Neoadjuvant Sintilimab Plus Chemoradiotherapy Improves pCR Rate in Resectable, Locally Advanced ESCC

The addition of sintilimab (Tyvyt) to neoadjuvant chemoradiotherapy (CRT) led to an improvement in pathological complete response (pCR) rate compared with CRT alone in patients with resectable, locally advanced esophageal squamous cell carcinoma (ESCC), according to preliminary data from the phase 3 SCIENCE trial (NCT05244798) presented at the 2025 Gastrointestinal Cancers Symposium.

However, an improvement in pCR rate was not observed for the experimental regimen of neoadjuvant sintilimab plus chemotherapy vs sintilimab plus CRT or CRT alone.

Findings from the study conducted at more than 14 centers in China showed that patients treated with sintilimab plus CRT (n = 45) achieved a pCR rate of 60% (95% CI, 44.3%-74.3%) compared with 13% (95% CI, 4.9%-26.3%) for those given sintilimab plus chemotherapy (n = 46; odds ratio [OR], 10; 95% CI, 3.7-30.8; P < .0001). The pCR rate was 47.3% (95% CI, 33.7%-61.2%) in patients given CRT alone (n = 55; OR vs sintilimab plus chemotherapy, 6; 95% CI, 2.3-17.8; P = .0005).

“Adding sintilimab…to neoadjuvant CRT may improve the pathological outcomes without increasing surgical risks,” lead study author Xuefeng Leng, MD, PhD, of the Department of Thoracic Surgery at Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, said in a presentation of the data. “Neoadjuvant CRT combined with [immunotherapy] has the potential to become the new standard of care [SOC] in the near future.”

Behind the SCIENCE (Trial)

During the presentation, Leng noted that neoadjuvant chemotherapy or CRT is the current SOC in East Asia for patients with resectable, locally advanced ESCC. “However, the optimal neoadjuvant treatment strategy [for this patient population] remains uncertain,” he explained. “This is why we focused on this question and started this study.”

In the randomized, multicenter SCIENCE trial, investigators enrolled patients 18 to 75 years of age with histologically diagnosed thoracic ESCC that was locally advanced (cT1N2-3M0 or cT2-4aN0-3M0) and previously untreated. An ECOG performance status of 0 or 1 was also required.

Patients were randomly assigned in a 1:1:1 fashion to receive neoadjuvant treatment with 200 mg of sintilimab plus 220 mg/m2 of nab-paclitaxel (Abraxane) and area under the curve 3 to 5 of carboplatin on day 1 of each 3-week cycle for 2 cycles; the combination of sintilimab, nab-paclitaxel, and carboplatin once every 3 weeks for 2 cycles with concurrent intensity modulated radiation therapy (IMRT) or image-guided radiation therapy (IGRT) totaling 41.4 Gy; or nab-paclitaxel plus carboplatin once every 3 weeks for 2 cycles with concurrent IMRT/IGRT.

Following neoadjuvant therapy, patients proceeded to surgery. For patients who achieved a R0 resection, those with a pCR underwent surveillance, and those without a pCR received adjuvant sintilimab. Adjuvant treatment for patients without a R0 resection was determined by a multidisciplinary team.

The study’s coprimary end points were pCR rate and event-free survival. Secondary end points included overall response rate, disease control rate, R0 resection rate, major pathological response rate, and safety. Biomarkers were an exploratory end point.

As of the September 2024 data cutoff, all enrolled patients in each arm received and completed 2 cycles of neoadjuvant therapy before undergoing definitive surgery.

At baseline, the median age of enrolled patients was 58.8 years (range, 55.3-75.5) for the sintilimab plus chemotherapy group, 66.0 years (range, 45.7-75.0) for the CRT group, and 64.1 years (range, 48.4-74.8) for the sintilimab plus CRT group. Notably, most patients in the sintilimab plus chemotherapy group (69.6%) and the sintilimab plus CRT group (53.3%) were under 65 years of age; the majority of patients in the CRT group were at least 65 years of age (60.0%).

