This activity examines first-line treatment strategies for advanced HER2-negative upper gastrointestinal cancers. Expert commentary highlights the role of biomarker testing, including PD-L1 CPS and CLDN18.2, in guiding therapeutic decisions. Key clinical trial data on anti-PD-1 therapies such as nivolumab, pembrolizumab, and tislelizumab are discussed, along with regimen-specific adverse event profiles. Patient case examples illustrate the application of guideline-based treatment selection utilizing biomarker status in clinical practice.