Esophageal squamous cell carcinoma (ESCC) is a significant global health concern, with a high mortality rate. In East Asia, neoadjuvant chemotherapy or chemoradiotherapy is standard for resectable locally advanced ESCC (LA-ESCC). While studies have shown benefits of neoadjuvant chemoradiotherapy, the optimal approach remains unclear. Immune checkpoint inhibitors (ICIs), such as camrelizumab (a PD-1 inhibitor), have shown promise in advanced ESCC. Several phase 1b and 2 trials have suggested high pathological complete response (PCR) rates with neoadjuvant camrelizumab plus chemotherapy, but confirmation through large-scale phase 3 trials was lacking. This study aimed to address this gap by comparing the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy (with either paclitaxel or albumin-bound paclitaxel) to chemotherapy alone in patients with resectable LA-ESCC.

Previous single-arm studies using neoadjuvant camrelizumab plus chemotherapy for LA-ESCC showed promising PCR rates (17.6% to 39.2%). However, a definitive phase 3 trial comparing this approach to standard chemotherapy was needed. The CROSS and NEOCRTEC5010 trials demonstrated the survival benefits of neoadjuvant chemoradiotherapy over surgery alone. The JCOG9907 trial showed improved overall survival with neoadjuvant chemotherapy compared to adjuvant therapy. More recent trials and meta-analyses have questioned the survival advantage of chemoradiotherapy over chemotherapy alone. The use of albumin-bound paclitaxel (nab-paclitaxel) has also shown promise in combination with immunotherapy in other cancer types.

This was a multicenter, randomized, open-label, phase 3 trial conducted across 24 centers in China. 391 patients with resectable thoracic LA-ESCC (T1b-3N1-3M0 or T3N0M0) were stratified by clinical stage (I/II, III, or IVA) and randomized 1:1:1 to receive two cycles of neoadjuvant therapy: 1) Cam+nab-TP (camrelizumab, albumin-bound paclitaxel, and cisplatin), 2) Cam+TP (camrelizumab, paclitaxel, and cisplatin), or 3) TP (paclitaxel and cisplatin). The Cam+nab-TP and Cam+TP groups also received adjuvant camrelizumab. The dual primary endpoints were pathological complete response (PCR) rate (assessed by a blinded independent review committee) and event-free survival (EFS). Secondary endpoints included major pathological response (MPR), R0 resection rate, ypTNM staging, overall survival (OS), disease-free survival (DFS), adverse events (AEs), and surgical complications. PD-L1 expression was assessed via immunohistochemistry. Statistical analysis was performed using SAS software version 9.4.

In the intention-to-treat population, the PCR rate was significantly higher in the Cam+nab-TP group (28.0%) and Cam+TP group (15.4%) compared to the TP group (4.7%). The difference in PCR rates was statistically significant (Cam+nab-TP vs. TP: p<0.0001; Cam+TP vs. TP: p=0.0034). MPR rates were also higher in the camrelizumab-containing groups. The rates of surgical complications and treatment-related AEs were comparable across the three groups and considered tolerable. The most common grade 3 or higher treatment-related adverse events were decreased neutrophil count and decreased white blood cell count. Event-free survival data were not yet mature at the time of the analysis. Post-hoc subgroup analyses showed that the benefit of adding camrelizumab was consistent across several subgroups, although the benefits were larger in patients with higher PD-L1 expression.

This study provides the first phase 3 evidence demonstrating a significant improvement in PCR rates with the addition of neoadjuvant camrelizumab to chemotherapy in LA-ESCC. These results support the potential of combining immunotherapy with chemotherapy as a neoadjuvant strategy for this cancer type. The observed improvement in PCR, although not yet reflected in EFS data, is encouraging because PCR is often associated with improved long-term outcomes. The comparable safety profiles of the treatment arms are also reassuring. However, the absence of mature EFS data limits the definitive interpretation of the long-term clinical benefit.

The ESCORT-NEO/NCCES01 trial demonstrates that adding camrelizumab to neoadjuvant chemotherapy significantly improves the pathological complete response rate in patients with locally advanced esophageal squamous cell carcinoma. The findings highlight the potential benefit of incorporating immunotherapy into neoadjuvant treatment strategies for this cancer. Further follow-up is needed to assess the impact on long-term survival outcomes. Future research could focus on refining treatment regimens, investigating optimal patient selection based on biomarkers, and conducting comparative studies against chemoradiotherapy.

This study has several limitations. First, it did not directly compare the two camrelizumab-containing chemotherapy regimens. Second, the study did not compare neoadjuvant immunochemotherapy to chemoradiotherapy. Third, the event-free survival data were not yet mature. Fourth, the study was conducted exclusively in China and thus might not be generalizable to other populations. Finally, the open-label design might introduce some bias. The relatively high number of patients with unknown PD-L1 status also restricts some interpretations.