Low-Dose Radiotherapy With Retlirafusp Alfa and Chemotherapy as Neoadjuvant Therapy for Resectable Locally Advanced Esophageal Squamous Cell Carcinoma

Low-Dose Radiotherapy Combined With Retlirafusp Alfa and Chemotherapy as Neoadjuvant Therapy for Resectable Locally Advanced Esophageal Squamous Cell Carcinoma: An Exploratory Phase II Study

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Esophageal Squamous Cell Carcinoma (ESCC)
• Intervention / Treatment: Drug: Low-dose radiotherapy + Retlirafusp alfa + nab-paclitaxel + cisplatin/carboplatin; Drug: Retlirafusp alfa + nab-paclitaxel + cisplatin/carboplatin

Detailed Description

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
• Enrollment (Estimated): 96
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Heilongjiang
    • Harbin, Heilongjiang, China, 150081
      • Harbin Medical University Cancer Hospital, No. 150 Haping Road, Nangang District, Harbin, Heilongjiang Province, China

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Voluntary participation with written informed consent.
2. Age 18-75 years, male or female.
3. Histologically or cytologically confirmed thoracic esophageal squamous cell carcinoma (ESCC).
4. Clinical stage T1-4aN1-3M0 or T3-4aN0M0 (AJCC 9th edition): T stage determined by CT combined with MRI or endoscopic ultrasound; nodal involvement confirmed by biopsy, EBUS/EUS, or mediastinoscopy, or imaging showing lymph node short-axis diameter ≥2.0 cm; distant metastasis (M1) excluded by FDG-PET/CT or chest/abdominal/brain CT/MRI; no suspicious metastatic lymph nodes on cervical ultrasound.
5. Potentially resectable thoracic esophageal lesion with anticipated R0 resection.
6. No prior systemic therapy for esophageal tumor (chemotherapy, targeted therapy, immunotherapy, radiotherapy, etc.).
7. ECOG performance status 0-1.
8. At least one measurable lesion per Japanese Classification of Esophageal Cancer, 12th edition.
9. Agreement to provide archived tumor tissue or undergo biopsy for biomarker analysis.
10. Adequate organ function (within 14 days prior to first dose, without blood products or growth factors):
11. Hematology: WBC ≥4×10⁹/L, ANC ≥2×10⁹/L, hemoglobin ≥90 g/L, platelets ≥90×10⁹/L.Hepatic: total bilirubin ≤1.5×ULN (≤3×ULN for Gilbert's syndrome), AST and ALT ≤2.5×ULN (≤5×ULN for liver metastases), alkaline phosphatase ≤3×ULN (≤5×ULN for liver/bone metastases), albumin ≥30 g/L. Renal: serum creatinine ≤1.5×ULN or CrCl ≥60 mL/min (Cockcroft-Gault formula). Coagulation: INR ≤1.5 (without anticoagulation).
12. Body weight >35 kg, with no >10% weight loss in the past 3 months.
13. Life expectancy >12 months.
14. Women of childbearing potential and men must use effective contraception during the study and for 3 months after the last dose; non-lactating; negative serum/urine HCG within 7 days before first dose for women of childbearing potential.

Exclusion Criteria:

1.History of hypersensitivity to any component of Retlirafusp alfa, paclitaxel, carboplatin, or other platinum agents.

2,Cervical esophageal cancer, esophageal adenocarcinoma, or other pathological types.

3.Clinical stage I/IIA, T4b unresectable, or distant metastasis (M1) confirmed by imaging.

4.History of other malignancies within 5 years, except cured basal cell carcinoma of the skin, cervical carcinoma in situ, etc.

5.Prior or current receipt of any of the following:

1. Any radiotherapy, chemotherapy, or other anti-tumor therapy for malignancy.
2. Use of immunosuppressive agents or systemic corticosteroids for immunosuppressive purposes (dose >10 mg/day prednisone or equivalent) within 2 weeks prior to first study drug administration. Inhaled or topical steroids and adrenal hormone replacement at doses >10 mg/day prednisone or equivalent are permitted in the absence of active autoimmune disease.
3. Receipt of live-attenuated vaccine within 4 weeks prior to first study drug administration.
4. Major surgery or severe trauma within 4 weeks prior to first study drug administration.

