Quad Shot Radiotherapy Combined With Tislelizumab and Platinum-Based Chemotherapy Before Surgery for Stage II-III Non-Small Cell Lung Cancer (QS-NSCLC)

A Single-Arm, Prospective, Exploratory Phase II Clinical Study of Quad Shot Radiotherapy Combined With Tislelizumab and Platinum-Based Doublet Chemotherapy as Neoadjuvant Treatment for Stage II-III Non-Small Cell Lung Cancer

This study aims to evaluate a new pre-surgery (neoadjuvant) treatment for patients with stage II-III non-small cell lung cancer (NSCLC). Currently, standard pre-surgery treatment involves immunotherapy combined with chemotherapy. While effective, many patients still have residual tumor cells after this standard treatment.

Radiation therapy can not only kill tumor cells but also help the immune system recognize and fight cancer. The type of radiation used in this study is called "Quad Shot" (QS) radiotherapy. It is a short, high-dose, cyclical treatment designed to boost the effects of immunotherapy with less toxicity than standard daily radiation.

Patients in this study will receive 3 cycles of QS radiotherapy combined with Tislelizumab (an immunotherapy drug) and standard platinum-based chemotherapy before surgery. The main goal of this study is to see if this combined approach can make the tumor completely disappear under a microscope (called pathological complete response, or pCR). Researchers will also monitor the safety of the treatment, side effects, and how well patients tolerate the treatment before undergoing surgery. Approximately 12 patients will be enrolled in this study.

Study Overview

• Status: Not yet recruiting
• Conditions: Non-Small Cell Lung Cancer
• Intervention / Treatment: Radiation: Quad Shot Radiotherapy; Drug: Tislelizumab; Drug: Carboplatin or cisplatin; Drug: Pemetrexed or Paclitaxel

Detailed Description

Background:

Neoadjuvant immune checkpoint inhibitor (ICI) combined with platinum-based chemotherapy has become a standard of care for resectable stage II-III NSCLC, as demonstrated by phase III trials such as CheckMate-816, KEYNOTE-671, and RATIONALE-315. However, a significant proportion of patients still fail to achieve deep pathological responses due to mechanisms such as poor antigen release, impaired antigen presentation, and an immunosuppressive tumor microenvironment (TME).

Radiotherapy possesses immunomodulatory properties, inducing immunogenic cell death and promoting antigen release. However, traditional continuous fractionated radiotherapy may deplete circulating lymphocytes and cause normal tissue damage. The "Quad Shot" (QS) regimen is a cyclical hypofractionated radiotherapy approach (14-14.8 Gy in 4 fractions over 2 days) that has shown low toxicity in palliative settings. Its cyclical, pulsatile nature may provide repeated immune stimulation and TME remodeling, making it a promising partner for immunotherapy.

Study Design:

This is a single-arm, prospective, exploratory phase II clinical study. Patients with histologically or cytologically confirmed, untreated, resectable stage II-IIIB NSCLC (including T3-4N2 IIIB, AJCC 9th edition) will be enrolled.

Patients will receive 3 cycles of neoadjuvant treatment (every 3 weeks):

Quad Shot radiotherapy (14-14.8 Gy/4 fractions, Day 1-2) Tislelizumab (200 mg, Day 3) Platinum-based doublet chemotherapy (Day 3): Carboplatin (AUC 5) or Cisplatin (75 mg/m²) combined with Pemetrexed (500 mg/m², for non-squamous) or Paclitaxel (175 mg/m², for squamous).

Following 3 cycles of neoadjuvant therapy, patients will undergo surgery 4-6 weeks (±7 days) after the last dose. Postoperative adjuvant therapy will be administered at the investigator's discretion according to NCCN and CSCO guidelines.

Objectives and Endpoints:

The primary objective is to evaluate the antitumor efficacy of this regimen, with the primary endpoint being the pathological complete response (pCR) rate. Secondary endpoints include major pathological response (MPR) rate, R0 resection rate, objective response rate (ORR) per RECIST v1.1, event-free survival (EFS), overall survival (OS), safety (NCI CTCAE v5.0), feasibility, surgical complications (Clavien-Dindo classification), and QS radiotherapy-related toxicities.

