Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide and ranks fifth in China,[1, 2] often presents insidiously in the early stages, with most patients diagnosed at locally advanced or metastatic stages. For unresectable locally advanced esophageal cancer, the standard treatment is definitive concurrent CRT (dCCRT) is recommended.[3, 4] Recent studies indicate that adding immunotherapy to chemotherapy improves outcomes, extending overall survival (OS) from 12.6 months to 16.7 months,[5–8] establishing it as a cornerstone in the treatment of unresectable advanced or metastatic esophageal cancer. Despite this progress, the OS for this population remains inadequate, underscoring the need for more effective and less toxic treatment combinations to further extend patient survival.

Sintilimab (Innovent, China), a human IgG4 anti-PD-1 monoclonal antibody, has been approved by the China National Medical Products Administration for treating locally advanced, unresectable, or metastatic esophageal cancer based on the results of the ORIENT-15 trial.[8] In that study, sintilimab combined with cisplatin and either paclitaxel or 5-fluorouracil demonstrated improved OS and progression-free survival (PFS). Despite the improved systemic response from chemo-immunotherapy, local failures remain a common pattern of progression for patients with metastatic esophageal squamous cell carcinoma.[9] Radiotherapy is a pivotal component in the management of esophageal cancer across all stages.[10] However, additional data are required to support the combination of PD-1 inhibitors with chemotherapy and radiotherapy for patients with unresectable advanced or metastatic esophageal cancer. Therefore, this study aims to assess the survival benefit of sintilimab combined with docetaxel and cisplatin chemotherapy, followed by radiotherapy, in patients with unresectable advanced or metastatic esophageal cancer.

This study builds on earlier work, the preliminary efficiency and safety results of this study was reported and published on 2025 ASCO Gastrointestinal Cancers Symposium (DOI:10.1200/JCO.2025.43.4suppl.437).

A total of 62 patients were assessed for eligibility, of which 51 patients were enrolled in the study at the cutoff date December 1, 2025. The median age of the participants was 64.5 years, and all patients were male, diagnosed with squamous-cell carcinoma. Among the 51 evaluable patients, 14 (27.5%) were classified as stage III, while 37 (72.5%) were at stage IV. Additionally, all patients tested PD-L1 expression, among them, 64.7% (33/51) exhibited PD-L1 expression levels of ≥ 5 (Combined Positive Score, CPS). The most common sites of distant metastasis were the lymph nodes and lungs (Table 1).

All 51 patients (100%) completed the induction phase, and 45 patients (88.2%) subsequently received radiotherapy at the cutting off date. Notably, no patients experienced a dose reduction in either chemotherapy or radiotherapy. Two patients (6.7%) underwent surgery following chemo-immunotherapy, one of whom achieved a pathological complete response (pCR). All patients received between 3 and 35 cycles of sintilimab, with a median of 17 treatment cycles. There was no premature cessation of sintilimab due to investigator decision.

The median follow-up duration was 17.5 months (95% CI: 5.0-28.5). All patients were evaluable for clinical response. After the completion of chemo-immunotherapy, 3 patients (5.9%) achieved a complete response (CR), while 26 patients (51.0%) exhibited a partial response (PR) (Table 2). The changes in target tumors in the intention-to-treat (ITT) population following chemo-immunotherapy were illustrated in Fig. 1.

able 2: Summary of Efficiency Measures After Chemo-immunotherapy (n = 51) (%)

The changes in target tumors in patients completed sequential chemo-immunotherapy and radiotherapy were illustrated in Fig. 2.

In terms of clinical stages, the response rate was 57.2% for stage III and 56.8% for stage IV (P > 0.05) (Fig. 3A). The median depth of response (mDpR) was 35% following chemo-immunotherapy and was 51% with the additional radiotherapy (P < 0.01) (Fig. 3B).

The median progression-free survival (mPFS) was 16.4 months (95% CI: 13.911–18.889) (Fig. 4A), and the median overall survival (mOS) 29.25 months (95% CI: 26.514–31.986) (Fig. 4B).

The mPFS for clinical stage Ⅲ was 16.40 months (95% CI: 13.129–19.671) and for stage Ⅳ was 15.50 months (95% CI: 9.170–21.830), there was no significant difference (P = 0.966) (Fig. 5A). The mPFS of patients with PD-L1 CPS ≥ 5 was 16.50 months (95% CI: 14.501–18.499), and was 11.0 months (95% CI: 2.391–19.609) with PD-L1 CPS < 5 (P = 0.129) (Fig. 5B).

5 patients expressed progression disease after the induction chemo-immunotherapy; they also received palliative esophageal irradiation for 50 Gy/25f/5w and santilimab maintenance therapy. The mPFS was 19.3 months (Fig. 6A) and the mOS was 26.2-Not reached (Fig. 6B) in patients had tumor response (Stable or better) after 4-cycle induction chemo-immunotherapy; and the mOS of patients with progression disease was 11.75 months (Fig. 6C).

All patients were included in the safety analyses. The most common adverse events observed were nausea, loss of appetite, decreased white blood cell count, and neutropenia. One patient experienced grade III immunotherapy-induced interstitial lung disease, resulting in discontinuation of sintilimab and radiotherapy. Importantly, no patients experienced treatment-related mortality (Table 3).

