Immunotherapy and Chemotherapy Strategies in Advanced Esophageal Squamous Cell Carcinoma

Advanced esophageal squamous cell carcinoma (ESCC) remains a formidable clinical challenge, with standard platinum-based chemotherapy offering modest survival gains and substantial toxicity. Over the past five years, immunotherapy agents—most notably inhibitors of the programmed death 1 (PD-1) pathway—have been integrated into first- and second-line regimens, reshaping the therapeutic landscape. In first-line settings, combination approaches pairing PD-1 inhibitors with fluoropyrimidine–platinum chemotherapy have demonstrated synergistic antitumour activity, prolonging progression-free survival (PFS) and overall survival (OS) in patients whose tumours express PD-L1 above defined thresholds. In the salvage setting, single-agent PD-1 blockade has achieved durable responses in a subset of patients, including those with low or heterogeneous PD-L1 expression. Beyond immune checkpoint inhibitors, refinements in cytotoxic regimens—optimising dose schedules of cisplatin, 5-fluorouracil and taxanes—have improved tolerability and quality of life. Biomarker-driven patient selection, encompassing PD-L1 scoring, tumour mutational burden and peripheral blood indices such as neutrophil-to-lymphocyte ratio, is emerging as a key determinant of benefit. Together, these advances herald a new era in which tailored immunochemotherapy combinations offer hope for extended survival with manageable safety profiles.

Research from Nature Portfolio

Recent randomised trials have established the efficacy of PD-1 inhibitors in combination with standard chemotherapy as a first-line strategy for PD-L1-positive advanced ESCC. In a large phase 3 study, the addition of an anti-PD-1 antibody to cisplatin and continuous 5-fluorouracil infusion significantly improved both PFS and OS compared with chemotherapy alone, with a tolerable safety profile. Patients with a PD-L1 combined positive score of ≥1 experienced the greatest benefit, underscoring the role of biomarker stratification. In the second-line setting, a phase 2 study compared a PD-1 inhibitor with investigator’s choice chemotherapy in previously treated ESCC and demonstrated a meaningful OS advantage for immunotherapy. Exploratory analyses revealed that high T-cell receptor clonality and low molecular tumour burden index conferred the most prolonged survival, while on-treatment neutrophil-to-lymphocyte ratio further refined prognostic assessment. These studies collectively validate PD-1 blockade as both first- and second-line therapy, linked to specific biomarkers of response.

Immunotherapy and Chemotherapy Strategies in Advanced Esophageal Squamous Cell Carcinoma publication trend

The graph below shows the total number of articles in immunotherapy and chemotherapy strategies in advanced esophageal squamous cell carcinoma across all publications each year (not limited to Nature Index journals).

Technical terms

Immune checkpoint inhibitor: a therapy that blocks inhibitory pathways in T cells (such as PD-1) to enhance antitumour immune responses.

Programmed death 1 (PD-1): a receptor on T cells whose engagement by PD-L1 dampens immune activity; its blockade restores T cell function.

Programmed death ligand 1 (PD-L1) combined positive score (CPS): a composite measure of PD-L1 expression on tumour and immune cells used to predict response to PD-1 blockade.

Progression-free survival (PFS): the interval from treatment initiation to disease progression or death from any cause.

Overall survival (OS): the interval from treatment initiation to death from any cause, reflecting the ultimate clinical benefit.

References

1. First-line serplulimab or placebo plus chemotherapy in PD-L1-positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial. Nature Medicine (2023).
2. Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial. Cancer Cell (2022).
3. Clinical and biomarker analyses of sintilimab versus chemotherapy as second-line therapy for advanced or metastatic esophageal squamous cell carcinoma: a randomized, open-label phase 2 study (ORIENT-2). Nature Communications (2022).
4. First-line nivolumab plus ipilimumab or chemotherapy versus chemotherapy alone in advanced esophageal squamous cell carcinoma: a Japanese subgroup analysis of open-label, phase 3 trial (CheckMate 648/ONO-4538-50). Esophagus (2022).