What is the role of Immune Checkpoint Inhibitors (ICIs) in Esophageal Squamous Cell Carcinoma (ESCC) patients with PD-L1 (Programmed Death-Ligand 1) negative status?

Immune Checkpoint Inhibitors in PD-L1 Negative ESCC: Current Evidence and Combination Strategies

Role of ICIs in PD-L1 Negative ESCC

In PD-L1 negative ESCC patients, ICI-chemotherapy combinations remain the standard first-line approach, as monotherapy ICIs have not demonstrated sufficient efficacy in this population. 1, 2

First-Line Treatment for PD-L1 Negative Patients

• ICI plus chemotherapy combinations show benefit regardless of PD-L1 status in ESCC, with trials demonstrating improved overall survival even in PD-L1 negative subgroups 1, 2
• The CheckMate-648 trial established nivolumab plus chemotherapy (platinum/fluoropyrimidine) as a first-line option for unresectable ESCC, with efficacy observed across PD-L1 expression levels 1
• Tislelizumab plus doublet chemotherapy (RATIONALE-306 trial) demonstrated superiority in overall survival compared to chemotherapy alone, regardless of PD-L1 expression, making it a first-line standard treatment 2
• ICI monotherapy is not recommended for PD-L1 negative ESCC patients in the first-line setting, as response rates are insufficient without chemotherapy backbone 1, 3

Second-Line Treatment Considerations

• Nivolumab monotherapy (ATTRACTION-3 trial) received approval for second-line treatment in ICI-naive ESCC patients, though efficacy is lower in PD-L1 negative populations 1
• For PD-L1 negative patients progressing after first-line chemotherapy, ICI monotherapy may still be considered if they have not received prior immunotherapy, though response rates are modest 1, 3

ICI Combinations Across Different PD-L1 Settings

High PD-L1 Expression (≥50% or ≥10% depending on assay)

• Dual ICI therapy with nivolumab plus ipilimumab demonstrated efficacy in CheckMate-648 for PD-L1 positive ESCC (CPS ≥1), offering a chemotherapy-free option 1
• ICI-chemotherapy combinations remain appropriate even in high PD-L1 expressors, as there is no definitive evidence that monotherapy or dual ICI approaches are superior to combination therapy in ESCC 1, 2
• The choice between dual ICI therapy versus ICI-chemotherapy should consider disease burden, symptom severity, and patient fitness—rapidly progressive disease or high tumor burden favors ICI-chemotherapy combinations 1

Low/Intermediate PD-L1 Expression (1-49%)

• ICI-chemotherapy combinations are the preferred approach for this population, as monotherapy ICIs show insufficient activity 1, 2
• Tislelizumab plus chemotherapy (RATIONALE-306) and nivolumab plus chemotherapy (CheckMate-648) both demonstrated benefit in this PD-L1 range 1, 2
• Dual ICI therapy (nivolumab/ipilimumab) may be considered in select cases with PD-L1 CPS ≥1, though data are less robust than for high expressors 1

PD-L1 Negative (<1%)

• ICI-chemotherapy combinations remain the only evidence-based immunotherapy approach for PD-L1 negative ESCC 1, 2
• Chemotherapy alone without ICI is inferior to combination therapy even in PD-L1 negative patients, based on subgroup analyses from RATIONALE-306 and CheckMate-648 1, 2
• Avoid ICI monotherapy in PD-L1 negative first-line ESCC, as response rates are inadequate (typically <10-15%) 3, 4

Emerging Biomarkers Beyond PD-L1

• Tumor mutation burden (TMB) and microsatellite instability-high (MSI-H) status show correlation with ICI efficacy in ESCC, though not yet validated for routine clinical use 3
• T cell-mediated tumor killing-related gene signatures (TTKPI) are under investigation as predictive biomarkers for immunotherapy response, with low-risk patients showing better outcomes with ICIs 4
• CD8+ T cell infiltration correlates with ICI response, though practical implementation for patient selection remains challenging 4
• PD-L1 expression remains the most clinically validated biomarker, but its absence does not preclude benefit from ICI-chemotherapy combinations 1, 3, 2

Critical Pitfalls and Caveats

• Never initiate ICI monotherapy in PD-L1 negative ESCC patients in the first-line setting—this represents suboptimal care with inferior outcomes 1, 2
• The benefit of ICIs in ESCC is observed across PD-L1 subgroups when combined with chemotherapy, but only 10-15% of patients achieve long-term disease control, emphasizing the need for better predictive markers 3, 4
• Dual ICI therapy (nivolumab/ipilimumab) requires PD-L1 positivity (CPS ≥1) and should not be used in PD-L1 negative patients outside clinical trials 1
• Immune-related adverse events occur in ≤30% of patients receiving anti-PD-1 agents, with grade ≥3 toxicity in ≤20%, requiring vigilant monitoring and early corticosteroid intervention when indicated 5
• Treatment-related mortality ranges from 1.5-5% across ICI trials, necessitating multidisciplinary toxicity management protocols 5