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Ma L, Liu X, Zhang Y, Luo Y. Clinical advances in later-line therapy for metastatic or refractory colorectal cancer. World J Gastroenterol 2027; 33(2): 123996 [DOI: 10.3748/wjg.123996]
World J Gastroenterol. Jan 14, 2027; 33(2): 123996 Published online Jan 14, 2027. doi: 10.3748/wjg.123996
Clinical advances in later-line therapy for metastatic or refractory colorectal cancer
Li Ma, Xia Liu, Ying Zhang, Yong Luo
Li Ma, Xia Liu, Division of Abdominal Tumor, Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
Ying Zhang, Division of Internal Medicine, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
Yong Luo, Cancer Center, West China Hospital, Sichuan University, Chengdu 610065, Sichuan Province, China
Co-first authors: Li Ma and Xia Liu.
Author contributions: Ma L and Liu X contributed equally as co-first authors. Ma L was involved in the collection and organization of the literature and the writing of the article; Liu X contributed to the collection and organization of the literature and the drafting of the tables; Zhang Y undertook the review of the figures and text; Luo Y was responsible for the review and revision of the article and tables. All authors approved the final version to publish.
AI contribution statement: We have thoroughly revised the language expression to improve its readability and academic fluency. It should be clearly stated that no AI-generated writing content was used throughout the entire writing and revision process.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Yong Luo, Cancer Center, West China Hospital, Sichuan University, No. 37 Guo Xue Alley, Chengdu 610065, Sichuan Province, China. luoyong@wchscu.edu.cn
Received: June 5, 2026 Revised: August 10, 2026 Accepted: September 24, 2026 Published online: January 14, 2027 Processing time: 157 Days and 7 Hours
Abstract
Metastatic colorectal cancer still ranks among the leading causes of cancer-related death globally owing to its poor treatment response. For patients with progression after first-line therapy, especially those with microsatellite-stable/proficient mismatch repair tumors or tumors harboring BRAF V600E or KRAS G12C mutations, high-quality evidence for optimal therapies remains scarce. This review summarizes clinical studies from the past 5 years on second-line and subsequent therapies for metastatic colorectal cancer, covering optimized combinations of chemotherapy, targeted therapy, immunotherapy, and radiotherapy, along with evaluations of novel agents. A review of these clinical advances reveals that chemotherapy regimens based on raltitrexed or trifluridine/tipiracil hydrochloride mixture (TAS-102) have demonstrated favorable efficacy in patients with fluoropyrimidine resistance. Antiangiogenic agents, epidermal growth factor receptor/human epidermal growth factor receptor 2/mesenchymal-epithelial transition factor blockade, BRAF inhibitors, and KRAS G12C inhibitors prolong survival. Immunotherapy yields durable responses in microsatellite instability-high/deficient mismatch repair metastatic colorectal cancer, especially with dual immune checkpoint inhibition. Combinations of drugs with different mechanisms of action may treat refractory microsatellite-stable/proficient mismatch repair disease. Novel antibody-drug conjugates and other antitumor agents offer new options for previously treated patients. Limited high-quality evidence hinders optimal regimen selection. Future work should focus on improving individualized therapy and multidisciplinary management.
Core Tip: This narrative review synthesizes the latest literature from PubMed and other databases published in the past 5 years. It mainly analyzes trial design, enrolled populations, and primary endpoints. By reviewing outcomes of combination regimens and phase I/II trials of novel agents, we evaluate the clinical applicability of various later-line therapies for colorectal cancer. Our team emphasizes combination strategies using existing drugs, highlighting that improved efficacy does not solely rely on new drug development.