Sample Size:

A total of 12 patients will be enrolled, with at least 10 evaluable patients included in the primary endpoint analysis to account for an estimated 2 dropouts.

Study Duration:

The estimated enrollment period is 6-12 months, with an anticipated study completion date of December 2031.

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Kunyu Yang, MD; Phone Number: 0086-13995595360; Email: yangkunyu@hust.edu.cn

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430022
      • Wuhan Union Hospital
      • Contact: Kunyu Yang, MD; Phone Number: 13995595360; Email: yangkunyu@hust.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18-75 years, either gender.
2. Histologically or cytologically confirmed, untreated stage II-IIIB non-small cell lung cancer (NSCLC) (including T3-4N2 IIIB, AJCC 9th edition). Baseline staging must include PET/CT (or chest + upper abdomen contrast-enhanced CT + whole body bone scan) + brain MRI. Stage III patients will be further subdivided into IIIA and IIIB per AJCC 9th edition for separate recording, evaluation, and analysis.
3. Evaluated as resectable by a multidisciplinary team including thoracic surgeons.
4. At least one evaluable target lesion per RECIST v1.1.
5. ECOG Performance Status 0-1.
6. Adequate major organ function: Neutrophils ≥ 1.5×10^9/L; Platelets ≥ 100×10^9/L; Hemoglobin > 9.0 g/dL; Serum creatinine ≤ 1.5×ULN or Creatinine Clearance (CrCl) ≥ 40 mL/min; AST/ALT ≤ 3×ULN; Total bilirubin ≤ 1.5×ULN; INR/APTT within normal range; FEV1 ≥ 1.2L or > 40% predicted.
7. Signed written informed consent prior to any study-related procedures.
8. Investigator judges that the patient is able to comply with the study protocol, willing and able to follow visit schedules, treatment plans, laboratory tests, and other study procedures.
9. Negative pregnancy test at screening (for women of childbearing potential). Subjects of childbearing potential (male and female) must agree to use effective contraception from screening until 180 days after the last dose.

Exclusion Criteria:

1. Known or suspected autoimmune disease (except vitiligo, Type I diabetes, or hypothyroidism requiring only hormone replacement therapy with no signs of recurrence).
2. Requires systemic corticosteroid therapy (>10 mg/day prednisolone or equivalent) or other immunosuppressive drugs within 14 days prior to enrollment (inhaled or topical steroids, and physiological replacement doses of adrenal corticosteroids are allowed).
3. History of thoracic radiotherapy.
4. Active bleeding before treatment.
5. Severe heart, lung, liver, or kidney dysfunction, hematopoietic system disease, cachexia, or other conditions that make the patient unable to tolerate chemoradiotherapy.
6. History of diabetes for more than 10 years with unsatisfactory blood glucose control.
7. History of interstitial lung disease or non-infectious pneumonitis.
8. NSCLC patients with EGFR sensitizing mutations or ALK fusion genes.
9. Prior or concurrent other malignancies (except cured non-melanoma skin cancer and carcinoma in situ; or malignancies in complete remission for ≥ 2 years without requiring additional anti-tumor therapy during the study period).
10. Prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, or other drugs targeting T-cell costimulatory or immune regulatory pathways.
11. Active hepatitis B (HBV DNA ≥ 2000 IU/mL or 10^4 copies/mL) or hepatitis C (HCV antibody positive and HCV-RNA above the lower limit of detection).
12. HIV positive or diagnosed with acquired immunodeficiency syndrome (AIDS).
13. Received live vaccine within 4 weeks prior to the start of study treatment.
14. Known or suspected allergy to the study drugs or any related drugs in this trial.
15. Pregnant or breastfeeding women.
16. Investigator considers that the patient has other factors that may prevent completion of the study or affect subject safety or data collection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Neoadjuvant Quad Shot Radiotherapy + Tislelizumab + Chemotherapy; Patients receive 3 cycles of neoadjuvant therapy (every 21 days). Each cycle consists of: Quad Shot radiotherapy (14-14.8 Gy/4 fractions on Day 1-2); Tislelizumab (200 mg, Day 3); Platinum-based doublet chemotherapy (Day 3): Carboplatin (AUC 5) or Cisplatin (75 mg/m²), combined with Pemetrexed (500 mg/m² for non-squamous) or Paclitaxel (175 mg/m² for squamous). Surgery is performed 4-6 weeks (±7 days) after the third cycle. Postoperative adjuvant therapy is administered at the investigator's discretion according to NCCN and CSCO guidelines.

