The importance of next-generation sequencing (NGS) and biomarker testing in treatment planning. An overview of second-line treatment options such as Tas-102 with Bevacizumab, Regorafenib, and Fruquintinib, along with their respective clinical trial data. Insights into side effect management and quality of life considerations for patients undergoing palliative treatment. A discussion on the recent STELLAR-303 study and its implications for immunotherapy in colorectal cancer.