This study aims to evaluate the efficacy and safety of neoadjuvant low-dose radiotherapy combined with Retlirafusp alfa and chemotherapy in the treatment of resectable locally advanced esophageal squamous cell carcinoma.
Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal cancer in China, accounting for approximately 90% of cases. Most patients are diagnosed at locally advanced stages. Although standard neoadjuvant chemoradiotherapy can achieve a pathological complete response (pCR) rate of around 43%, over 30% of patients still experience postoperative recurrence, and non-pCR patients have a poor prognosis. Immunotherapy has opened new avenues for locally advanced ESCC, with neoadjuvant immunochemotherapy achieving pCR rates of approximately 20%-35%, indicating room for further improvement. Low-dose radiotherapy (LDRT, 8 Gy/4 fractions) can remodel the tumor immune microenvironment, promoting the conversion of "cold tumors" to "hot tumors" and enhancing the antitumor efficacy of immune checkpoint inhibitors. Retlirafusp alfa is an anti-PD-L1/TGF-βRII bifunctional fusion protein developed by Hengrui Medicine, which simultaneously blocks both the PD-L1 and TGF-β signaling pathways, thereby activating T-cell-mediated tumor killing. This study innovatively combines low-dose radiotherapy, Retlirafusp alfa, and chemotherapy to explore its value in the neoadjuvant setting for resectable locally advanced ESCC. This is a prospective, cohort, phase II clinical trial planned to enroll 96 patients with previously untreated resectable locally advanced ESCC (AJCC 9th edition stage T1-4aN1-3M0 or T3-4aN0M0). Cohort A receives low-dose radiotherapy (8 Gy/4 fractions) combined with Retlirafusp alfa and nab-paclitaxel plus cisplatin/carboplatin for 2 cycles; Cohort B receives Retlirafusp alfa plus nab-paclitaxel and cisplatin/carboplatin (without radiotherapy). Radical surgery is performed 4-6 weeks after neoadjuvant therapy. The primary endpoint is pCR rate. Secondary endpoints include major pathological response (MPR), R0 resection rate, objective response rate (ORR), event-free survival (EFS), overall survival (OS), and safety. This study will provide important evidence for the "low-dose radiotherapy + immunotherapy + chemotherapy" neoadjuvant treatment model in locally advanced ESCC, with the potential to further improve pCR rates and long-term patient survival.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
96
Low-dose radiotherapy: 8 Gy in 4 fractions, 2 Gy per fraction, targeting the primary tumor and metastatic lymph nodes. Retlirafusp alfa: 1800 mg or 30 mg/kg on D1, q3w, for 2 cycles. Nab-paclitaxel: 125 mg/m² on D1 and D8, plus cisplatin 75 mg/m² on D1 or carboplatin AUC=5 on D1, q3w, for 2 cycles.
Retlirafusp alfa: 1800 mg or 30 mg/kg on D1, q3w, for 2 cycles. Nab-paclitaxel: 125 mg/m² on D1 and D8, plus cisplatin 75 mg/m² on D1 or carboplatin AUC=5 on D1, q3w, for 2 cycles.
Harbin Medical University Cancer Hospital, No. 150 Haping Road, Nangang District, Harbin, Heilongjiang Province, China
Harbin, Heilongjiang, China
Pathological Complete Response (pCR)
pCR is defined as the absence of residual invasive carcinoma cells in both the resected primary tumor and lymph nodes.
Time frame: Assessed via pathological examination of surgical specimens within 2 weeks post-surgery; follow-up up to 6 months.
Major Pathological Response (MPR)
Proportion of patients with ≤10% residual viable tumor cells in the postoperative specimen.
Time frame: Assessed via pathological examination of surgical specimens within 2 weeks post-surgery; follow-up up to 6 months.
R0 Resection Rate
Proportion of patients achieving radical resection with negative surgical margins (including distal, proximal, and circumferential margins).
Time frame: Assessed via pathological examination of surgical specimens within 2 weeks post-surgery; follow-up up to 6 months.
Objective Response Rate (ORR)
Proportion of patients achieving complete response (CR) or partial response (PR).
Time frame: Assessed via imaging after completion of neoadjuvant therapy; follow-up up to 6 months.
Disease Control Rate (DCR)
Proportion of patients achieving CR, PR, or stable disease (SD) sustained for the minimum required duration.
Time frame: Assessed via imaging after completion of neoadjuvant therapy; follow-up up to 6 months.
Event-Free Survival (EFS)
Time from enrollment to disease progression, inoperability, postoperative recurrence, or death from any cause (whichever occurs first).
Time frame: From enrollment to first event, assessed every 3 months; follow-up up to 36 months.
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Overall Survival (OS)
Time from enrollment to death from any cause.
Time frame: From enrollment to death or last follow-up, assessed every 3 months; follow-up up to 36 months.
Adverse Event Rate
Incidence and severity of adverse events (AEs), serious adverse events (SAEs), and treatment-related adverse events (TRAEs), graded per NCI-CTCAE v6.0.
Time frame: Continuous monitoring from informed consent to 90 days after the last dose; follow-up up to 36 months.
Quality of Life Assessment Score
Evaluated using the EORTC QLQ-C30 and QLQ-OES18 questionnaires.
Time frame: Assessed at screening, Cycle 1 Day 1, Cycle 2 Day 1(each cycle is 21 days), and at 1, 3, 6, and 12 months post-surgery (7 time points in total); follow-up up to 12 months.
Biospecimen collection time points (tissue and blood samples)
before treatment, after radiotherapy completion, during combination therapy, and after treatment. Biopsy samples (for single-cell sequencing, mIHC, and spatial transcriptomics) and plasma (for Olink/proteomics and metabolomics) to explore biomarkers with potential clinical value.
Time frame: Tissue and blood samples were collected at four time points: before treatment, after radiotherapy, during combination therapy (Cycle 1 Day 1 to Cycle 2 Day 1; 21 days per cycle), and before surgery; follow-up continued up to 6 months.