6.Active or history of autoimmune disease, including but not limited to: interstitial pneumonia, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism (may be considered after hormone replacement therapy). Patients with psoriasis or childhood asthma/allergy that has fully resolved and requires no intervention in adulthood may be considered; however, those requiring bronchodilators for medical intervention are excluded.

7.Immunodeficiency, including HIV positivity, other acquired or congenital immune deficiencies, or history of organ or allogeneic bone marrow transplantation.

8.Poorly controlled cardiac conditions, including but not limited to: (1) NYHA class ≥II heart failure, (2) unstable angina, (3) myocardial infarction within 1 year, (4) clinically significant supraventricular or ventricular arrhythmias uncontrolled despite intervention.

9.Severe infection (CTCAE grade ≥2) within 4 weeks prior to first study drug administration, such as severe pneumonia requiring hospitalization, bacteremia, or infectious complications; active pulmonary inflammation on baseline chest imaging; signs/symptoms of infection or need for oral/IV antibiotics within 14 days prior to first dose (except prophylactic antibiotics).

10.Active pulmonary tuberculosis by history or CT, history of active tuberculosis within 1 year prior to enrollment, or history of active tuberculosis >1 year ago without adequate treatment.

11.Active hepatitis B (HBV DNA ≥2000 IU/mL or 10⁴ copies/mL), or hepatitis C (HCV antibody positive with HCV RNA above the lower limit of detection).

12.Diagnosis of other malignancy within 5 years prior to first study drug administration, except those with low risk of metastasis or death (5-year survival >90%), such as adequately treated basal cell or squamous cell skin cancer, or cervical carcinoma in situ.

13.Pregnant or lactating women. 14.Other conditions deemed by the investigator to potentially necessitate premature study termination, such as other serious diseases (including psychiatric disorders) requiring concomitant treatment, alcoholism, drug abuse, or family/social factors that may affect patient safety or compliance.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low-dose radiotherapy + Retlirafusp alfa + chemotherapy; Low-dose radiotherapy + Retlirafusp alfa + nab-paclitaxel + cisplatin/carboplatin	Drug: Low-dose radiotherapy + Retlirafusp alfa + nab-paclitaxel + cisplatin/carboplatin; 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.
Experimental: Retlirafusp alfa + chemotherapy; Retlirafusp alfa + nab-paclitaxel + cisplatin/carboplatin	Drug: Retlirafusp alfa + nab-paclitaxel + cisplatin/carboplatin; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Complete Response (pCR)	pCR is defined as the absence of residual invasive carcinoma cells in both the resected primary tumor and lymph nodes.	Assessed via pathological examination of surgical specimens within 2 weeks post-surgery; follow-up up to 6 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Pathological Response (MPR)	Proportion of patients with ≤10% residual viable tumor cells in the postoperative specimen.	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).	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).	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.	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).	From enrollment to first event, assessed every 3 months; follow-up up to 36 months.
Overall Survival (OS)	Time from enrollment to death from any cause.	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.	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.	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.	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.

Collaborators and Investigators

• Sponsor: Harbin Medical University
• Collaborators: Shanxi Province Cancer Hospital; Peking Union Medical College Hospital; Henan Cancer Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2026
• Primary Completion (Estimated): May 30, 2028
• Study Completion (Estimated): May 30, 2029

Study Registration Dates

• First Submitted: June 22, 2026
• First Submitted That Met QC Criteria: June 28, 2026
• First Posted (Actual): July 2, 2026

Study Record Updates

• Last Update Posted (Actual): July 2, 2026
• Last Update Submitted That Met QC Criteria: June 28, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: neoadjuvant; Esophageal Squamous Cell Carcinoma; Retlirafusp alfa
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Esophageal Diseases; Carcinoma; Neoplasms, Squamous Cell; Carcinoma, Squamous Cell; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Organic Chemicals; Therapeutics; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Coordination Complexes; Platinum Compounds; Carboplatin; Cisplatin; Radiotherapy; 130-nm albumin-bound paclitaxel
• Other Study ID Numbers: MA-EC-II-032

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No