Background: Immune checkpoint inhibitors, especially PD-1/PD-L1 inhibitors can promote tumor regression and long-term survival in patients with advanced solid tumors. Despite the characteristic durability of response to ICI, unfortunately some patients may develop acquired resistance after an initial response. The underlying mechanism and effective measure are remarkably limited, perhaps restraining development of immunotherapies. The PRaG trial as a salvage therapy in patients with refractory metastatic solid tumors has obtained satisfactory results(Yuehong Kong et al. ASTRO 2021). With great surprise we found that patients with PD-1/PD-L1 inhibitors acquired resistance are more likely to benefit from the PRaG regimens. This is the PRaG regimen rechallenge that could represent an attractive option in advanced solid tumors. We retrospectively analyzed the clinical efficacy and safety of PRaG regimen (PD-1 inhibitors combined with radiotherapy and GM-CSF with or not IL-2) rechallenge to treat immunotherapy-refractory patients with advanced solid tumors. Methods: This is a retrospective analysis of patients who showed initial resistance to PD-1/PD-L1 inhibitors were retrospectively collected from PRaG serial trails (ChiCTR1900020175 and NCT04892498). Patients received SBRT or HFRT (2-3 doses of 5-8Gy) to a target metastatic site, PD-1 inhibitor was dosing intravenously within one week after completion of SBRT or HFRT, and GM-CSF subcutaneous (SC) injection once daily for 14 days after radiotherapy(the PRaG 2.0 regimen, GM-CSF 200µg SC d1-7, sequentially IL-2 2million IU d8-14.). The specific PRaG regimens had been reported at the meeting of 2020 ASCO. Pooled analysis of response rate (ORR), median progression-free survival (mPFS), and treatment-related adverse events were calculated. Results: A total of 15 multi-metastatic patients were enrolled between October 2020 and February 2022. Thirteen patients showed acquired resistance and underwent at least one assessment, 5 patients were lung cancer, 3 patients were renal cancer, 2 patients were liver cancer, 2 patient was colon cancer, 1 patient was sarcoma. The ORR was 18.2%, and the disease control rate (DCR) was 90.9%. The median PFS was 8.87 months (95%CI, 1.41 to 16.33 months). One lung cancer achieved complete remission, with PFS over 17 months. Treatment-related adverse events of any grade occurred in 11 of 15(73.3%) patients, while there was no grade 3 or higher adverse events. Conclusions: Our preliminary results suggested that PRaG regimens rechallenge maybe an active and feasible strategy in PD-1/PD-L1 inhibitors acquired resistance. The therapy was well tolerated and had acceptable toxicity. A phase III prospective study is being planned to clarify the role of rechallenge after acquired resistance. Clinical trial information: ChiCTR1900020175 and NCT04892498.