Hypofractionated versus conventional chemoradiotherapy followed by consolidative immunotherapy for locally advanced NSCLC

Hypofractionated Chemoradiotherapy Followed by Consolidative Immunotherapy Versus Conventional Fractionated Chemoradiotherapy Followed by Consolidative Immunotherapy in Locally Advanced Non-small Cell Lung Cancer: A Randomized, Phase III Controlled Study

This trial tests whether a shorter, higher-dose (hypofractionated) chemoradiotherapy course followed by up to 12 months of immunotherapy works as well or better than standard fractionated chemoradiotherapy plus the same immunotherapy for people with unresectable, locally advanced non-small cell lung cancer.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 311 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Sun Yat-sen University (Academic / other)
• Drugs / interventions: tislelizumab, chemotherapy, immunotherapy, radiation, prednisone
• Locations: 3 sites (Chongqing, Chongqing Municipality and 2 other locations)
• Trial ID: NCT07052669 on ClinicalTrials.gov

What this trial studies

This is a phase III, randomized controlled trial enrolling patients with unresectable stage III non-small cell lung cancer to compare two radiotherapy fractionation strategies given with concurrent chemotherapy, each followed by consolidative immunotherapy for up to 12 months. Patients are randomized 2:1 to hypofractionated chemoradiotherapy or conventional fractionated chemoradiotherapy, with both arms receiving the same schedule of consolidative immunotherapy afterward. Key eligibility includes age 18–75, WHO performance status 0–1, EGFR wild-type and ALK-negative disease, and available tumor tissue. The trial will compare efficacy and safety outcomes including disease control and treatment-related toxicity between the two approaches.

Who should consider this trial

Good fit: Ideal candidates are adults 18–75 with unresectable stage III NSCLC, WHO performance status 0 or 1, EGFR wild-type and ALK-negative, adequate life expectancy and organ function, and able to provide archived tumor tissue.

Not a fit: Patients with targetable driver mutations (EGFR or ALK positive), poor performance status (>1), resectable disease, or those unable to travel to a study site are unlikely to benefit from participating.

Why it matters

Potential benefit: If successful, the hypofractionated approach could shorten radiation treatment time while maintaining or improving cancer control and allowing the same benefit from consolidative immunotherapy.

How similar studies have performed: Consolidative immunotherapy after chemoradiotherapy became standard based on the PACIFIC trial, but direct phase III comparisons of hypofractionated versus conventional chemoradiotherapy in this setting are limited.

Eligibility criteria

Inclusion Criteria:

* Signed and Dated Informed Consent: Written informed consent must be provided prior to any study procedures, with the consent form signed and dated by the participant.
* Age Range: Male or female patients aged 18 to 75 years.
* Diagnosis: Patients must have locally advanced, unresectable (stage III) non-small cell lung cancer (NSCLC), with histological or cytological confirmation of the diagnosis.
* Previous Treatment: Treatment-naïve or previously treated with induction chemotherapy ± immunotherapy.
* Tumor Sample Requirement: Tumor tissue samples must be provided, and they should be sufficient for analysis. The samples must be unstained and archived.
* Driver gene testing: EGFR wild-type, ALK rearrangement-negative.
* Life Expectancy: Patients must have an expected survival of at least 12 weeks.
* Performance Status (PS): The patient's WHO Performance Status (PS) must be 0 or 1.
* Pregnancy Testing: Postmenopausal women, or women who have had a negative urine or serum pregnancy test within 14 days before the study medication (HCG sensitivity ≥ 25 IU/L or equivalent).
* Breastfeeding: Women must not be breastfeeding.
* Women of childbearing potential (WOCBP) must agree to use contraception during the study treatment period and for 5 months after the last dose of the investigational drug (i.e., 30 days \[ovulation cycle\] + approximately 5 half-lives of the study drug).
* Men who have sexual relations with WOCBP must agree to use contraception during the study treatment period and for 7 months after the last dose of the investigational drug (i.e., 90 days \[sperm renewal cycle\] + approximately 5 half-lives of the study drug).
* Males with no sperm production are exempt from contraception requirements. WOCBP who are not sexually active are exempt from contraception but must still undergo pregnancy testing as outlined above.
* Organ and Bone Marrow Function: The following laboratory parameters must be met:

