Background: The first-line treatments in metastatic colorectal cancer were FOLFOX, CAPOX, FOLFIRI and even FOLFOXIRI as basic chemotherapy regimen combined with targeted therapy. XELIRI regimen was not recommended because of the concerns about the toxicity, efficacy and controversy in optimal dosage. An increasing number of studies indicated promising efficacy with manageable safety profile of dosage and administration-adjusted XELIRI regimen. Therefore, the present study investigated the efficacy, safety and appropriate dosage of mXELIRI regimen in the first-line treatment of advanced colorectal cancer. Methods: The EXIST study was a multicenter, randomized controlled, non-inferiority study and we performed stratification based on the tumor location (left or right side). In the mXELIRI+Bev group, patients received intravenous infusion of irinotecan (a reduced dosage,150mg/m²) with bevacizumab (5mg/kg) on day 1 and oral administration of capecitabine (2000mg/m²/day) tablet on day 1-10/Q14 days. Patients in FOLFIRI+Bev group received intravenous infusion of irinotecan (180mg/m²), calcium folinate (400mg/m²) and 5-Fu (400mg/m²) bolus with bevacizumab (5mg/kg) on day 1 followed by a 46-hour continuous infusion of 5-Fu (2400mg/m²)/Q14 days. The primary endpoint was progression-free survival rate at 12 month(PFSR_12m) and the secondary endpoints included ORR,OS and safety. Results: 142 patients were enrolled and randomly assigned to receive mXELIRI+Bev (n=76) or FOLIRI+Bev (n=66) in our center between May 2018 and April 2021. Baseline characteristics were well balanced between two groups. In the mXELIRI+Bev group, 70 patients were evaluable with an ORR of 60.0% (1 complete response, CR; 41 partial response, PR; 24 stable disease, SD; 4 progression disease PD). While 57 patients were evaluable in the FOLFIRI+Bev group, with an ORR of 63.2% (36 PR; 15 SD; 6 PD). The PFSR_12m for two groups were 32.3% and 21.3%, the median PFS were 9.72 months and 8.77 months, respectively. For safety profiles, no statistical differences were observed in adverse events, such as nausea, vomiting, diarrhea, bone marrow suppression and abnormal liver function. While 10 serious adverse events were recorded in the mXELIRI+Bev group, including intestinal obstruction occurred in 8 patients, intestinal perforation occurred in 1 patients and venous thrombosis occurred in 1 patient. In the FOLIRI+Bev group, intestinal obstruction, venous thrombosis and pulmonary thrombosis was reported in one patient respectively. Conclusions: The modified biweekly XELIRI plus bevacizumab regimen demonstrated promising effect and could be well tolerated based on the data from a single center. Clinical trial information: NCT04247984.