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

Sponsor

Zhejiang Cancer Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06031597

Collaborator

(none)

105

Enrollment

Arms

27.5

Anticipated Duration (Months)

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Non-small Cell Lung Cancer Stage III	Radiation: radiotherapy Drug: Platinum-Based Drug Drug: Immunotherapy Drug: Immunotherapeutic Agent	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

105 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Radiotherapy Combined With Immune Checkpoint Inhibitors (ICIs) as Treatment for Locally Advanced Non-small-cell Lung Cancer After Failing Induction Immuno-chemotherapy: a Prospective, Real-world Cohort Study.

Anticipated Study Start Date :

Sep 15, 2023

Anticipated Primary Completion Date :

Dec 31, 2025

Anticipated Study Completion Date :

Dec 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A: concurrent chemoradiotherapy combined with ICIs 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.	Radiation: radiotherapy Radiotherapy techniques: Volumetric-modulated arc therapy (VMAT) and image guided radiotherapy (IGRT). Radiotherapy dose: Radical prescription dose of 60 gray (Gy) ± 10%, 2 Gy per session, once a day, 5 days a week. Drug: Platinum-Based Drug Cisplatin 25 mg/m2 once per week for a total of 5-6 cycles. For participants who have not completed 4 cycles of conversion chemotherapy in combination with immunotherapy, the original chemotherapy regimen may also be used, with the total number of chemotherapy cycles not exceeding 6 cycles. Other Names: Cisplatin Drug: Immunotherapy Concurrent programmed cell death 1 (PD-1) or programmed cell death L1 (PD-L1) inhibitors every 3 weeks during radiotherapy and no more than 3 doses during the course of radiotherapy. Other Names: Nivolumab Atezolizumab Durvalumab Pembrolizumab Tislelizumab Sugemalimab Sintilimab Camrelizumab Drug: Immunotherapeutic Agent All participants will be evaluated within 1-42 days after receiving radiation (chemotherapy). If disease progression does not occur, adjuvant therapy with a PD-1 or PD-L1 inhibitor is continued until disease progression up to 1 year. Other Names: Nivolumab Atezolizumab Durvalumab Pembrolizumab Tislelizumab Sugemalimab Sintilimab Camrelizumab
Experimental: Cohort B: concurrent radiotherapy combined with ICIs 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.	Radiation: radiotherapy Radiotherapy techniques: Volumetric-modulated arc therapy (VMAT) and image guided radiotherapy (IGRT). Radiotherapy dose: Radical prescription dose of 60 gray (Gy) ± 10%, 2 Gy per session, once a day, 5 days a week. Drug: Immunotherapy Concurrent programmed cell death 1 (PD-1) or programmed cell death L1 (PD-L1) inhibitors every 3 weeks during radiotherapy and no more than 3 doses during the course of radiotherapy. Other Names: Nivolumab Atezolizumab Durvalumab Pembrolizumab Tislelizumab Sugemalimab Sintilimab Camrelizumab Drug: Immunotherapeutic Agent All participants will be evaluated within 1-42 days after receiving radiation (chemotherapy). If disease progression does not occur, adjuvant therapy with a PD-1 or PD-L1 inhibitor is continued until disease progression up to 1 year. Other Names: Nivolumab Atezolizumab Durvalumab Pembrolizumab Tislelizumab Sugemalimab Sintilimab Camrelizumab
Experimental: Cohort C: 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.	Radiation: radiotherapy Radiotherapy techniques: Volumetric-modulated arc therapy (VMAT) and image guided radiotherapy (IGRT). Radiotherapy dose: Radical prescription dose of 60 gray (Gy) ± 10%, 2 Gy per session, once a day, 5 days a week. Drug: Immunotherapeutic Agent All participants will be evaluated within 1-42 days after receiving radiation (chemotherapy). If disease progression does not occur, adjuvant therapy with a PD-1 or PD-L1 inhibitor is continued until disease progression up to 1 year. Other Names: Nivolumab Atezolizumab Durvalumab Pembrolizumab Tislelizumab Sugemalimab Sintilimab Camrelizumab

Arm

Intervention/Treatment

Experimental: Cohort A: concurrent chemoradiotherapy combined with ICIs

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.