Forced expiratory volume in 1 second (FEV1) ≥ 800 mL Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L Platelets ≥ 100 × 10⁹/L Hemoglobin ≥ 9.0 g/dL Calculated creatinine clearance using the Cockcroft-Gault formula ≥ 50 mL/min Serum bilirubin ≤ 1.5 × upper limit of normal (ULN) AST and ALT ≤ 2.5 × ULN

Exclusion Criteria:

* Patients meeting any of the following criteria should not be enrolled in the study:
* Concurrent participation in another clinical trial, except for observational (non-interventional) studies.
* Histological subtype of mixed small-cell and non-small-cell lung cancer. Use of immunosuppressive drugs within 28 days before treatment, except for intranasal or inhaled corticosteroids at physiological doses or systemic corticosteroids ≤10 mg/day of prednisone or equivalent.
* Major surgery within 4 weeks prior to enrollment (excluding procedures for vascular access).
* History or active autoimmune diseases within the past two years.
* Active or a history of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
* History of primary immunodeficiency.
* History of organ transplantation requiring immunosuppressive therapy.
* Average corrected QT interval (QTc) ≥470 ms calculated from three ECG cycles using the Bazett formula.
* Uncontrolled comorbidities, including but not limited to: Persistent or active infections. Symptomatic congestive heart failure. Poorly controlled hypertension. Unstable angina. Cardiac arrhythmias. Active peptic ulcer disease or gastritis. Active bleeding disorders. Hepatitis C or HIV infection. HBsAg-positive patients with HBV DNA \>500 IU/mL. Mental or social conditions that may limit adherence to study requirements or compromise the ability to provide informed consent.
* Known history of tuberculosis.
* Receipt of a live attenuated vaccine within 30 days before study initiation or planned during the study period.
* History of another primary malignancy within the past 5 years, except for adequately treated basal or squamous cell carcinoma of the skin or in situ cervical cancer.
* Pregnancy, breastfeeding, or not using effective contraception (for men and women of reproductive potential).

Patients in the experimental group should not proceed to concurrent chemoradiotherapy if any of the following criteria are met:

* Presence of distant metastases.
* Locoregional progression making definitive concurrent chemoradiotherapy unfeasible due to normal tissue dose constraints (assessed by the radiation oncologist).
* WHO performance status score of 2-4.
* Impaired organ or bone marrow function, including:

Forced expiratory volume in 1 second (FEV1) \<800 mL. Absolute neutrophil count (ANC) \<1.5 × 10⁹/L. Platelets \<100 × 10⁹/L. Hemoglobin \<9.0 g/dL. Creatinine clearance (Cockcroft-Gault formula) \<50 mL/min. Serum bilirubin \>1.5 × upper limit of normal (ULN). AST and ALT \>2.5 × ULN.

\- Patient withdrawal from the study.

Patients should not proceed to consolidation immunotherapy if any of the following criteria are met:

* Disease progression during concurrent chemoradiotherapy.
* Use of immunosuppressive drugs within 28 days before the first dose of tislelizumab, except for physiological doses of intranasal or inhaled corticosteroids or systemic corticosteroids ≤10 mg/day of prednisone or equivalent. Use of corticosteroids to manage chemoradiotherapy-related toxicity is permitted.
* Persistent unresolved CTCAE grade \>2 toxicities from prior chemoradiotherapy.
* Grade ≥2 pneumonitis resulting from prior chemoradiotherapy.
* Any prior grade ≥3 immune-related adverse event (irAE) or unresolved irAE \> grade 1.

Where this trial is running

Chongqing, Chongqing Municipality and 2 other locations

• The First Affiliated Hospital of Chongqing Medical University — Chongqing, Chongqing Municipality, China (Recruiting)
• Gansu Provincial Cancer Hospital — Lanzhou, Gansu, China (Recruiting)
• Sun yat-sen University Cancer Center — Guangzhou, Guangdong, China (Recruiting)

Study contacts

• Principal investigator: Hui Liu, Professor — Sun yat-sen universtiy cancer center
• Study coordinator: Bo Qiu, Professor

Conditions Locally Advanced Non-Small Cell Lung Cancer; Hypofractionated radiotherapy; Conventionally fractionated radiotherapy; Concurrent Chemoradiotherapy; Consolidative immunotherapy