Radiotherapy Combined With ICIs as Treatment for LA-NSCLC After Failing Induction Immunochemotherapy

Phase 3

Not yet recruiting

• Conditions: Non-small Cell Lung Cancer Stage III
• Interventions: Radiation: radiotherapy; Drug: Platinum-Based Drug; Drug: Immunotherapeutic Agent; Drug: Immunotherapy

• Registration Number: NCT06031597
• Lead Sponsor: Zhejiang Cancer Hospital

Brief Summary

Patients with stage III non-small-cell lung cancer initially evaluated as unresectable are selected for the program, who are remained unresectable after 2-4 cycles of conversion chemotherapy combined with immune checkpoint inhibitors. Investigators will stratify the treatment according to different performance status scores and radiotherapy plan bi-lung receptor volume to evaluate the safety and efficacy of immunotherapy followed by combined radiotherapy.

Detailed Description

This is a prospective, real-world cohort study, which aimed to evaluate the safety and efficacy of immunotherapy followed by combined radiotherapy. Participants will be selected and entered into three different cohorts according to different performance status(PS) scores and radiotherapy schedules based on the amount of bilateral lungs treated. Cohort A: PS=0-1 and bilateral lung V20≤20%, mean lung dose(MLD)≤11 gray(Gy), radiotherapy and immunotherapy, followed by immunotherapy for up to 1 year; Cohort B: PS=0-1 and 20%\<bilateral lung V20≤25% or 11 Gy\<MLD≤13 Gy, radiotherapy combined with immunotherapy, followed by immunotherapy for up to 1 year; Cohort C: PS=2 or 25%\<bilateral V20≤30% and 3 Gy \<MLD≤ 17 Gy, radiotherapy alone, followed by immunotherapy for up to 1 year.

Study Timeline

• Status Verified: 2023-08
• Study First Submitted: 2023-08-28
• Study First Submitted QC: 2023-09-04
• Last Update Submitted: 2023-09-10
• Study First Posted: 2023-09-11
• Last Update Posted: 2023-09-13
• Study Start: 2023-09-15
• Primary Completion: 2025-12-31
• Study Completion: 2025-12-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 105

Inclusion Criteria

1. Histologically or cytologically confirmed non-small cell lung cancer
2. Presence of at least one measurable lesion according to RECIST 1.1 criteria
3. Classified as American Joint Committee on Cancer staging system, eighth edition (AJCC-8) Stage III, initially evaluated as unresectable and reevaluated as unresectable after 2-4 cycles of induction chemotherapy combined with immunotherapy
4. Age 18-75
5. Eastern Cooperative Oncology Group (ECOG) physical state score of 0-2
6. Patients with the pathologic type of adenocarcinoma should be negative for driver genes (EGFR, anaplastic lymphoma kinase, ROS1)
7. Serum hemoglobin ≥ 90 g/L, platelets ≥ 90 × 109/L, absolute neutrophil count ≥ 1.2 × 109/L
8. Serum creatinine ≤ 1.25 times upper limit of normal(ULN) or creatinine clearance ≥ 60 mL/min
9. Serum bilirubin ≤ 1.5 times ULN, (AST) and alanine aminotransferase aspartate aminotransferase (ALT) ≤ 2.5 times ULN, alkaline phosphatase ≤ 5 times ULN
10. Forced expiratory volume in one second (FEV1)>0.8 liter
11. Normal coagulation function (Prothrombin time prolonged by no more than 3s and activated partial thromboplastin time prolonged by no more than 10s)
12. Patients signed a formal informed consent form to indicate that they understood that the study complied with the hospital's policies and ethical requirements

