Anlotinib versus bevacizumab added to standard first-line chemotherapy among patients with RAS/BRAF wild-type, unresectable metastatic colorectal cancer: A multicenter, prospective, randomised, phase 3 clinical trial (ANCHOR trial).

Abstract

LBA3502 Background: Anti-VEGF antibodies combined with chemotherapy remain first-line treatment for unresectable metastatic colorectal cancer (mCRC), but no randomised trials have evaluated oral VEGFR-TKI plus chemotherapy in this setting. Methods: In this Chinese multicenter, randomised, non-inferiority, phase 3 trial, treatment-naïve RAS/BRAF wild-type mCRC patients with MDT-assessed unresectable metastases were 1:1 randomised to receive anlotinib (12mg, QD, days 1-14) or bevacizumab (7.5mg/kg, IV, day 1), both combined with oxaliplatin (130mg/m², IV, day 1) and capecitabine (anlotinib group:850mg/m2, bevacizumab group 1000mg/m², BID, days 1-14) in 3-week cycles. After 4-8 induction cycles, maintenance therapy with anlotinib or bevacizumab plus capecitabine continued until progression/unacceptable toxicity. Stratification factors were tumor location (right/left) and prior adjuvant chemotherapy (yes/no). Primary endpoint was IRC-assessed PFS (non-inferiority margin HR≤1.09); secondary endpoints included investigator-assessed PFS, ORR, DCR, DoR, OS, liver metastases resection rate, and quality of life. With one-sided α=0.025 and 81.2% of power, 524 PFS events were required. Results: Between May 25th, 2021 to August 30th, 2023, 748 patients were randomly assigned and included in the intention-to-treat population, with 373 in anlotinib group and 375 in bevacizumab group. Patients had a median age of 59.0 years (IQR, 53.0-67.0) and 227 (30.35%) of all 748 patients were female. The median follow-up was 25.10 months (95% CI, 23.82-26.25). The median IRC-assessed PFS in anlotinib and bevacizumab group were 11.04 months (95% CI, 9.82-11.17) and 11.04 months (9.69-11.17), respectively, with HR 1.00 (0.84-1.18). Serious adverse events occurred in 143 (38.34%) of 373 patients in anlotinib group, and in 129 of 375 (34.40%) patients in bevacizumab group. Conclusions: In unresectable RAS/BRAF wild-type mCRC patients, anlotinib plus CapeOX showed comparable PFS time and safety compared with bevacizumab plus CapeOX. The results provide a new treatment option for unresectable RAS/BRAF wild-type mCRC patients. Clinical trial information: NCT04854668 . Anlotinib plus CapeOX (n=373) Bevacizumab plus CapeOX (n=375) HR (95% CI) ORR (95% CI), % 61.93% (56.79-66.88) 62.13% (57.01-67.06) DCR (95% CI), % 92.76% (89.64-95.18) 93.07% (90.01-95.42) Median DoR (95% CI), months 9.66 (8.31-9.99) 9.69 (8.48-11.01) 1.04 (0.84-1.27) Resection rate of liver metastases, % 3.75% 2.93% Grade ≥3 TEAE, n (%) 276 (73.99) 222 (59.20) TEAE leading to treatment discontinuation, n (%) 30 (8.04) 34 (9.07) TEAE leading to death, n (%) 16 (4.29) 17 (4.53)