Pulse Radiotherapy to Overcome Metastatic Immune System Evasion in Lung Cancer

Background: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and is a leading cause of cancer-related death globally. Despite the success of immune checkpoint inhibitors (ICIs) targeting PD-1 and PD-L1, many patients develop resistance to these therapies, either at the start (primary resistance) or over time (secondary resistance). This resistance leads to disease progression during or after treatment, posing a major clinical challenge. Recent studies suggest that combining ICIs with radiotherapy may improve treatment outcomes. Advances in pulsed radiotherapy, including stereotactic radiation cycles, have shown promising results in overcoming ICI resistance in metastatic disease. Objective: This phase I prospective study aims to evaluate the safety (primary objective) and efficacy of pulsed radiotherapy in combination with PD(L)-1 inhibitors (with or without chemotherapy) in patients with polymetastatic NSCLC who have developed systemic resistance. The hypothesis is that this combination approach could improve patient outcomes by directly reducing tumor burden and enhancing the immune response, while maintaining an acceptable toxicity profile. Methods: This single-arm phase I study will enroll 32 patients with NSCLC who show disease progression in ≥ 5 extracranial sites while on PD(L)-1 inhibitors (with or without chemotherapy). Pulsed radiotherapy will be delivered in up to 3 cycles, targeting 2 to 5 progressive lesions per cycle. Eligible participants must be 18 years or older, with systemic progression of NSCLC in ≥ 5 sites during treatment with ICIs, and an ECOG performance status of 0-2. Brain metastases are permitted but will not be included in the lesion count. The primary endpoint is dose-limiting toxicity (DLT), defined by the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, focusing on grade 3-5 adverse events related to radiotherapy within 180 days of treatment. Secondary endpoints include the development of a clinical workflow for adaptive pulsed radiotherapy, progression-free survival (PFS), overall survival (OS), local recurrence, time to the next systemic treatment, and patient-reported quality of life.