441TiP A multicenter, randomized, open-label, phase III study of anlotinib plus CAPEOX versus bevacizumab plus CAPEOX as first-line therapy in patients with RAS/BRAF wild-type metastatic colorectal cancer

Abstract

Anlotinib is an oral small molecule tyrosine kinases inhibitor mainly targeting VEGFR 1/2/3, FGFR 1-4, and PDGFR α/β. It has shown potential antitumor activity and manageable safety in patients with RAS/BRAF wild type (WT) metastatic colorectal cancer (mCRC) in a phase II study (NCT04080843) when combined with CAPEOX. This phase III study is designed to compare the efficacy and safety of anlotinib plus CAPEOX with standard first-line treatment in patients with RAS/BRAF WT mCRC. This is a multicenter, randomized, open-label, parallel-controlled, non-inferiority, phase III study. Enrolled patients should have an ECOG PS of 0/1 with confirmed RAS/BRAF WT colorectal adenocarcinoma, and unresectable metastasis assessed by MDT. Patients classified as MSI-H or dMMR or resectable or potentially resectable metastases or with previous systemic therapy for mCRC will be excluded. A total of 698 patients stratified by primary tumor location and prior adjuvant therapy will be randomized in a 1:1 ratio to anlotinib group or bevacizumab group. Patients in both groups will receive 4 to 8 cycles of induction therapy (CAPEOX plus anlotinib or bevacizumab), then maintenance treatment (capecitabine plus anlotinib or bevacizumab) until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) assessed by an independent review committee. Secondary endpoints are investigator-assessed PFS, overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), resection rate of liver metastases, quality of life, and safety. The planned sample size provides 81.2% power to detect a non-inferiority margin of 1.09 in terms of HR for the primary endpoint after 524 events with a one-sided significance level of 0.025. This trial was initiated in May 2021, and enrollment is ongoing. NCT04854668. Chia Tai Tianqing Pharmaceutical Group Co., Ltd.