PD-1 Inhibitors Combined with Radiotherapy and GM-CSF, Sequentially Followed by IL-2 (PRaG 2.0) Regimen in Metastatic Tumors: A Prospective, Multicenter, Single-Arm Clinical Trial

Abstract

<h3>Purpose/Objective(s)</h3> It has been well demonstrated that radiotherapy is able to stimulate the immune response and might synergize with PD-1/PD-L1 inhibitors in the clinical treatment of malignancies. Our previous PRaG trial also demonstrated that SBRT/HFRT in combination with PD-1 inhibitors and granulocyte macrophage-colony stimulating factor (GM-CSF) could improve clinical response in patients with metastatic tumors. Notably, in PRaG trial, we observed that T cell decreasing occurred in some patients during the treatment which might be one of the reasons leading to their poor response. To further improve the efficacy of radiotherapy combined with immunotherapy, we optimized the PRaG regimen and added interleukin-2(IL-2), which amplifies and activates T cells. We conducted PRaG 2.0 trial to further explore the effect of T cells on efficacy. <h3>Materials/Methods</h3> Patients with metastatic tumors who lacked or were intolerant to the available standard of care were enrolled to receive PRaG 2.0 regimen. A treatment cycle consisted of SBRT or HFRT (5 or 8Gy × 2-3f) delivered for one metastatic lesion, PD-1 inhibitor dosing within one week after completion of radiotherapy, GM-CSF 200μg subcutaneous (SC) injection once daily for 7 days, and then sequentially followed by IL-2 2million IU SC once daily for 7 days. PRaG 2.0 regimen was repeated every 21 days for at least 2 cycles until no appropriate lesions for irradiation or reached the tolerance dose of normal tissues. Patients who could not continue radiotherapy and had not yet developed progression disease (PD) allowed PD-1 inhibitors to be continued as maintenance therapy until PD or unacceptable toxicity but no more than one year. The primary endpoint was Progression-Free Survival (PFS). <h3>Results</h3> With the cutoff date of 15 February 2022, a total of 38 patients were enrolled, in which 31 patients (81.5%) completed at least 1 tumor assessment with a median follow-up time of 6.0 months (95%CI: 5.1, 6.9). Median PFS and overall survival (OS) were currently not reached. The objective response rate (ORR) was 22.5%, and the disease control rate (DCR) was 74.2% by RECIST1.1. Compared to baseline, no significant decrease of T cells, including CD3⁺, CD4⁺, and CD8⁺ T cells, have been observed in 20 patients who completed ≥ 4 treatment cycles. Treatment-related adverse events (TRAE) occurred in 29 of 38 (76.3%) patients, Grade ≥ 3 TRAEs occurred in four patients (10.5%). TRAEs leading to treatment interruption occurred in three patients (7.9%). <h3>Conclusion</h3> These preliminary results of PRaG 2.0 trial demonstrate that PD-1 inhibitors in combination with SBRT/HFRT, GM-CSF, and IL-2 could potentially maintain the T cells and improve clinical outcomes in patients with metastatic tumors with acceptable toxicity. This trial was registered at www.clinicaltrials.gov with identifier number NCT04892498.