Radiotherapy Plus Anti-PD-1 Versus Anti-PD-1 Alone in ypTanyN⁺M0 NSCLC

Postoperative Involved-field Nodal Radiotherapy Plus Anti-PD-1 Maintenance Versus Anti-PD-1 Maintenance Alone in Patients With ypTanyN⁺M0 NSCLC After Neoadjuvant Chemoimmunotherapy and R0 Resection: A Single-center Randomized Phase II Study

Patients with stage III non-small-cell lung cancer (NSCLC) who receive neoadjuvant chemoimmunotherapy may achieve good response in the primary tumor but still have residual nodal disease after surgery (ypTanyN⁺M0), which is associated with poor prognosis in retrospective analyses from our center. In prior trials such as LungART and PORT-C, postoperative radiotherapy (PORT) did not improve disease-free survival in completely resected stage IIIA-N2 NSCLC after adjuvant chemotherapy, suggesting that PORT should not be used indiscriminately. However, recent preclinical and translational data indicate that radiotherapy can enhance antitumor immunity, remodel the tumor microenvironment, and synergize with immune checkpoint inhibitors via immunogenic cell death, improved T-cell trafficking, and tertiary lymphoid structure formation.

This single-center randomized phase II study will evaluate whether adding postoperative involved-field nodal radiotherapy to standard PD-1 maintenance therapy can improve disease-free survival compared with PD-1 maintenance alone in patients with ypTanyN⁺M0 NSCLC after neoadjuvant chemoimmunotherapy and R0 resection.

Study Overview

• Status: Not yet recruiting
• Conditions: NSCLC (Advanced Non-small Cell Lung Cancer); Post Surgical
• Intervention / Treatment: Radiation: radiotherapy; Drug: PD -1/PD-L1 monoclonal antibody

• Study Type: Interventional
• Enrollment (Estimated): 38
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age 18-75 years, male or female.
• Histologically confirmed NSCLC (adenocarcinoma, squamous cell carcinoma, or other NSCLC subtypes).
• Clinical stage IIIA/IIIB at initial diagnosis, deemed suitable for neoadjuvant chemoimmunotherapy followed by surgery according to MDT.
• Completed 2-4 cycles of platinum-based doublet chemotherapy plus PD-1 inhibitor as neoadjuvant therapy.
• Underwent R0 resection (anatomical lobectomy or pneumonectomy with mediastinal lymph node dissection).
• Postoperative pathological stage ypT_anyN⁺M0 (residual nodal metastasis in mediastinal or hilar lymph nodes).
• ECOG performance status 0-1.
• Adequate hematologic, hepatic, and renal function per protocol-defined lab thresholds.
• Able to start postoperative radiotherapy and/or PD-1 maintenance within 4-10 weeks after surgery (or after recovery from postoperative complications, as clinically appropriate).
• Signed written informed consent.

Exclusion Criteria:

• Positive surgical margins (R1 or R2) or incomplete resection.
• Prior thoracic radiotherapy that would overlap with planned treatment fields.
• Active, uncontrolled infection or unresolved ≥ Grade 2 immune-related adverse events.
• History of severe autoimmune disease requiring systemic immunosuppression.
• Uncontrolled interstitial lung disease or significant pulmonary fibrosis.
• Symptomatic or untreated central nervous system metastases at enrollment.
• Any condition that, in the investigator's judgment, would compromise patient safety or protocol compliance.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Involved-field radiotherapy to regional draining lymph nodes + PD-1 maintenance	Radiation: radiotherapy; Postoperative external beam radiotherapy to regional draining lymph nodes (e.g., ipsilateral mediastinal and hilar nodal stations involved or at high risk), based on pre-treatment imaging and surgical/pathologic findings. Suggested dose: 50-54 Gy in 25-27 fractions (2.0-2.16 Gy per fraction, once daily, 5 days per week), delivered with 3D-CRT or IMRT per institutional standards.; Drug: PD -1/PD-L1 monoclonal antibody; Anti-PD-1 monoclonal antibody administered intravenously every 3 weeks for up to 1 year (or until disease recurrence, unacceptable toxicity, or withdrawal). The specific agent and dose will follow the neoadjuvant regimen and local regulatory approval.
Active Comparator: No radiotherapy (standard of care) + PD-1 maintenance	Drug: PD -1/PD-L1 monoclonal antibody; Anti-PD-1 monoclonal antibody administered intravenously every 3 weeks for up to 1 year (or until disease recurrence, unacceptable toxicity, or withdrawal). The specific agent and dose will follow the neoadjuvant regimen and local regulatory approval.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease-Free Survival (DFS)	Time from date of surgery to first documented recurrence (locoregional or distant) or death from any cause, whichever occurs first.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Time from surgery to death from any cause (up to 5 years).	5 years
Incidence of Treatment-Emergent Adverse Events	Incidence, type, and severity of adverse events graded by CTCAE v5.0, including radiation pneumonitis and immune-related toxicities.	Through treatment completion, an average of 1 year

Collaborators and Investigators

• Sponsor: Shanghai Zhongshan Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2030
• Study Completion (Estimated): June 1, 2032

Study Registration Dates

• First Submitted: January 12, 2026
• First Submitted That Met QC Criteria: January 19, 2026
• First Posted (Actual): January 20, 2026

Study Record Updates

• Last Update Posted (Actual): January 20, 2026
• Last Update Submitted That Met QC Criteria: January 19, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Radiotherapy; Adjuvant therapy; Lymph node
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; Therapeutics; Radiotherapy
• Other Study ID Numbers: B2026GRI

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