A Review of the Treatment Options in Third-Line mCRC and Therapy Sequencing Strategies

The management of treatment-refractory metastatic colorectal cancer (mCRC) has evolved with 3 distinct therapeutic options, each offering modest but meaningful survival benefits. Rather than focusing on traditional “line of therapy” designations, treatment decisions should consider prior drug exposures, including all available cytotoxic therapies and targeted agents like anti-VEGF and anti-EGFR antibodies. The CORRECT trial established regorafenib as the first option in this space, followed by the RECOURSE trial with TAS-102, both showing progression-free survival improvements of approximately 2 months with overall survival benefits under 2 months.

The SUNLIGHT trial demonstrated that combining TAS-102 with bevacizumab improves outcomes compared to TAS-102 alone, making this combination the preferred approach unless bevacizumab is contraindicated. Most recently, the FRESCO-2 trial validated fruquintinib, another VEGF tyrosine kinase inhibitor, in patients who had progressed on both regorafenib and TAS-102. These developments provide multiple sequential options for maintaining disease control, with progression-free survival benefits ranging from 2 to 6 months and overall survival improvements of 2 to 4 months across different agents.

The modest nature of these benefits necessitates careful patient selection and shared decision-making, as quality of life considerations become paramount in this heavily pretreated population. Treatment decisions should balance survival benefits against toxicity profiles, with particular attention to performance status and patient preferences. The availability of multiple options allows for personalized sequencing strategies, though clinical trial participation remains the preferred first choice when available, offering the potential for more substantial therapeutic advances.