Bevacizumab Plus Chemotherapy versus Chemotherapy Alone As First-Line Treatment for Patients with <i>RAS</i> Mutant Unresectable Colorectal Liver-Limited Metastases: The BECOME Single Center Randomized Control Trial

Background: To assess the effects of bevacizumab plus chemotherapy as first-line treatment for RAS mutant unresectable colorectal liver metastases (CLMs). Methods: From October 2013 to December 2017, patients with RAS mutant unresectable liver-limited metastases from colorectal cancer were randomly assigned to receive mFOLFOX6 (modified fluorouracil, leucovorin,and oxaliplatin) plus bevacizumab (arm A) or mFOLFOX6 alone (arm B). The resectability of liver metastases was determined by a local multidisciplinary team. The primary end point was the rate of patients converted to resection for liver metastases. Secondary end points included tumor response, survival and toxicity. Block randomization method was used. Result: The intent-to-treat population comprised 241 patients. 121 patients were randomly assigned to arm A and 120 to arm B. For all patients, 35.7% (86/241) had right-sided colon cancer; 47.3% (114/241) had primary tumor resection before randomization; 86.3% (208/241) had liver metastases more than three; 33.2 (80/241) with the largest diameter of liver metastases more than 5 cm; 78.4% (189/241) were bilobar metastases. The median follow-up time was 37.0 months for all patients. The R0 resection rates for LMs were 22.3% (27 of 121 patients) in arm A and 5.8% (7 of 120 patients) in arm B, with significant difference (P < 0.01). Patients in arm A had significantly better objective response rates (54.5% v 36.7%; P < 0.01), median PFS (9.5 v 5.6 months; P < 0.01) and median OS (25.7 v 20.5 months; P =0.03) compared with those in arm B. Addition of bevacizumab was associated with more frequent proteinuria (9.9% v 3.3%; P = 0.04) and hypertension (8.3% v 2.5%; P < 0.05). Conclusion: For patients with initially unresectable RAS mutant CLMs, bevacizumab combined with chemotherapy improved the resectability of liver metastases and improved response rates and survival compared with chemotherapy alone. Trial Registration: This study was registered on ClinicalTrials.gov (NCT01972490). Funding Statement: This work was supported by grants from National Natural Science Foundation of China (8147222); Clinical science and technology innovation project of Shanghai (SHDC12016104); Shanghai Science and Technology Committee Project (17411951300); The National Key Research and Development Program of China (2017YFC0908205). Declaration of Interests: The author(s) indicated no potential conflicts of interest. Ethics Approval Statement: The protocol was approved by the local ethic committees.