PD-1 Inhibitor Combined with Hypofractionated Radiotherapy and GM-CSF with or without IL-2 (PRaG Regimens) Rechallenge for Acquiring Resistance to PD-1/PD-L1 Inhibitor in Advanced Solid Tumors

Abstract

<h3>Purpose/Objective(s)</h3> With the extensive use of PD-1/PD-L1 inhibitor, more patients with advanced solid tumors obtain tumor regression and long-term survival. Despite the characteristic durability of response to PD-1/PD-L1 inhibitor, unfortunately some patients may develop acquired resistance after an initial response. Finding an effective treatment to rescue with resistance of PD-1/PD-L1 inhibitor has been an urgent problem. The PRaG trial as a salvage therapy in advanced solid tumors has obtained satisfactory results. With great surprise we found that patients with PD-1/PD-L1 inhibitors acquired resistance are more likely to benefit from the PRaG regimens (PD-1 inhibitors combined with radiotherapy and GM-CSF with or not IL-2). 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 rechallenge to treat immunotherapy-refractory advanced solid tumors. <h3>Materials/Methods</h3> A total of 15 patients who showed initial resistance to PD-1/PD-L1 inhibitor were retrospectively collected from PRaG serial trails. They received stereotactic body radiation therapy or hypofractionated radiotherapy (2-3 doses of 5-8Gy) to a target metastatic site, PD-1 inhibitor was dosing within one week after completion of radiotherapy, 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.). Pooled analysis of response rate (ORR), median progression-free survival (mPFS), and treatment-related adverse events were calculated. <h3>Results</h3> By February 2022, a total of 15 multi-metastatic patients were examined. Thirteen patients showed acquired resistance and underwent first-time assessment, involving in lung cancer, renal cancer, liver cancer, colon cancer and sarcoma. The ORR was 18.2%, and the disease control rate (DCR) was 90.9%. The mPFS was 9.03 months (95%CI, 1.5 to 16.5 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. <h3>Conclusion</h3> Our preliminary results suggested that PRaG regimens rechallenge was an active and feasible strategy in PD-1/PD-L1 inhibitors acquired resistance. The therapy was well tolerated with acceptable toxicity. A III phase prospective study is in the plan to clarify the role of rechallenge after acquired resistance. The PRaG trial was registered in chictr.org.cn (No. ChiCTR1900020175) and the PRaG 2.0 trial was registered at www.clinicaltrials.gov (No. NCT04892498).