Trial Title: Hybrid dose-fraction Radiotherapy for metastatic driven-genes negative non-small cell lung cancer: A phase II multi-institutional study Trial Objective: To explore the safety and primary efficacy of the combination of hybrid dose-fraction radiotherapy with ICI for metastatic driven-genes negative non-small cell lung cancer patients.~Trial Design: This trial is designed to enroll 74 patients with metastatic driven-genes negative non-small cell lung cancer to receive the combination of hybrid dose-fraction radiotherapy with ICI.~Staging Examination before Radiotherapy: a. ECOG scoring. b. Cranial contrast MRI and PET-CT (Positron Emissions Tomography), or cranial contrast MRI (preferred), chest contrast CT, abdominal ultrasonography and bone scan. c. Bronchoscopy for centrally located lung cancer.~Inductive therapy ICI±chemotherapy for 4-6 cycles. Pembrolizumab and Tislelizumab are preferred. Chemotherapy regimens could be referred to NCCN (National Comprehensive Cancer Network) guidelines.~Restaging examination after inductive therapy is mandatory: a. ECOG scoring. b. Cranial contrast MRI, chest contrast CT, abdominal ultrasonography.~Patients with disease PR or SD (RECIST v1.1) evaluated by restaging after inductive therapy could be included into this trial. Patients would receive hybrid dose-fraction radiotherapy and ICI maintenance.~Radiotherapy CT Simulation: CT with intravenous contrast is recommended for simulation. Scan thickness should be less than 5 mm from lower margin of mandibular to lower margin of L2. For pulmonary lesions, 4D-CT (Four-Dimensional CT) localization is recommended.~Delineation of Targets:~For patients with oligometastasis, including synchronous oligometastatic disease & metachronous oligorecurrence, all lesions should be prescribed with an ablative dose. The dose-fraction modalities are as following:~Thoracic lesions: 50Gy/5f (50 Gray/5 fractions), 60Gy/8f, 60Gy/15f, 48Gy/12f. Intracranial lesions: 30Gy/10f (Whole Brain Irradiation), 30Gy/3f, 30Gy/5f, 45Gy/15f.~Hepatic lesions: 50Gy/5f, 40Gy/5f, 32Gy/4f. Adrenal lesions: 50Gy/5f, 40Gy/5f, 32Gy/4f. Osseous lesions: 27Gy/3f, 40Gy/5f, 30Gy/5f, 39Gy/13f. Other lesions: Refer to the above dose-fraction. For patients with systemic metastasis, high-dose should be prescribed to 1-3 lesions (longest diameter>1cm). All of the remaining lesions should be given low-dose. High-dose includes 24-40Gy/3-5f. Low-dose includes 6-15Gy/4-10f.~The Planning Target Volume (PTV) was defined as an 8-mm margin of the GTV (Gross Tumor Volumn) for tumor motion and set-up variations.~The delivery of ablative dose and high-dose should utilize the technology of SABR (Stereotactic Ablative Body Radiotherapy).~Dosimetric Limitation of Organ at Risk: 95% prescription dose should cover 100% PTV and 95% PTV should receive 100% prescription dose.~The dose constraints of organs at risk could refer to TG 101 (Task Group 101) report.~Treatment Implementation: Radiotherapy is implemented every day. Cone-beam CT should be utilized every day to minimize set-up error.~Follow-up: Patients should be follow-up every three months right after the completion of radiotherapy to disease progression.~Primary Endpoint: Progress-free Survival (PFS).
The combination of immune checkpoint inhibitors (ICI) and local ablative radiotherapy has been demonstrated to be able to increase the survival of patients with metastatic driven-genes negative non-small cell lung cancer. Various dose-fraction of radiotherapy could exert different effects on the immune system. Ablative-dose could induce immunogenic cell death through the activation of CD8+(Cluster of Differentiation) T cells. Low-dose could modulate immune microenvironment from immunosuppression to inflammatory anti-tumor phenotype. This trial is designed to validation the safety and primary efficacy of the combination of hybrid dose-fraction radiotherapy with ICI for metastatic driven-genes negative non-small cell lung cancer patients.