A Prospective Clinical Trial of Radiotherapy Combined with PD-1 Inhibitors and GM-CSF, Sequentially Followed by IL-2 (PRaG 2.0) Regimen in Advanced Refractory Solid Tumors

Abstract

Radiotherapy could 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 advanced refractory solid tumors (ChiCTR1900026175). To further improve the efficacy of immunotherapy combined with radiotherapy, we conducted the PRaG 2.0 trial (ClinicalTrials.gov: NCT04892498) and optimized the PRaG regimen by adding interleukin-2 (IL-2). Preliminary results of PRaG 2.0 had been reported in the 64th ASTRO. Now we report an updated result. The PRaG 2.0 regimen was administered to patients with advanced refractory solid tumors who lacked or were unable to tolerate standard-of-care treatments. A treatment cycle consisted of SBRT or HFRT (5 or 8 Gy×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). As of 31st October 2022, 51 patients were enrolled in the study, and 42 completed at least one tumor assessment. The median Progression-Free Survival (PFS) was 5.8 months, and the median overall survival (OS) was 13.5 months. The objective response rate (ORR) was 21.4%, and the disease control rate (DCR) was 61.9% according to RECIST version 1.1. Lower plasma levels of Interleukin (IL)-6 and IL-17 at baseline were found to be associated with improved PFS. Treatment-related adverse events (TRAE) occurred in 34 of 42 (78.6%) patients, Grade ≥ 3 TRAEs occurred in 4 patients (9.5%). TRAEs leading to discontinuation of all study treatments occurred in three patients (7.1%). The PRaG 2.0 trial demonstrates that PD-1 inhibitors in combination with SBRT/HFRT, GM-CSF, and IL-2 could be a potential treatment regimen for patients with advanced refractory solid tumors, with an acceptable benefit/risk profile.