Radiation: radiotherapy

Radiotherapy techniques: Volumetric-modulated arc therapy (VMAT) and image guided radiotherapy (IGRT). Radiotherapy dose: Radical prescription dose of 60 gray (Gy) ± 10%, 2 Gy per session, once a day, 5 days a week.

Drug: Platinum-Based Drug

Cisplatin 25 mg/m2 once per week for a total of 5-6 cycles. For participants who have not completed 4 cycles of conversion chemotherapy in combination with immunotherapy, the original chemotherapy regimen may also be used, with the total number of chemotherapy cycles not exceeding 6 cycles.

Other Names:

Cisplatin

Drug: Immunotherapy

Concurrent programmed cell death 1 (PD-1) or programmed cell death L1 (PD-L1) inhibitors every 3 weeks during radiotherapy and no more than 3 doses during the course of radiotherapy.

Other Names:

Nivolumab

Atezolizumab

Durvalumab

Pembrolizumab

Tislelizumab

Sugemalimab

Sintilimab

Camrelizumab

Drug: Immunotherapeutic Agent

All participants will be evaluated within 1-42 days after receiving radiation (chemotherapy). If disease progression does not occur, adjuvant therapy with a PD-1 or PD-L1 inhibitor is continued until disease progression up to 1 year.

Other Names:

Nivolumab

Atezolizumab

Durvalumab

Pembrolizumab

Tislelizumab

Sugemalimab

Sintilimab

Camrelizumab

Experimental: Cohort B: concurrent radiotherapy combined with ICIs

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.

Radiation: radiotherapy

Drug: Immunotherapy

Concurrent programmed cell death 1 (PD-1) or programmed cell death L1 (PD-L1) inhibitors every 3 weeks during radiotherapy and no more than 3 doses during the course of radiotherapy.

Other Names:

Nivolumab

Atezolizumab

Durvalumab

Pembrolizumab

Tislelizumab

Sugemalimab

Sintilimab

Camrelizumab

Drug: Immunotherapeutic Agent

Other Names:

Nivolumab

Atezolizumab

Durvalumab

Pembrolizumab

Tislelizumab

Sugemalimab

Sintilimab

Camrelizumab

Experimental: Cohort C: 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.

Radiation: radiotherapy

Drug: Immunotherapeutic Agent

Other Names:

Nivolumab

Atezolizumab

Durvalumab

Pembrolizumab

Tislelizumab

Sugemalimab

Sintilimab

Camrelizumab

Outcome Measures

Primary Outcome Measures

radiation pneumonitis [Within 6 months after radiation therapy]
Incidence of grade 2 or higher radiation pneumonitis.

Secondary Outcome Measures

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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytologically confirmed non-small cell lung cancer
Presence of at least one measurable lesion according to RECIST 1.1 criteria
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
Age 18-75
Eastern Cooperative Oncology Group (ECOG) physical state score of 0-2
Patients with the pathologic type of adenocarcinoma should be negative for driver genes (EGFR, anaplastic lymphoma kinase, ROS1)
Serum hemoglobin ≥ 90 g/L, platelets ≥ 90 × 109/L, absolute neutrophil count ≥ 1.2 × 109/L
Serum creatinine ≤ 1.25 times upper limit of normal(ULN) or creatinine clearance ≥ 60 mL/min
Serum bilirubin ≤ 1.5 times ULN, (AST) and alanine aminotransferase aspartate aminotransferase (ALT) ≤ 2.5 times ULN, alkaline phosphatase ≤ 5 times ULN
Forced expiratory volume in one second (FEV1)>0.8 liter
Normal coagulation function (Prothrombin time prolonged by no more than 3s and activated partial thromboplastin time prolonged by no more than 10s)
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:

The pathologic type is lung carcinoid or small cell lung cancer
Patients with any distant metastases
Grade 2 or higher unresolved toxic effects after conversion therapy (according to the Common Terminology Criteria for Adverse Events CTCAE)
A recent efficacy rating of PD after conversion therapy
Radiotherapy plan for normal lung tissue V20 > 30%, or average lung dose MLD > 17 Gy
Active or previous autoimmune disease (within the past 2 years) or history of primary immunodeficiency
Patients with any other previous or current malignancy, except non-melanoma skin or cervical cancer in situ
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)
Pregnant or nursing women
Women and men who are at risk of becoming pregnant but are unwilling to use adequate contraception
Evidence of hereditary bleeding disorders or coagulation disorders.