Most patients were male (sintilimab plus chemotherapy, 87.0%; CRT, 89.1%; sintilimab plus CRT, 93.3%), had an ECOG performance status of 0 (89.1%; 94.5%; 93.3%), had a smoking history (63.0%; 58.2%; 73.3%), had T3 disease (87.0%; 94.5%; 97.8%), had N2 disease (60.9%; 61.8%; 53.3%), and had stage III disease (82.6%; 70.9%; 64.4%). A middle tumor location was the most common in each group at 47.8% for sintilimab plus chemotherapy, 50.9% for CRT, and 55.6% for sintilimab plus CRT.

Additional Efficacy and Safety Findings

All patients in the sintilimab plus CRT arm experienced a response. The tumor regression grades in this arm were 0 (60.0%), 1 (24.4%), and 2 (15.6%); no patients had a tumor regression grade of 3. In the sintilimab plus chemotherapy arm, tumor regression grades were 0 (13.0%), 1 (13.0%), 2 (52.2%), and 3 (21.7%). In the CRT arm, these grades were 0 (47.3%), 1 (25.5%), 2 (21.8%), and 3 (5.5%).

R0 resection was achieved by all patients in all 3 arms. The median duration of surgery was 4.2 hours (range, 2.0-8.1) in the sintilimab plus chemotherapy arm, 4.0 hours (range, 2.2-7.3) in the CRT arm, and 4.4 hours (range, 2.5-8.0) in the sintilimab plus CRT arm. A thoracoscopic McKeown procedure was used for 50.0%, 63.6%, and 71.1% of patients, respectively. The respective rates of robotic-assisted McKeown procedures were 47.8%, 34.5%, and 28.9%. An Ivor-Lewis procedure was used for 2.2%, 1.8%, and 0% of patients, respectively.

Surgical complications were reported in 71.7% of patients in the sintilimab plus chemotherapy arm, 49.1% of patients in the CRT arm, and 46.7% of patients in the sintilimab plus CRT arm. Anastomotic leak did not occur in any patients in the sintilimab plus chemotherapy arm compared with 5.5% of patients in the CRT group and 2.2% of patients in the sintilimab plus CRT group. The rates of postoperative hemorrhage were 10.9%, 1.8%, and 0% for the sintilimab plus chemotherapy, CRT, and sintilimab plus CRT groups, respectively. The respective rates of pulmonary infection were 67.4%, 47.3%, and 44.4%.

Safety data showed that the most common any-grade treatment-emergent adverse effects (TEAEs) reported in at least 5% of patients in any arm included decreased white blood cell count (sintilimab plus chemotherapy, 8.7%; CRT, 56.4%; sintilimab plus CRT, 75.6%), decreased neutrophil count (4.3%; 27.3%; 55.6%), hypoalbuminemia (19.6%; 50.9%; 13.3%), decreased lymphocyte count (2.2%; 41.8%; 24.4%), decreased platelet count (4.3%; 34.5%; 35.6%), anemia (2.2%; 30.9%; 22.2%), increased alanine aminotransferase (0%; 0%; 8.9%), increased aspartate aminotransferase (0%; 0%; 6.7%), and esophageal anastomotic leak (0%; 5.5%; 0%).

Grade 3 or higher TEAEs included lymphopenia (sintilimab plus chemotherapy, 0%; CRT, 30.9%; sintilimab plus CRT, 11.1%), leukopenia (4.3%; 29.1%; 24.4%), neutropenia (2.2%; 16.4%; 8.9%), thrombocytopenia (2.2%; 1.8%; 4.4%), anemia (0%; 1.8%; 0%), hyperglycemia (0%; 1.8%; 0%), and hypernatremia (0%; 1.8%; 0%).

Disclosures: Dr Leng did not report any relationships.

Reference

Leng X, He W, Lyu J, et al. Preliminary results from the multicenter, randomized phase III trial (SCIENCE): Comparing chemotherapy plus sintilimab and chemoradiotherapy plus sintilimab versus chemoradiotherapy for neoadjuvant treatment in resectable locally advanced esophageal squamous cell carcinoma. J Clin Oncol. 2025;43(suppl 4):LBA329. doi:10.1200/JCO.2025.43.4_suppl.LBA329