When treating patients with locally advanced esophageal squamous cell carcinoma (ESCC) in the neoadjuvant setting, chemoradiotherapy with or without sintilimab results in significantly higher pathological complete response (pCR) rates compared with chemotherapy plus sintilimab, according to preliminary data from the phase III SCIENCE trial from China.

In a cohort of 146 patients, pCR was achieved in 60.0 percent of those who received neoadjuvant chemoradiotherapy plus sintilimab and 47.3 percent of those who received neoadjuvant chemoradiotherapy alone as opposed to only 13.0 percent of those who received neoadjuvant chemotherapy plus sintilimab. The differences in pCR rates of 47 percent and 34.2 percent, respectively, were statistically significant (p<0.0001 and p=0.0005, respectively). [ASCO GI 2025, abstract LBA329]

Compared with chemotherapy plus sintilimab, chemoradiotherapy plus sintilimab was associated with tenfold greater odds of achieving pCR (odds ratio [OR], 10.0, 95 percent confidence interval, 3.7?30.8). Meanwhile, the odds were sixfold higher with chemoradiotherapy alone (OR, 6.0, 95 percent CI, 2.3?17.8).

Lead investigator Dr Xuefeng Leng from Sichuan Cancer Hospital & Institute, Chendu, China, reported that all patients who received the chemoradiotherapy plus sintilimab regimen demonstrated a treatment response.

“This study addresses the persistent challenge of high post-surgical recurrence rates in resectable locally advanced ESCC, despite the adoption of neoadjuvant chemoradiotherapy (CROSS and NEOCRTEC5010) as the current standard of care. Notably, this is the first three-arm randomized trial to evaluate immune checkpoint inhibitor-based combination treatment modalities against the standard neoadjuvant chemoradiotherapy,” Leng said.

He emphasized that integrating immune checkpoint inhibitors into neoadjuvant chemoradiotherapy protocols could substantially improve long-term survival rates by elevating the pathologic complete response rate and reducing recurrence and possibly enabling organ preservation. “This innovative approach of the integration of immunotherapy with chemoradiotherapy could lead to more personalized and effective treatment strategies, ultimately translating to better patient outcomes over time.”

Surgical outcomes and safety

The patients included in the study had thoracic ESCC clinically staged as locally advanced (cT1N2-3M0 or cT2-4aN0-3M0) and had not received any prior treatment. Most of them had clinical stage III disease (72.6 percent) and tumours located in the middle thoracic esophagus (51.4 percent).

For the neoadjuvant treatment, the patients were randomly assigned to receive chemoradiotherapy plus sintilimab (n=45; mean age 62.8 years, 93.3 percent male), chemoradiotherapy alone (n=55; mean age 64.6 years, 89.1 percent male), or chemotherapy plus sintilimab (n=46; mean age 62.3 years, 87.0 percent male). Chemotherapy consisting of nab-paclitaxel plus carboplatin was given for two cycles, and radiotherapy was either intensity-modulated or image-guided at a dose of 41.4 Gy. The co-primary endpoints were pCR rate and event-free survival, evaluated according to RECIST 1.1 criteria.

All patients completed the neoadjuvant treatment, underwent surgical resection 6?8 weeks after, and subsequently achieved a 100-percent R0 resection rate, Leng said. Surgical complications such as anastomotic leakage was low (0 percent with chemotherapy plus sintilimab, 2.2 percent with chemoradiotherapy plus sintilimab, and 5.5 percent with chemoradiotherapy), whereas pulmonary infection was high (67.4 percent, 44.4 percent, and 47.3 percent, respectively), although the symptoms were not very severe. There were no reports of perioperative death.

Treatment-emergent adverse events (TEAEs) during neoadjuvant treatment occurred more frequently in the neoadjuvant chemoradiotherapy plus sintilimab and neoadjuvant chemoradiotherapy arms than in the neoadjuvant chemotherapy plus sintilimab arm. The most common any-grade TEAEs included reduced white blood cell count (75.6 percent, 56.4 percent, and 8.7 percent, respectively), reduced neutrophil count (55.6 percent, 27.3 percent, and 4.3 percent), and hypoalbuminemia (13.3 percent, 50.9 percent, and 19.6 percent). The most common grade 3 or higher TEAEs were lymphopenia (11.1 percent, 30.9 percent, and 0 percent, respectively), leukopenia (24.4 percent, 29.1 percent, and 4.3 percent), and neutropenia (8.9 percent, 16.4 percent, and 2.2 percent).