A new phase II clinical trial has demonstrated promising efficacy of sequential immunotherapy following chemoradiotherapy in patients with advanced esophageal cancer, potentially establishing a new treatment paradigm for this challenging disease.
The EPOC1802 TENERGY trial evaluated atezolizumab immunotherapy administered after definitive chemoradiotherapy in patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC). The study enrolled 40 patients in the primary cohort between December 2018 and March 2021.
Key Clinical Outcomes
The trial met its primary endpoint with a complete clinical response rate of 42.1% (90% confidence interval: 28.5-56.7%). At a median follow-up of 12.5 months, the median overall survival was 31.0 months with a one-year overall survival rate of 65.8%. The median progression-free survival was 3.2 months with a 12-month rate of 29.6%.
The safety profile proved manageable, with only 5% of patients experiencing grade 3 or higher pneumonitis. No treatment-related deaths were observed during the study period.
Scientific Rationale and Mechanism
Detailed molecular analyses revealed that chemoradiotherapy enhanced antitumor immune responses through multiple mechanisms:
- Activation of DNA/RNA sensing pathways
- Increased interferon responses
- Enhanced antigen presentation
- Recruitment and activation of effector T cells
- Upregulation of PD-L1 expression
These findings provided strong scientific rationale for the sequential combination with PD-L1 blockade using atezolizumab.
Biomarker Analysis
The study identified several potential biomarkers of treatment response:
- High levels of PD-1-expressing CD8+ T cells
- Low infiltration of regulatory T cells
- Expression patterns of specific genes related to epithelial-mesenchymal transition
Conversely, certain factors were associated with treatment resistance:
- Driver gene mutations (EGFR, PIK3CA, PTEN, KEAP1)
- MYC amplification
- High expression of MMP1 and MMP13
Clinical Implications
This trial represents a significant advance in the treatment of unresectable locally advanced ESCC. The sequential combination approach demonstrated both safety and efficacy, with promising complete response and survival rates in a difficult-to-treat patient population.
The study's comprehensive translational analysis provides valuable insights into resistance mechanisms and potential biomarkers that could help optimize patient selection in future trials.
Future Directions
While these results are promising, the researchers acknowledge the need for validation in larger randomized trials. The ongoing phase III SKYSCRAPER-07 trial will further evaluate this approach and potentially confirm the survival benefits of anti-PD-L1 therapy following chemoradiotherapy.
The identification of resistance mechanisms, including the role of IL-1β and regulatory T cells, suggests potential strategies for improving outcomes through combination approaches targeting these pathways.