Exclusion Criteria

1. The pathologic type is lung carcinoid or small cell lung cancer
2. Patients with any distant metastases
3. Grade 2 or higher unresolved toxic effects after conversion therapy (according to the Common Terminology Criteria for Adverse Events CTCAE)
4. A recent efficacy rating of PD after conversion therapy
5. Radiotherapy plan for normal lung tissue V20 > 30%, or average lung dose MLD > 17 Gy
6. Active or previous autoimmune disease (within the past 2 years) or history of primary immunodeficiency
7. Patients with any other previous or current malignancy, except non-melanoma skin or cervical cancer in situ
8. Any other disease or condition suggesting a contraindication to radiotherapy (e.g., active infection, within 6 months of myocardial infarction, symptomatic cardiac disease including unstable angina pectoris, congestive heart failure, or uncontrolled arrhythmias, immunosuppressive therapy)
9. Pregnant or nursing women
10. Women and men who are at risk of becoming pregnant but are unwilling to use adequate contraception
11. Evidence of hereditary bleeding disorders or coagulation disorders.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort B: concurrent radiotherapy combined with ICIs	Immunotherapeutic Agent	For PS=0-1 and 20%\<both lungs V20≤25% or 11Gy\<MLD≤13Gy, radiotherapy alone combined with concurrent immunotherapy, followed by immunotherapy up to 1 year. Participants eligible for enrollment will receive radiotherapy within 8 weeks of the end of chemotherapy combined with ICIs at a radical prescribed dose of 60 Gy ± 10% at 2 Gy once daily for 5 days per week. Marketed PD-1 or PD-L1 inhibitors are chosen as immunotherapy agents. Immunotherapy will be given every 3 weeks, with no more than 3 cycles of immunotherapy during radiotherapy. The dosage is recommended according to the drug insert.
Cohort A: concurrent chemoradiotherapy combined with ICIs	radiotherapy	For performance status (PS)=0-1 and both lungs V20≤20%, mean lung dose (MLD)≤11 gray(Gy), then the patient should be treated with concurrent chemo-radiotherapy and immunotherapy, and immunotherapy should be given after chemo-radiotherapy to maintain up to 1 year. Participants eligible for enrollment will receive radiotherapy within 8 weeks of the end of chemotherapy combined with Immune checkpoint inhibitors (ICIs) at a radical prescribed dose of 60 Gy ± 10% at 2 Gy once daily for 5 days per week. The chemotherapy regimen will be cisplatin at a dose of 25 mg/m2 once a week for 5-6 cycles. Marketed programmed cell death 1 (PD-1) or programmed cell death L1 (PD-L1) inhibitors are chosen as immunotherapy agents. Immunotherapy will be given every 3 weeks, with no more than 3 cycles of immunotherapy during radiotherapy. The dosage is recommended according to the drug insert.
Cohort A: concurrent chemoradiotherapy combined with ICIs	Immunotherapeutic Agent	For performance status (PS)=0-1 and both lungs V20≤20%, mean lung dose (MLD)≤11 gray(Gy), then the patient should be treated with concurrent chemo-radiotherapy and immunotherapy, and immunotherapy should be given after chemo-radiotherapy to maintain up to 1 year. Participants eligible for enrollment will receive radiotherapy within 8 weeks of the end of chemotherapy combined with Immune checkpoint inhibitors (ICIs) at a radical prescribed dose of 60 Gy ± 10% at 2 Gy once daily for 5 days per week. The chemotherapy regimen will be cisplatin at a dose of 25 mg/m2 once a week for 5-6 cycles. Marketed programmed cell death 1 (PD-1) or programmed cell death L1 (PD-L1) inhibitors are chosen as immunotherapy agents. Immunotherapy will be given every 3 weeks, with no more than 3 cycles of immunotherapy during radiotherapy. The dosage is recommended according to the drug insert.
