Short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab for locally advanced esophageal squamous cell carcinoma (SCALE-1): a single-arm phase Ib clinical trial

Abstract

Background: The optimal dosages, timing, and treatment sequencing for standard-of-care neoadjuvant chemoradiotherapy necessitate re-evaluation when used in conjunction with immune checkpoint inhibitors for patients with resectable, locally advanced esophageal squamous cell carcinoma (RLaESCC). The SCALE-1 phase Ib study aimed to evaluate the safety and efficacy of short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab in this patient population.

Methods: RLaESCC patients with clinical stages cT3-4aN0M0/cT1-4aN+M0 received neoadjuvant paclitaxel (135 mg/m²), carboplatin (area under the curve=5), and toripalimab (240 mg) every 3 weeks for two cycles. Short-course neoadjuvant radiotherapy (30 Gy in 12 fractions; 5 days per week) was administered between neoadjuvant immune-chemotherapy (nICT) doses. Esophagectomies were scheduled 4-6 weeks after completing neoadjuvant treatment. The primary endpoint was safety, with secondary endpoints including pathological complete response (pCR) rate, postoperative complications, progression-free survival (PFS), and overall survival (OS). Exploratory biomarker analysis used gene expression profiles via the nCounter platform.

Results: Of the 23 patients enrolled, all completed neoadjuvant radiotherapy, while 21 cases finished full nICT doses and cycles. Common grade 3/4 adverse events included neutropenia (57%), leukopenia (39%), and skin rash (30%). No grade 3 or higher esophagitis or pneumonitis occured. Twenty patients underwent surgery, and 11 achieved pCR (55%). Two patients (10%) experienced grade IIIb surgical complications. At the database lock, a 2-year PFS rate of 63.8% (95% CI 43.4% to 84.2%) and 2-year OS rate was 78% (95% CI 64.9% to 91.1%) were achieved. Tumor immune microenvironment analysis indicated that tumors with pCR exhibited significantly higher pretreatment T-cell-inflamed score and post-treatment reshaping of antitumor immunity.

Conclusions: Combining short-course neoadjuvant radiotherapy with chemotherapy and toripalimab demonstrated favorable safety and promising efficacy in RLaESCC patients.

Trial registration number: ChiCTR2100045104.

Keywords: Esophageal Cancer; Immune Checkpoint Inhibitors; Neoadjuvant; Radioimmunotherapy.

Figure 1

Study flow chart. BMI, body mass index; ESCC, esophageal squamous cell carcinoma; ITT, intention-to-treat; mITT, modified intentionto-treat

Figure 2

Pathological assessment of the response to neoadjuvant treatment in the primary tumor. Pathological regression in the resected primary esophageal tumor after neoadjuvant treatment, according to the percentage of remaining viable tumor cells, for each of the 20 patients who underwent surgical resection. The dashed horizontal line indicates the threshold for a major pathological response (90% regression). Clinical and pathological features that include programmed death ligand 1 (PD-L1) expression (CPS≥5 or <5), tumor length (≥5 cm or <5 cm), smoking status, preoperative radiological response (according to Response Evaluation Criteria in Solid Tumors (RECIST)), and presence or absence of lymph-node (LN) metastases in the surgical specimen are annotated for each patient. CPS, Combined Positive Score of PD-L1; CR, complete response; PR, partial response.

Figure 3

Survival outcomes for patients in the ITT population (n=23). (A) Overall survival; (B) Progression-free survival. ITT, intention-to-treat.

Figure 4

Comparison of the pretreatment tumor immune microenvironment (TIME) between tumors that achieved pCR and non-pCR, and the change of TIME after treatment. (A) Boxplot representing the T-cell-inflamed score (TIS), which appears significantly higher in tumors that achieved a pathological complete response (pCR) compared with non-pCR tumors (Wilcoxon rank-sum test, p<0.05); (B) Heatmap of the expression levels of 18 genes constructing the TIS score (rows denote genes and columns represent samples; red indicates relatively upregulated, while blue indicates downregulated); (C) change of immune cell infiltration scores between pretreatment and post-treatment in the pCR and non-pCR groups (Wilcoxon rank-sum test, p<0.05); (D) change of immune signature scores between pretreatment and post-treatment in the pCR and non-pCR groups (Wilcoxon rank-sum test, p<0.05).