Endostar combined with PD-1 blockade, radiotherapy, GM-CSF, and IL-2 (PRaG 2.0E) for refractory non-small cell lung cancer: a single-arm, phase II clinical trial (PRaG2.0E Study Protocol).

Background: The lack of effective standard-of-care options for advanced refractory non-small cell lung cancer (NSCLC) represents an urgent unmet clinical need. PRaG 2.0, an optimized combination regimen comprising programmed cell death protein 1 (PD-1) inhibitors, radiotherapy, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-2 (IL-2), builds upon the synergistic efficacy of the original PRaG therapy by incorporating IL-2 to support T-cell homeostasis and expansion. Concurrently, recombinant human endostatin (Endostar) induces tumor vascular normalization and alleviates immunosuppression by inhibiting regulatory T cells (Tregs). Therefore, this study proposes the PRaG 2.0E regimen, which integrates Endostar with PRaG 2.0. This innovative strategy aims to leverage the dual mechanisms of anti-angiogenesis and immune microenvironment remodeling to establish a highly effective, low-toxicity salvage therapy for patients with advanced refractory NSCLC. Methods: This is a prospective, single-center, single-arm, phase II clinical study. It will enroll 30 patients with recurrent or metastatic NSCLC who have no standard treatment options or are intolerant to standard therapies. Upon enrollment, participants will receive the combination of Endostar and the PRaG 2.0 regimen (comprising hypofractionated radiotherapy, a PD-1 inhibitor, GM-CSF, and IL-2). The primary endpoint is the objective response rate (ORR). Clinical tumor imaging assessments will be performed every 6 weeks using RECIST 1.1 criteria. Safety assessments will be conducted according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, with adverse events recorded throughout the study period and up to 30 days post-treatment. Following treatment completion, all subjects will undergo survival follow-up every 6 weeks. Discussion: The PRaG 2.0E regimen integrates radiotherapy, dual cytokines (GM-CSF and IL-2), immune checkpoint inhibitors, and the anti-angiogenic agent Endostar to target multidimensional resistance in refractory NSCLC. By synergizing immunogenic cell death, enhanced antigen presentation, and vascular normalization, this strategy aims to dismantle the immunosuppressive microenvironment. Trial Registration: The study is registered in ClinicalTrials. gov (NCT06047860).