Adding Immunotherapy to Chemoradiotherapy Improves Complete Response Rates in Esophageal Squamous Cell Cancer

For esophageal squamous cell carcinoma (ESCC), combining preoperative immunotherapy with chemoradiotherapy offers a promising treatment approach, according to preliminary results from the SCIENCE trial.

This phase 3 trial, presented at the 2025 ASCO Gastrointestinal Cancers Symposium in San Francisco (#ASCOGI25), showed that adding the PD-1 inhibitor sintilimab to chemoradiotherapy increased the pathological complete response (pCR) rate to 60% without increasing surgical risks.

Although neoadjuvant chemoradiotherapy or chemotherapy is standard treatment for esophageal squamous cell cancer, the optimal neoadjuvant (preoperative) treatment strategy remains uncertain in the immunotherapy era. The trial found that adding sintilimab to neoadjuvant chemoradiotherapy increased pCR rates from 47% to 60% and suggests that this regimen could become standard care in the future.

The SCIENCE Trial

SCIENCE enrolled 146 patients at four high-volume centers in China between November 2022 and June 2024.

Patients had previously untreated, resectable, locally advanced thoracic ESCC at stage cT1N2-3M0 or cT2-4aN0-3M0 (see detailed esophageal cancer staging).

Patients were randomly assigned to three neoadjuvant treatment groups:

• Group A: Sintilimab plus chemotherapy (nab-paclitaxel and carboplatin).
• Group B: Sintilimab plus concurrent chemoradiotherapy (nab-paclitaxel, carboplatin and 41.4 Gy radiotherapy).
• Group C: Concurrent chemoradiotherapy without sintilimab.

All patients underwent surgery 6-8 weeks after completing neoadjuvant treatment.

NOTE: Although sintilimab is approved in China for certain cancers, it has not yet been approved in the US. It was developed by the China-based biotechnology company Innovent Biologics, which has also undertaken international collaborative work with Eli Lilly and Company as part of its development partnerships.

How Does Sintilimab Affect Response Rates?

The pathological complete response (pCR) rate was the trial's primary endpoint. The findings were:

• Group A: 13%
• Group B: 60%
• Group C: 47.3%

Adding sintilimab to chemoradiotherapy (Group B) produced a 47% higher pCR rate than combining it with chemotherapy (Group A) (OR: 10.0, P < 0.0001). Group C outperformed Group A by 34.2% (OR: 6.0, P = 0.0005).

This high efficacy may be explained as follows:

In addition to directly targeting tumor cells, radiotherapy releases tumor antigens and increases immune activation. Sintilimab complements this effect by strengthening the immune response. Chemotherapy reduces tumor burden and makes the tumor microenvironment more immunogenic.

Surgical and Safety Outcomes

All patients completed neoadjuvant treatment and underwent surgery. R0 resection was achieved in 100%. Surgery was performed mainly using minimally invasive techniques, including thoracoscopic and robot-assisted McKeown procedures.

Treatment-related adverse events:

• Group A: 50%
• Group B: 86.7%
• Group C: 85.5%
• Severe adverse events (grade ≥ 3): Group C (36.4%), Group B (31.1%), Group A (8.7%).

Lower rates of adverse events such as lymphopenia and neutropenia were reported in the group receiving added sintilimab (Group B).

Commentary

These preliminary findings show considerable potential for integrating immunotherapy into the treatment of resectable ESCC. However, it remains unclear how the improvement in pCR will translate into long-term survival.

Long-term survival data from SCIENCE will be crucial in determining the clinical impact of this strategy. Given the strong association between pCR and long-term survival, the improved pCR rates with sintilimab may also have a positive effect on survival.

If these findings are confirmed, this sintilimab-containing regimen could become a new standard for ESCC. Future research focuses on developing biomarkers to predict immunotherapy response and personalize treatment.

In conclusion, SCIENCE illustrates the potentially transformative role of immunotherapy as a neoadjuvant option for ESCC. These findings may help develop effective treatment options for a broader patient population.