Sequential versus concurrent neoadjuvant immunochemotherapy in locally advanced esophageal squamous cell carcinoma: a randomized, controlled, open-label, phase 2 trial (HCHTOG1906).

Background: Neoadjuvant chemotherapy combined with PD-1 inhibitors has shown application potential in esophageal squamous cell carcinoma (ESCC), however, optimization strategies for administration timing (sequential vs. concurrent) still lack support from prospective evidence. Methods: This open-label, phase II randomized controlled trial enrolled a total of 70 patients with resectable locally advanced ESCC from July 2019 to June 2023. Patients were randomized 1:1 to the sequential group (paclitaxel/cisplatin on day 1, toripalimab on day 3) or the concurrent group (all drugs on day 1). The primary outcome was pathological complete remission (pCR). The secondary outcomes were to explore the safety of chemotherapy combined with toripalimab as neoadjuvant treatment under different administration sequences, evaluating treatment-related adverse events (AEs), overall survival (OS) and disease-free survival (DFS). Results: All 70 patients completed neoadjuvant treatment, and 54 patients underwent surgery. The overall pCR rate was 22.2% (12/54), with no significant difference between the sequential group and the concurrent group (17.8% vs. 26.9%, P = 0.636). In terms of safety, the incidence of grade 3-5 TRAEs was 14.2% (10/70). The concurrent group had significantly higher incidences of nausea and diarrhea (P<0.05). A total of 6 treatment-related deaths occurred, with 5 cases in the concurrent group and 1 case in the sequential group. There were no statistically significant differences in OS (P = 0.780) or DFS (P = 0.632) between the two groups. Conclusions: There was no significant difference in pCR or survival outcomes between sequential and concurrent immunochemotherapy, but the concurrent strategy was associated with increased risks of nausea, diarrhea, and fatal immune-related adverse events (irAEs).