Nearly half of individuals diagnosed with esophageal cancer present with metastatic disease. Despite the widespread use of chemotherapy and targeted therapies, the prognosis remains exceedingly poor.[14] Geographic variation and differing etiologies contribute to a notably high incidence of esophageal squamous-cell carcinoma (ESCC) in Asian countries, particularly China. Key risk factors for ESCC include heavy alcohol consumption, nutritional deficiencies, exposure to nitrosamines, and the consumption of pickled vegetables and very hot foods.[2, 15]

For early-stage and less invasive esophageal cancers, esophagectomy and endoscopic treatments remain the primary clinical options.[19] In case of locally advanced, resectable esophageal or junctional cancers, preoperative chemoradiotherapy (CRT) is utilized to reduce primary tumor volume, enhance R0 resection rate, and eliminate micrometastases, thereby reducing recurrence risk and prolonging overall survival (OS).[4, 5] However, persistent pathological lymph node metastasis is a poor prognostic factor in locally advanced ESCC, even following successful neoadjuvant CRT and esophagectomy.[17] To address these challenges, the introduction of immune checkpoint inhibitors (ICIs) in neoadjuvant therapy has shown promise in improving disease-free survival.[18]

The ETOG8501 study established a foundation for treating locally advanced unresectable esophageal cancer with definitive concurrent chemoradiotherapy (dCCRT). Nevertheless, local relapse and distant metastases remain prevalent.[19, 20] The combination of induction chemotherapy and radiotherapy may provide an alternative for patients unable to tolerate concurrent chemoradiotherapy. While randomized trials indicated that the addition of induction chemotherapy does not improve response rates or survival outcomes in unselected ESCC patients, those who responded to induction chemotherapy exhibited significantly better survival compared to non-responders.[21] Recent studies have yielded favorable results for the combination of durvalumab and tremelimumab with dCCRT, achieving 24-month progression-free survival (PFS) and OS rates of 57.5% and 75%, respectively.[22] Recent studies have shown favorable results for combinations of durvalumab and tremelimumab with dCCRT, achieving 24-month progression-free survival (PFS) and OS rates of 57.5% and 75%, respectively.[23] Furthermore, the integration of camrelizumab or sintilimab with CCRT also demonstrated benefits in local control and survival outcomes in locally advanced ESCC.[24, 25]

PD-1 inhibitors in conjunction with chemotherapy is the current standard treatments for unresectable locally advanced or metastatic esophageal cancer, improving both PFS and OS.[8–11, 26] Despite these advancements, clinical improvements remain limited, with median PFS ranging from 5.7 to 7.2 months and median OS between 12.4 to 17 months. Consequently, there is a critical imperative to develop novel combination treatment strategies that offer greater therapeutic efficacy while minimizing systemic toxicity.

In this study, the depth of response (mDpR) was 35.0% following chemo-immunotherapy and increased to 51.0% after the adimiistration of additional radiotherapy. Patients with PD-L1 CPS ≥ 5demonstrated a higher PFS compared to those with CPS < 5, however, this result did not reach significant difference. This lack of significance may be attributed to the limited sample size of this study. Furthermore, the response rates of 57.2% and 56.8% in clinical stages III and IV, respectively, did not yield a statistically significant difference, indicating that clinical stage may not be a predictor of response in esophageal cancer treated with chemo-immunotherapy.

The introduction of radiotherapy after four cycles of chemo-immunotherapy resulted in an increase in median depth of response (mDpR) from 35% to 51.0%. In this cohort, the median PFS was 16.4 months, and the median OS reached 29.25 months. These outcomes are notably higher than those observed in previous studies utilizing chemo-immunotherapy alone,[27] a disparity likely attributabe to the synergistic effects of ICIs and radiotherapy.

Mechanistically, PD-1 inhibitors enhance radiosensitivity by reactivating T cells and inducing G2/M phase arrest in esophageal squamous cell carcinoma.[28] They also stimulate CD4 + T lymphocytes through vessel normalization, altering the cytokine environment, releasing cytokines, and promoting tumor cell apoptosis.[29–31] Furthermore, PD-1 inhibitors enhance the sensitivity of radiotherapy by upregulating PD-L1 expression on tumor cells and neoantigens, facilitating the expansion of exhausted T cells and increasing IFN-γ expression.[32–34]

Regarding the study demographics, no female patient were diagnosed across the three participating centers during the enrollment period, consequently, the study population consisted entirely of male patients. This gender distribution is likely due to regional lifestyle factors, specifically smoking and drinking habits. Several limitations exist, including its single-arm design, limited sample size, and relatively short follow-up duration. Future research should involve randomized controlled trials with larger cohorts and extended follow-up periods, along with comprehensive analyse of relationships between survival outcomes, biomarkers, and the tumor microenviroment.

The combination of four cycles of sintilimab with cisplatin and docetaxel, followed by radiotherapy and maintenance sintilimab, demonstrated a high response rate, prolonged PFS and OS, and tolerable toxicity in patients with advanced or metastatic esophageal squamous-cell carcinoma. Patients with early progression during the chemo-immunotherapy induction phase had an unfavorable outcome, indicating a need for further study.