First-line anlotinib versus bevacizumab plus CapeOX in RAS/BRAF wild-type unresectable metastatic colorectal cancer (ANCHOR): a multicenter, prospective, randomized, phase 3 trial.

Bevacizumab plus chemotherapy is the standard first-line therapy for metastatic colorectal cancer (mCRC). To date, no phase 3 trial has compared first-line oral multitargeted TKI versus bevacizumab plus chemotherapy in RAS/BRAF wild-type mCRC. The open-label, noninferiority, randomized, phase 3 trial (ANCHOR; NCT04854668; CTR20210940) evaluated first-line anlotinib versus bevacizumab plus oxaliplatin and capecitabine (CapeOX) in this setting. Patients were centrally randomized (1:1) to receive 4-8 cycles of CapeOX in combination with either anlotinib (12 mg once daily on days 1-14) or bevacizumab (7.5 mg/kg on day 1) every 3 weeks, followed by maintenance therapy with anlotinib or bevacizumab plus capecitabine until unacceptable toxicity or disease progression. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee in the intention-to-treat population. The hazard ratio (HR) for the noninferiority margin was 1.09. Between May 25, 2021, and August 30, 2023, 373 patients were assigned to the anlotinib group and 375 to the bevacizumab group. As of February 2, 2025, the median follow-up was 25.1 months (95% confidence interval [CI] 23.8-26.3). The median PFS was 11.0 months (95% CI 9.8-11.2) in the anlotinib group versus 11.0 months (9.7-11.2) in the bevacizumab group (stratified HR, 1.00; 95% CI 0.84-1.18; p = 0.87). The incidences of grade ≥3 treatment-related adverse events were 64.9% and 44.8%, respectively. Compared with bevacizumab plus CapeOX, anlotinib plus CapeOX showed similar antitumor activity but failed to reach the prespecified noninferiority margin for PFS and was associated with increased manageable toxicity.