Two landmark clinical trials have fundamentally transformed the treatment landscape for advanced esophageal squamous cell carcinoma (ESCC), establishing chemo-immunotherapy combinations as the new first-line standard of care. CheckMate 648 and KEYNOTE-590 both demonstrated that adding PD-1 inhibitors to platinum-based chemotherapy produces meaningful improvements in overall survival compared with chemotherapy alone.
CheckMate 648 Results Define Nivolumab Combination Efficacy
In CheckMate 648, the addition of nivolumab to platinum-based chemotherapy produced a meaningful overall survival improvement compared with chemotherapy alone in patients with advanced ESCC. The magnitude of benefit was particularly pronounced in patients whose tumors expressed PD-L1, measured as tumor-cell ≥1%. This biomarker-driven finding reinforced the importance of PD-L1 testing in treatment selection for ESCC patients.
The trial demonstrated that median survival in the nivolumab combination arm approached or exceeded the one-year mark, representing a clinically significant improvement over historical outcomes with chemotherapy alone. Safety findings were consistent with the known profiles of PD-1 inhibitors and cytotoxic therapy, with no unexpected signals observed.
KEYNOTE-590 Validates Pembrolizumab Combination Strategy
KEYNOTE-590 provided complementary evidence for the chemo-immunotherapy approach, demonstrating that pembrolizumab combined with chemotherapy significantly prolonged overall survival versus chemotherapy alone. The study showed particularly strong benefits in patients with PD-L1 CPS ≥1, consistent with the biomarker-driven findings reported in CheckMate 648.
Similar to CheckMate 648, median survival in the pembrolizumab combination arm approached or exceeded one year, reinforcing the clinical impact of these combinations. The safety profile remained manageable and consistent with expectations for PD-1 inhibitor and chemotherapy combinations.
Clinical Practice Implications and Chemotherapy Backbone Considerations
Both global trials typically incorporated cisplatin as the platinum backbone, though oxaliplatin-based regimens are more commonly used in U.S. clinical practice. This difference highlights important considerations for real-world implementation of these combination strategies.
The consistent demonstration of survival benefits across both trials, particularly in PD-L1-expressing tumors, has established chemo-immunotherapy as a key first-line standard in advanced ESCC. The biomarker-driven nature of the greatest benefits underscores the importance of PD-L1 testing in optimizing treatment selection for patients with advanced esophageal squamous cell carcinoma.
