression-free survival (mPFS) of 11.4 months in RAS/BRAF wild-type unresectable mCRC pts using anlotinib plus CAPEOX (ALTER-C002 trial, NCT04080843). Additionally, preliminary encouraging ORR (78.3%), DCR (93.5%) and mPFS (8.38 months) was observed in advanced ESCC pts treated with anlotinib plus cisplatin and paclitaxel (ALTER-E002 trial, NCT04063683). Based on these results, this multicohort, multicenter phase II ALTER-G-001 trial was launched to evaluate efficacy and safety of anlotinib plus chemotherapy as first-line therapy in gastrointestinal tumor pts with unresectable LMs. Methods: Previously untreated and histologically or cytologically confirmed gastrointestinal tumor pts with unresectable LMs were eligible, who will be divided into 3 cohorts, including mCRC (n = 45), ESCC (n = 31) and others (n = 25). Pts must be aged 18-75 years, with an ECOG PS of 0/1, adequate organ function, and at least one measurable LMs lesion according to RECIST v1.1. HER2-positive gastric adenocarcinoma, and pts with a high risk of bleeding, perforation or fistulas will be excluded. During first 6 cycles (3 weeks per cycle) of inducing treatment, mCRC pts will receive anlotinib (12mg, po, qd, d1-d14), oxaliplatin (130 mg/m², iv, d1) and capecitabine (850 mg/m², po, bid, d1-d14). ESCC pts will be treated with anlotinib, cisplatin (60-750 mg/m², i.v., d1/d1-3) along with paclitaxel (135 mg/m², i.v., d1) or docetaxel (75 mg/m², i.v., d1). And pts in others cohort will receive anlotinib plus standard first-line chemotherapy. Then, pts without PD and LMs resection, will receive anlotinib and metronomic capecitabine (500mg, po. bid, d1-21, q3w) until PD or unacceptable toxicity. Primary endpoint is investigator-assessed ORR (RECIST 1.1). Secondary endpoints include duration of response (DoR), PFS, overall survival, DCR, radical resection rate for LMs and safety (NCI-CTCAE v5.0). Research sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Clinical trial information: ChiCTR2100050872.