Background: Irinotecan and fluorouracil are the most effective drugs in the treatment of metastatic colorectal cancer (mCRC). But XELIRI (irinotecan plus capecitabine) has not been recommended in the 1^st-L setting due to the toxicity in the Western countries. While, modified 3-weekly XELIRI has been proved to be effective and safe in the 2^nd-L therapy in Asian mCRC patients. Therefore, this study aimed to assess the efficacy and safety of biweekly mXELIRI with reduced dose of irinotecan in the 1^st-L treatment of mCRC. Methods: This was a randomized, open-label, non-inferiority study undertaken at 11 hospitals in China. Eligible patients were aged ≥18 years with unresectable metastatic histologically diagnosed colorectal adenocarcinoma; had an ECOG of 0 or 1 and at least one measurable disease according to the RECIST v 1.1 without any systemic chemotherapy for metastatic disease. Patients were randomly assigned (1:1) stratified by the location of primary tumor (left or right site) to receive 9 cycles of mXELIRI + bevacizumab (Bev) (irinotecan 150mg/m² D1, capecitabine 1000mg/m² bid D1-10, Bev 5mg/kg D1, Q2W) or FOLFIRI + Bev (irinotecan 180mg/m² D1, CF 400mg/m² D1, 5-Fu 400mg/m² bolus D1, 5-Fu 2400mg/m² civ 46h D1, Bev 5mg/kg D1, Q2W) followed by maintenance treatments with capecitabine + Bev or 5-FU + CF + Bev. The primary endpoint was 12-month progression-free survival (PFS) rate. The secondary endpoints included objective response rate (ORR), PFS, overall survival (OS) and safety. Results: From May, 2018 to Apr, 2021, 264 pts were randomized (mXELIRI + Bev 132; FOLFIRI + Bev 132). The median age was 61 (29-80) years old. 62.5% of the patients were men. With a median follow-up of 17.1 months, the 12-month PFS rates were 43.9% vs. 28.8% in the mXELIRI + Bev and FOLFIRI + Bev groups, respectively. The HR was 0.72 (95%CI 0.51 -1.02) which didn’t cross the predefined non-inferiority margin of 1.18 (upper bound < 1.18). The median PFS were 10.5 months vs. 9.6 months (p = 0.056, HR 0.74, 95%CI 0.55-1.01). The median OS was still not mature. The ORR were 51.5% vs. 47.0% (p = 0.460), respectively. The incidence of treatment related adverse events (TRAEs) between these two groups were similar. The most common TRAEs were neutropenia (mXELIRI + Bev vs. FOLFIRI + Bev: 51.8% vs. 57.0%), leukopenia (43.9% vs. 55.3%), anemia (54.4% vs. 45.6%), nausea (31.6% vs. 40.4%), ALT/AST increased (22.8% vs. 23.7%), diarrhea (21.1% vs. 16.7%), fatigue (20.2% vs. 23.7%), vomiting (17.5% vs. 20.2%) and hyperbilirubinemia (14.9% vs. 17.5%). No treatment- related deaths were reported. Conclusions: Biweekly mXELIRI with reduced dose of irinotecan plus bevacizumab was noninferior to the standard dose of FOLFIRI + Bev in PFS, with similar safety profile in the patients with untreated mCRC. Clinical trial number: NCT04247984. Research Sponsor: No Clinical trial information: NCT04247984.