Cohort A: concurrent chemoradiotherapy combined with ICIs	Platinum-Based Drug	For performance status (PS)=0-1 and both lungs V20≤20%, mean lung dose (MLD)≤11 gray(Gy), then the patient should be treated with concurrent chemo-radiotherapy and immunotherapy, and immunotherapy should be given after chemo-radiotherapy to maintain up to 1 year. Participants eligible for enrollment will receive radiotherapy within 8 weeks of the end of chemotherapy combined with Immune checkpoint inhibitors (ICIs) at a radical prescribed dose of 60 Gy ± 10% at 2 Gy once daily for 5 days per week. The chemotherapy regimen will be cisplatin at a dose of 25 mg/m2 once a week for 5-6 cycles. Marketed programmed cell death 1 (PD-1) or programmed cell death L1 (PD-L1) inhibitors are chosen as immunotherapy agents. Immunotherapy will be given every 3 weeks, with no more than 3 cycles of immunotherapy during radiotherapy. The dosage is recommended according to the drug insert.
Cohort A: concurrent chemoradiotherapy combined with ICIs	Immunotherapy	For performance status (PS)=0-1 and both lungs V20≤20%, mean lung dose (MLD)≤11 gray(Gy), then the patient should be treated with concurrent chemo-radiotherapy and immunotherapy, and immunotherapy should be given after chemo-radiotherapy to maintain up to 1 year. Participants eligible for enrollment will receive radiotherapy within 8 weeks of the end of chemotherapy combined with Immune checkpoint inhibitors (ICIs) at a radical prescribed dose of 60 Gy ± 10% at 2 Gy once daily for 5 days per week. The chemotherapy regimen will be cisplatin at a dose of 25 mg/m2 once a week for 5-6 cycles. Marketed programmed cell death 1 (PD-1) or programmed cell death L1 (PD-L1) inhibitors are chosen as immunotherapy agents. Immunotherapy will be given every 3 weeks, with no more than 3 cycles of immunotherapy during radiotherapy. The dosage is recommended according to the drug insert.
Cohort B: concurrent radiotherapy combined with ICIs	radiotherapy	For PS=0-1 and 20%\<both lungs V20≤25% or 11Gy\<MLD≤13Gy, radiotherapy alone combined with concurrent immunotherapy, followed by immunotherapy up to 1 year. Participants eligible for enrollment will receive radiotherapy within 8 weeks of the end of chemotherapy combined with ICIs at a radical prescribed dose of 60 Gy ± 10% at 2 Gy once daily for 5 days per week. Marketed PD-1 or PD-L1 inhibitors are chosen as immunotherapy agents. Immunotherapy will be given every 3 weeks, with no more than 3 cycles of immunotherapy during radiotherapy. The dosage is recommended according to the drug insert.
Cohort B: concurrent radiotherapy combined with ICIs	Immunotherapy	For PS=0-1 and 20%\<both lungs V20≤25% or 11Gy\<MLD≤13Gy, radiotherapy alone combined with concurrent immunotherapy, followed by immunotherapy up to 1 year. Participants eligible for enrollment will receive radiotherapy within 8 weeks of the end of chemotherapy combined with ICIs at a radical prescribed dose of 60 Gy ± 10% at 2 Gy once daily for 5 days per week. Marketed PD-1 or PD-L1 inhibitors are chosen as immunotherapy agents. Immunotherapy will be given every 3 weeks, with no more than 3 cycles of immunotherapy during radiotherapy. The dosage is recommended according to the drug insert.
Cohort C: radiotherapy	radiotherapy	For PS=2 or 25%\<both lungs V20≤30% or 13Gy\<MLD≤17Gy, radiotherapy alone, followed by immunotherapy for up to 1 year. Participants eligible for enrollment will receive radiotherapy within 8 weeks of the end of chemotherapy combined with ICIs at a radical prescribed dose of 60 Gy ± 10% at 2 Gy once daily for 5 days per week. Marketed PD-1 or PD-L1 inhibitors are chosen as immunotherapy agents. The dosage is recommended according to the drug insert.
Cohort C: radiotherapy	Immunotherapeutic Agent	For PS=2 or 25%\<both lungs V20≤30% or 13Gy\<MLD≤17Gy, radiotherapy alone, followed by immunotherapy for up to 1 year. Participants eligible for enrollment will receive radiotherapy within 8 weeks of the end of chemotherapy combined with ICIs at a radical prescribed dose of 60 Gy ± 10% at 2 Gy once daily for 5 days per week. Marketed PD-1 or PD-L1 inhibitors are chosen as immunotherapy agents. The dosage is recommended according to the drug insert.

Primary Outcome Measures

Name	Time	Method
radiation pneumonitis	Within 6 months after radiation therapy	Incidence of grade 2 or higher radiation pneumonitis.

Secondary Outcome Measures

Name	Time	Method
progression-free survival	2 years	Time from enrolment to disease progression or death from any cause or censored at the last follow-up.
overall survival	3 years	Time from enrolment to death or censored at the last follow-up.