Radiation: Quad Shot Radiotherapy; 3.7 Gy per fraction, twice daily (with an interval of at least 6 hours), for 4 fractions over 2 consecutive days (Days 1-2 of each cycle). Total dose of 14.8 Gy per cycle, repeated every 3 weeks for 3 cycles (cumulative dose 44.4 Gy). Delivered using IMRT or VMAT.; Drug: Tislelizumab; 200 mg administered via intravenous infusion on Day 3 of each 21-day cycle for 3 cycles.; Drug: Carboplatin or cisplatin; Carboplatin (AUC 5) or Cisplatin (75 mg/m²) administered intravenously on Day 3 of each 21-day cycle for 3 cycles.; Drug: Pemetrexed or Paclitaxel; Pemetrexed (500 mg/m²) for non-squamous NSCLC or Paclitaxel (175 mg/m²) for squamous NSCLC, administered intravenously on Day 3 of each 21-day cycle for 3 cycles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Complete Response (pCR) Rate	The proportion of patients with no residual viable tumor cells in the resected primary tumor and regional lymph nodes, as assessed by pathological review. Patients who do not undergo surgery will be considered as not achieving pCR.	After completion of neoadjuvant therapy and surgery (approximately 4-6 weeks after the last dose of neoadjuvant therapy)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Pathological Response (MPR) Rate	The proportion of patients with ≤10% viable tumor cells in the resected specimen.	After completion of neoadjuvant therapy and surgery (approximately 4-6 weeks after the last dose of neoadjuvant therapy)
R0 Resection Rate	The proportion of patients achieving microscopically margin-negative resection.	At time of surgery
Objective Response Rate (ORR) per RECIST v1.1	The proportion of patients achieving a confirmed complete or partial response according to RECIST v1.1.	Up to 14 days before surgery
Event-Free Survival (EFS) and 2-Year EFS Rate	Time from enrollment to disease progression, local recurrence, distant metastasis, or death from any cause.	Up to 60 months after enrollment
Overall Survival (OS) and 2-Year OS Rate	Time from enrollment to death from any cause.	Up to 60 months after enrollment
Incidence and Severity of Adverse Events (AEs), Serious Adverse Events (SAEs), and Immune-Related Adverse Events (irAEs)	Evaluated according to NCI CTCAE v5.0.	From informed consent to 90 days after the last dose of study treatment
Feasibility (Completion Rate of Neoadjuvant Therapy and Surgery)	Proportion of patients completing 3 cycles of neoadjuvant therapy and undergoing surgery as planned; surgical delay rate.	Up to 4-6 weeks after the last dose of neoadjuvant therapy
QS Radiotherapy-Related Toxicity	Incidence and severity of radiation pneumonitis, esophagitis, dermatitis, myelosuppression, and myocarditis, graded according to NCI CTCAE v5.0.	Up to 90 days after the last dose of radiotherapy

Collaborators and Investigators

• Sponsor: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

Study record dates

Study Major Dates

• Study Start (Estimated): October 10, 2026
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): December 31, 2031

Study Registration Dates

• First Submitted: September 21, 2026
• First Submitted That Met QC Criteria: September 27, 2026
• First Posted (Actual): September 29, 2026

Study Record Updates

• Last Update Posted (Actual): September 29, 2026
• Last Update Submitted That Met QC Criteria: September 27, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: NSCLC; Immunotherapy; Neoadjuvant Therapy; Tislelizumab; Pathological Complete Response; Quad Shot Radiotherapy; Platinum-based Chemotherapy
• 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; Amino Acids, Peptides, and Proteins; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Hydrocarbons; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Coordination Complexes; Guanine; Hypoxanthines; Purinones; Purines; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Dicarboxylic; Taxoids; Cyclodecanes; Diterpenes; Platinum Compounds; Pemetrexed; Carboplatin; Paclitaxel; Cisplatin; tislelizumab
• Other Study ID Numbers: QS-NSCLC-2026-01

Drug and device information, study documents

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